Hepatic paraganglioma and multifocal gastrointestinal stromal tumor in a female: Incomplete Carney triad.
The Carney triad (CT) describes the coexistence of multiple neoplasms including gastrointestinal stromal tumors (GISTs), extra-adrenal paraganglioma and pulmonary chondroma. At least two neoplastic tumors are required for diagnosis. In most cases, however, CT is incomplete. We report a case of an incomplete CT in a 34-year-old woman with a multifocal GIST and non-functional paraganglioma of the liver. Preoperative evaluation with a gastrofiberscope and abdominal computed tomography revealed multiple gastric tumors resembling GISTs and a single liver lesion which was assumed to have metastasized from the gastric tumors. The patient underwent total gastrectomy and partial hepatectomy. Histologic findings confirmed multiple gastric GISTs and paraganglioma of the liver. We report a case of a patient with incomplete expression of CT.


Mucosal IFN-gamma gene transfer inhibits pulmonary allergic responses in mice.
Th2 cytokines are associated with the airway inflammation and hyperreactivity in allergic asthma and are potential targets for developing novel therapies. The efficacy of a mucosal cytokine-gene transfer approach was examined in a mouse model for allergic asthma. We showed first that mucosal IFN-gamma gene transfer results in a significant expression of IFN-gamma in the pulmonary epithelium. Significantly, this approach inhibits both Ag- and Th2-cell-induced pulmonary eosinophilia and airway hyperreactivity. These findings suggest that mucosal IFN-gamma gene transfer is effective in modulating pulmonary allergic responses and provides a basis for developing a novel therapeutic approach.


Efficacy of Nivolumab for Head and Neck Cancer Patients with Primary Sites and Histological Subtypes Excluded from the CheckMate-141 Trial.
In the CheckMate-141 trial, nivolumab conferred a survival benefit in patients with recurrent or metastatic refractory squamous cell carcinoma (SCC) head and neck cancer (HNC). Here, we examined the efficacy of nivolumab in patients with histological subtypes or primary sites of HNC not included in the CheckMate-141 trial. This was a retrospective analysis of data collected prospectively from 97 patients who were treated with nivolumab for recurrent or metastatic HNC at our institution. The patients were assigned to three groups based on HNC primary site: 1) oral cavity, pharynx, and larynx, which were included in CheckMate-141 (n = 68), 2) nasopharynx (excluded in CheckMate-141, n = 7) and 3) other primary sites excluded in CheckMate-141 (n = 22) and assigned to two groups according to histological subtype: 1) SCC (included in CheckMate-141, n = 83) and 2) non-SCC (all sites excluded in CheckMate-141, n = 14). Survival outcomes and nivolumab treatment response were compared between the primary site and histological subgroups. The median number of nivolumab treatments was 7 cycles (range, 1-53 cycles) and the median follow-up time was 9.1 months (range, 0.66-33.0 months). There were no significant differences in response rates between the three primary site subgroups (CheckMate-141 sites 22%, nasopharynx 43%, others 18%; p=0) or the two histological subtype subgroups (SCC 25%, non-SCC 7%, p=0). Similarly, overall survival and progression-free survival were comparable for patients stratified by primary site or histological subtype. No significant difference in response rates or survival outcomes was detected between nivolumab-treated HNC patients with primary sites and histological subtypes that were included versus excluded in the CheckMate-141 trial. These data provide a potential rationale for nivolumab therapy for all HNC patients in clinical practice.


Changes in distribution of three isoforms of nitric oxide synthase in ulcerative colitis.
Nitric oxide (NO) has an important role both in normal physiology and pathological events of the colon. Our aim was to study possible changes of the three nitric oxide synthases in ulcerative colitis (UC). Tissue samples from normal colon and least and moderately affected regions of ulcerative colitis colon were obtained at surgery and immunostained for NOS-1, NOS-2, NOS-3, and GAP-43, a marker of nerve fibers. Quantitative analysis of NOS-1 immunoreactivity was performed on the circular muscle layer. NOS-1-immunoreactive fibers in the muscularis mucosae disappeared in least affected and moderately affected UC colon. Quantitative analysis of NOS-1-immunoreactive nerve fibers in the circular muscle showed no differences between normal and diseased colon. NOS-2 immunoreactivity appeared apically in the epithelial cells. In normal colon some specimens showed immunoreactivity in lower parts of crypts. NOS-2 immunoreactivity increased according to the severity of UC. NOS-3 immunoreactivity was exclusively localized in the vascular endothelium. The difference in NOS-3 staining intensity between the lamina propria and submucosa observed in normal tissue disappeared in moderately affected UC colon. The number of NOS-3-immunoreactive vascular profiles increased in the lamina propria of UC colon. All three NOS isoforms show specific changes in UC colon.


Phase 1 study of clofarabine in pediatric patients with relapsed/refractory acute lymphoblastic leukemia in Japan.
A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.


Association of putative origins of replication with the nuclear matrix in normal human fibroblasts.
Several metabolic processes, such as DNA organization and replication, transcription, and RNA processing are closely associated with the nuclear matrix. Nuclear matrix attachment regions are nucleotide sequences holding DNA tightly complexed with the nuclear scaffold and are resistant to extractions with detergents and high salt solutions. The role of matrix attachment regions in DNA replication has not been completely clarified, but they have been identified in close association with origins of replication in mammalian cells. We isolated nuclear matrix-associated DNA from normal human fibroblasts synchronized to different phases of the cell cycle and cloned compatible fragments into pUC19. We tested the homology of a fraction of the available clones to DNA replicated at the beginning of the S phase in human fibroblasts. We confirmed that nuclear matrix-associated DNA isolated from cells in G0 and G1 phases of the cell cycle contains sequences that are among the earliest replicated regions in the human genome. This finding supports the hypothesis that matrix attachment regions in human DNA are located in close proximity to origins of DNA replication.


UBE2C Is Upregulated by Estrogen and Promotes Epithelial-Mesenchymal Transition via p53 in Endometrial Cancer.
Ubiquitin-conjugating enzyme E2C (UBE2C) plays important roles in tumor progression; nevertheless, its function in endometrial cancer remains unclear. This study elucidated the impact of UBE2C on endometrial cancer and its underlying mechanism. Human endometrial cancer and normal endometrial tissues were acquired from patients at Wuhan Union Hospital and UBE2C expression was detected by Western blotting and qRT-PCR. Endometrial cancer cells were transfected with a UBE2C overexpression plasmid or UBE2C-specific short hairpin RNA (shRNA) to up- or downregulate UBE2C expression, respectively. CCK8 and transwell assays were applied to assess the effects of UBE2C on cell proliferation, migration, and invasion. We found a significant elevation of UBE2C expression in patients with endometrial cancer, and that UBE2C upregulation was associated with advanced histologic grade, FIGO stage, recurrence, and shorter overall survival. UBE2C knockdown inhibited endometrial cancer cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), whereas UBE2C overexpression exerted the opposite effects. UBE2C downregulation increased p53 and its downstream p21 expression, with p53 overexpression reversing the EMT-promoting effects of UBE2C. UBE2C enhanced p53 ubiquitination to facilitate its degradation in endometrial cancer cells. Estradiol (E2) induced UBE2C expression via estrogen receptor α, which binds directly to the UBE2C promoter element. Silencing of UBE2C inhibited E2-promoted migration, invasion, and EMT in vitro and in vivo. IMPLICATIONS: UBE2C-mediated tumor EMT promotion by estrogen is a novel mechanism for the progression of estrogen-induced endometrial cancer, which could offer new biomarkers for diagnosis and therapy of endometrial cancer in the future.


Smart Glasses-Based Personnel Proximity Warning System for Improving Pedestrian Safety in Construction and Mining Sites.
A smart glasses-based wearable personnel proximity warning system (PWS) was developed for pedestrian safety in construction and mining sites. The smart glasses receive signals transmitted by Bluetooth beacons attached to heavy equipment or vehicles, with the proximity determined by the signal strength. A visual alert is displayed to the wearer when in close proximity. The media access control address of the Bluetooth beacon provides information on the approaching equipment or vehicle, which is displayed to the wearer so that they can respond appropriately. There was a detection distance of at least 10 m regardless of the direction the pedestrian was looking and the alert was successful in all 40 trials at ≥10 meters. The subjective workload was evaluated using the NASA task load index on ten subjects, either without a personal PWS, with a smartphone-based PWS, or with the smart glasses-based PWS. The mental, temporal, and physical stresses were lowest when using the smart glasses-based PWS. Smart glasses-based PWSs can improve work efficiency by freeing both hands of the pedestrians, and various functions can be supported through application development. Therefore, they are particularly useful for pedestrian safety in construction and mining sites.


Reconstruction of the upper eyelid crease and fold.
For good cosmesis the upper eyelid creases and folds must be symmetric. The lid creases must be the same height above the upper lid margins. The skin below the crease must be smooth and firmly attached to the tarsus, or, in cases with a short tarsus, adherent to the short tarsus and levator muscle up to the crease. The skin above the crease must be loosely attached so that it forms symmetric folds over the crease. We have developed surgical procedures aimed at the following: (1) equalizing the upper lid creases and folds where they are asymmetric, (2) creating lid creases and folds where absent, as in Orientals, (3) removing excess unsightly skin folds, as in dermatochalasis, and (4) forming a lid fold by skin grafting where there is insufficient skin above the crease.


Geochemistry of high arsenic groundwater in Chia-Nan plain, Southwestern Taiwan: possible sources and reactive transport of arsenic.
Major ion, trace element, and stable isotope analyses were performed on groundwater samples collected during November 2005 and 2006 in Chia-Nan plain of southwestern Taiwan to examine As mobilization in aquifers. The high concentrations of As, Fe and Mn in the groundwater is consistent with low Eh values (under moderately reduced state). Moreover, the observed Na/Cl and SO(4)/Cl molar ratios in groundwater demonstrate the influence of seawater intrusion. Seawater intrusion could provide required electron acceptors (i.e., SO(4)) for bacterial sulfate reduction and promote reducing conditions that are favorable for As mobilization. The concurrent increases in the concentrations of Fe and Mn from 2005 to 2006 may be caused by bacterial Fe(III) and Mn(IV) reduction. Geochemical modeling demonstrate that As(III) is the dominant As species and the presence of Fe-bearing carbonates, sulfides, and oxide phases may locally act as potential sinks for As. Mud volcano fluids were also collected and analyzed to assess the possible source of As in the Chia-Nan plain groundwater. The oxygen and hydrogen isotopic signatures indicate that the As-rich mud volcano fluids may have been modified by chemical exchange with (18)O-rich crustal rocks and possibly originated from mixing of deep brines with circulating meteoric water. Thus As in the Chia-Nan plain groundwater may have been evolved from deep crustal fluids or rock sources. The hydrogeochemistry and widespread As enrichment in groundwater of Chia-Nan plain result from multiple processes, e.g., de-watering of deep crustal fluids, seawater intrusion, and biogeochemical cycling of Fe, As, and S in alluvial sediments.


The use of the reamer-irrigator-aspirator to harvest mesenchymal stem cells.
The scarcity of mesenchymal stem cells (MSCs) in iliac crest bone marrow aspirate (ICBMA), and the expense and time in culturing cells, has led to the search for alternative harvest sites. The reamer-irrigation-aspirator (RIA) provides continuous irrigation and suction during reaming of long bones. The aspirated contents pass via a filter, trapping bony fragments, before moving into a 'waste' bag from which MSCs have been previously isolated. We examined the liquid and solid phases, performed a novel digestion of the solid phase, and made a comparative assessment in terms of number, phenotype and differentiation capacity with matched ICBMA. The solid fraction from the filtrate was digested for 60 minutes at 37° C with collagenase. Enumeration was performed via the colony-forming unit fibroblast (CFU-F) assay. Passage (P2) cells were differentiated towards osteogenic, adipogenic and chondrogenic lineages, and their phenotypes assessed using flow cytometry (CD33, CD34, CD45, CD73, CD90, and CD105). MSCs from the RIA phases were able to differentiate at least as well as those from ICBMA, and all fractions had phenotypes consistent with other established sources. The median number of colonies for the three groups was: ICBMA = 8.5 (2 to 86), RIA-liquid = 19.5 (4 to 90), RIA-solid = 109 (67 to 200) per 200 μl. The mean total yield of cells for the three groups was: ICBMA = 920 (0 to 4275), RIA-liquid = 114,983 (16,500 to 477,750), RIA-solid = 12,785 (7210 to 28 475). The RIA filtrate contains large numbers of MSCs that could potentially be extracted without enzymatic digestion and used for bone repair without prior cell expansion.


Intracellular vesicular stomatitis virus leader RNAs are found in nucleocapsid structures.
Previous studies demonstrated that cytoplasmic extracts of cells infected with vesicular stomatitis virus contain plus-strand leader RNAs which sediment at 18S on sucrose gradients as a complex with viral N protein. The work presented in this paper demonstrated that these 18S complexes were stable on CsCl density gradients, banding at a buoyant density near that of genome nucleocapsids, and exhibited a morphology in an electron microscope similar to the disk structures found in virus genome nucleocapsids. Minus-strand leader RNAs were also found in 18S complexes on sucrose gradients. Quantitation of intracellular leader RNA suggested that, late in infection, approximately three-quarters of total intracellular leader RNA was encapsidated.


Enhanced Solubility, Permeability and Anticancer Activity of Vorinostat Using Tailored Mesoporous Silica Nanoparticles.
Suberoylanilide hydroxamic acid (SAHA) or vorinostat (VOR) is a potent inhibitor of class I histone deacetylases (HDACs) that is approved for the treatment of cutaneous T-cell lymphoma. However, it has the intrinsic limitations of low water solubility and low permeability which reduces its clinical potential especially when given orally. Packaging of drugs within ordered mesoporous silica nanoparticles (MSNs) is an emerging strategy for increasing drug solubility and permeability of BCS (Biopharmaceutical Classification System) class II and IV drugs. In this study, we encapsulated vorinostat within MSNs modified with different functional groups, and assessed its solubility, permeability and anti-cancer efficacy in vitro. Compared to free drug, the solubility of vorinostat was enhanced 2.6-fold upon encapsulation in pristine MSNs (MCM-41-VOR). Solubility was further enhanced when MSNs were modified with silanes having amino (3.9 fold) or phosphonate (4.3 fold) terminal functional groups. Moreover, permeability of vorinostat into Caco-2 human colon cancer cells was significantly enhanced for MSN-based formulations, particularly MSNs modified with amino functional group (MCM-41-NH₂-VOR) where it was enhanced ~4 fold. Compared to free drug, vorinostat encapsulated within amino-modified MSNs robustly induced histone hyperacetylation and expression of established histone deacetylase inhibitor (HDACi)-target genes, and induced extensive apoptosis in HCT116 colon cancer cells. Similar effects were observed on apoptosis induction in HH cutaneous T-cell lymphoma cells. Thus, encapsulation of the BCS class IV molecule vorinostat within MSNs represents an effective strategy for improving its solubility, permeability and anti-tumour activity.


Proapoptotic, anti-cell proliferative, anti-inflammatory and anti-angiogenic potential of carnosic acid during 7,12 dimethylbenz[a]anthracene-induced hamster buccal pouch carcinogenesis.
The present study has investigated the modulating effect of carnosic acid on the expression pattern of cell proliferative (proliferating cell nuclear antigen (PCNA) cyclin D1 and a transcription factor c-fos), apoptotic (p53, Bcl-2, Bax caspase -3 and 9), inflammatory (Nuclear factor kappa B (NFκB) and cyclooxygenase-2 (COX- 2) and angiogenic (vascular endothelial growth factor (VEGF) markers during 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster buccal pouch carcinogenesis. Oral tumors were developed in the hamsters buccal pouches by painting with 0.5% DMBA in liquid paraffin three times a week for 14 weeks. Hundred per cent tumour formation (well-differentiated squamous cell carcinoma) accompanied by deregulation in the above mentioned molecular markers was noticed in hamsters treated with DMBA alone (tumour bearing hamsters). Oral administration of carnosic acid at dose of 10mg/kg bw to hamsters treated with DMBA not only completely prevented the tumour formation, but also corrected the abnormalities in the expression pattern of molecular markers. The present study suggests that carnosic acid might have inhibited the tumour formation by exerting anti-cell-proliferative, anti-inflammatory, anti-angiogenic and apoptotic potential during DMBA-induced hamster buccal pouch carcinogenesis.


Maspin--a novel protease inhibitor with tumor-suppressing activity in breast cancer.
Maspin (mammary serpin) is a novel serine protease inhibitor related to the serpin family with a tumor-suppressing function in breast cancer. Maspin was originally identified from normal mammary epithelium by subtractive hybridization and might function as a class II tumor-suppressor gene. Maspin's decreased expression with increased level of malignancy and its loss in metastatic cells is regulated at the transcriptional level. Cytosin methylation and heterochromatinization in the promoter region might account for this down-regulation of maspin. Transfection of tumor cells with maspin cDNA inhibits invasion and motility and decreases tumor growth and metastatic ability in nude mice. Maspin interacts with the p53 tumor-suppressor pathway and function as an inhibitor of angiogenesis in vitro and in vivo. The progressive loss of expression of maspin during tumor progression makes this new protein an interesting diagnostic and prognostic marker. The re-expression of maspin by pharmacological intervention potentially offers a promising approach as a therapeutic option in breast cancer therapy.


Phosphorus speciation in broiler litter and turkey manure produced from modified diets.
Modifying poultry diets by reducing mineral P supplementation and/or adding phytase may change the chemical composition of P in manures and affect the mobility of P in manure-amended soils. We studied the speciation of P in manures produced by broiler chickens and turkeys from either normal diets, or diets with reduced amounts of non-phytate phosphorus (NPP) and/or phytase, using a combination of chemical fractionation and synchrotron X-ray absorption near edge structure (XANES) spectroscopy. All broiler litters were rich in dicalcium phosphate (65-76%), followed by aqueous phosphate (13-18%), and phytic acid (7-20%); however, no hydroxylapatite was observed. Similarly, normal turkey manure had 77% of P as dicalcium phosphate and had no hydroxylapatite, while turkey manure from diets that had reduced NPP and phytase contained equal proportions of dicalcium phosphate (33-45%) and hydroxylapatite (35-39%). This is attributed to the higher total Ca to P ratio (>2) in modified turkey manures that resulted in transformation of more soluble (dicalcium phosphate) to less soluble P compounds (hydroxylapatite). Chemical fractionation showed that H2O-extractable P was the predominant form in broiler litter (56-77%), whereas aqueous phosphate determined with XANES was <18% indicating that H2O probably dissolved mineral forms of P (e.g., dicalcium phosphate). Results show that HCl extraction primarily removed phytic acid from broiler litters and normal turkey manure, while it removed a mixture of hydroxylapatite and phytic acid from modified turkey manures. The combination of chemical fractionation and XANES provided information about the nature of P in these manures, which may help to devise best management practices for manure use.


Ultrafiltration versus diuretics in congestive heart failure.
Acute decompensated heart failure often coexists with renal failure, and together they increase in-hospital mortality. Sometimes either condition arises because of the decompensation of chronic kidney disease or chronic heart failure. High-dose diuretics along with vasodilators and other medications are the standard first-line therapy but are sometimes ineffective because of the development of diuretic resistance or acute kidney injury. Fluid can be removed with different forms of dialytic techniques, but controversy exists about how and when to perform these procedures. This article explores the risks and benefits of technological approaches and the existing evidence for the best course of action.


The physical basis of the hard/soft acid/base principle.
The dependence of molecular properties on the chemical hardness is explored. As the chemical hardness of a molecule increases, its size and polarizability typically decrease and its charge and electronegativity typically increase. On the basis of these properties, the interaction energy between hard and soft acids and bases is quantified, and the physical basis of the global and local hard/soft acid/base (HSAB) principles is elucidated.


Re-examining the association between residential exposure to magnetic fields from power lines and childhood asthma in the Danish National Birth Cohort.
A study reported an increased risk of asthma in children whose mothers were exposed to magnetic field (MF) levels above 0.2 μT during pregnancy. We re-examined this association using data from mothers and children in the Danish National Birth Cohort (DNBC). This study included 92,676 singleton-born children and their mothers from the DNBC. MF exposure from power lines was estimated for all residences where the mothers lived during pregnancy and for all children from birth until the end of follow up. Exposure was categorized into 0 μT, 0.1 μT, and ≥ 0.2 μT for analysis. Definitive and possible asthma cases were identified using data from three independent data sources: 1) mothers' reports, 2) a national hospitalization register, 3) a national prescription drug register. We calculated hazard ratios (HR) and 95% confidence intervals (CI) for the association between the highest level of exposure during pregnancy and asthma in children, adjusting for several potential confounding factors. We also examined the sensitivity of the risk estimates to changes in exposure and outcome definitions. No differences or trends in the risk of asthma development were detected between children with different levels of MF exposure regardless of the asthma case definition or outcome data source. For definitive cases, the HR (95% CI) for those with any exposure was 0.72 (0.27-1.92), and it was 0.41 (0.06-2.92) for those exposed to ≥ 0.2 μT. Adjustments for confounding and variations in the exposure definition did not appreciably alter the results. We did not find evidence that residential exposure to MF during pregnancy or early childhood increased the risk of childhood asthma. This interpretation is in line with the lack of an established biological mechanism directly linking MF exposure to asthma, but high exposure was very rare in this cohort.


Friendship and social functioning following early institutional rearing: The role of ADHD symptoms.
Early institutional rearing is associated with increased risk for subsequent peer relationship difficulties, but the underlying mechanisms have not been identified. Friendship characteristics, social behaviors with peers, normed assessments of social problems, and social cue use were assessed in 142 children (mean age = 10.06, SD = 2.02; range 7-13 years), of whom 67 were previously institutionalized (PI), and 75 were raised by their biological families. Anxiety and attention-deficit/hyperactivity disorder (ADHD) symptoms, often elevated among PI children, were examined as potential mediators of PI status and baseline social functioning and longitudinal follow-ups (2 and 4 years later). Twenty-seven percent of PI children fell above the Child Behavior Checklist Social Problems cutoff. An examination of specific social behaviors with peers indicated that PI and comparison children did not differ in empathic concern or peer social approach, though parents were more likely to endorse aggression/overarousal as a reason that PI children might struggle with friendships. Comparison children outperformed PI children in computerized testing of social cue use learning. Finally, across these measures, social difficulties exhibited in the PI group were mediated by ADHD symptoms with predicted social problems assessed 4 years later. These findings show that, when PI children struggle with friendships, mechanisms involving attention and behavior regulation are likely contributors.


Multi-anode enhanced the bioelectricity generation in air-cathode microbial fuel cells towards energy self-sustaining wastewater treatment.
Microbial fuel cells (MFCs) hold considerable promise for harnessing the substantial energy resources present in wastewater. However, their practical application in wastewater treatment is limited by inadequate removal of organic matter and inefficient power recovery. Previous studies have investigated aeration as a method to enhance the removal of organic matter, but this method is energy-intensive. To address this issue, this study proposed using MFC-recovered bioelectricity for aeration, thereby mitigating the associated expenses. An air-cathode MFC with multi-anode was constructed and optimized to maximize electricity supply for aeration. Carbon-felt anodes were chosen as the most effective anode configuration, due to the high abundance of electroactive bacteria and genes observed in the biofilm generated on their surface. By incorporating six carbon felt anodes, the MFC achieved a 1.7 and 1.1 fold enhancement in the maximum power and current density, respectively. The optimized MFC unit achieved a stable current density of 0.32 A/m2 and achieved COD removal of 60% in the long-term operation of 140 days in a 50 L reactor. In a reactor scaled up to 1600 L, 72 MFCs successfully powered a mini air pump work for 10 s after an 81-s charging period. The intermittent aeration resulted in partial increases in DO concentrations to 0.03-3.5 mg/L, which is expected to promote the removal of nitrogen compounds by the nitrification-anammox process. These groundbreaking results lay the foundation for self-sustaining wastewater treatment technologies.


Cryosurgery of benign skin lesions.
Cryosurgery is a widely used treatment modality in dermatology. Its place in cutaneous malignant and premalignant disease is well established; however, it also has great utility with benign lesions. Vascular, infectious, fibrotic diseases, solar damage, acne, as well as some cosmetic defects are amenable to freezing. The mechanism of treatment involves inducing tissue damage, vascular stasis and occlusion, as well as inflammation, to destroy unwanted tissue. After destruction of epidermal lesions, healing involves rapid re-epithelialization over a relatively cold-insensitive dermal network. Side effects are common but shortlived and are rarely severe. The equipment required is relatively economical and readily available. The technique is straightforward and reproducible, making cryosurgery an attractive option for many commonly encountered benign skin conditions. This review outlines treatment with the timed spot freeze technique of some commonly encountered benign lesions.


Non-interventional research and usual care: definition, regulatory aspects, difficulties and recommendations.
Non-interventional research is an essential approach to gathering data in different situations and it often complements other research methodologies, such as biomedical research and research aimed at evaluating usual care. Yet the legislative framework for this type of research is nonexistent, and this void poses a number of problems for non-interventional researchers, including an absence of any guarantee of quality and therefore of reliability, a limited recognition of the research beyond our borders, cumbersome administrative procedures, and a lack of visibility. In light of the growing demand for data, particularly in post marketing authorisation for drugs, which largely relies on non-interventional methods, the Round Table participants have issued a set of proposals for a future legislative framework for this type of research.


A Brief History of Bronchitis in England and Wales.
Chronic bronchitis is associated with hypertrophy of airway submucosal glands and with mucus and squamous metaplasia of the surface epithelium. A historical review of research on these and other pathological changes is provided. Next, from annual reports of the Registrar-General's Office (and later the Office of National Statistics), death rates per unit population from acute and chronic bronchitis (a term that here includes chronic obstructive pulmonary disease [COPD]) are calculated for England and Wales from 1838 to the present. It is argued that a large increase in the death rate between 1838 and 1879, from all forms of bronchitis combined, was due primarily to increased levels of atmospheric coal smoke, whereas a decrease from 1879 to 1935 was due to progressively cleaner air. Between 1935 and the mid-1960s, mortality from chronic bronchitis among men increased dramatically, after which it has fallen, a pattern that parallels changes in cigarette smoking. Finally, a brief historical review of the treatments for chronic bronchitis is presented.


Longitudinal blood biomarker trajectories in preclinical Alzheimer's disease.
Plasma biomarkers are altered years prior to Alzheimer's disease (AD) clinical onset. We measured longitudinal changes in plasma amyloid-beta (Aβ)42/40 ratio, pTau181, pTau231, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in a cohort of older adults at risk of AD (n = 373 total, n = 229 with Aβ and tau positron emission tomography [PET] scans) considering genetic and demographic factors as possible modifiers of these markers' progression. Aβ42/40 ratio concentrations decreased, while NfL and GFAP values increased over the 4-year follow-up. Apolipoprotein E (APOE) ε4 carriers showed faster increase in plasma pTau181 than non-carriers. Older individuals showed a faster increase in plasma NfL, and females showed a faster increase in plasma GFAP values. In the PET subsample, individuals both Aβ-PET and tau-PET positive showed faster plasma pTau181 and GFAP increase compared to PET-negative individuals. Plasma markers can track biological change over time, with plasma pTau181 and GFAP markers showing longitudinal change in individuals with preclinical AD. Longitudinal increase of plasma pTau181 and glial fibrillary acidic protein (GFAP) can be measured in the preclinical phase of AD. Apolipoprotein E ε4 carriers experience faster increase in plasma pTau181 over time than non-carriers. Female sex showed accelerated increase in plasma GFAP over time compared to males. Aβ42/40 and pTau231 values are already abnormal at baseline in individuals with both amyloid and tau PET burden.


Novel oral anticoagulants: a review of the literature and considerations in special clinical situations.
Novel oral anticoagulants (OACs), including dabigatran etexilate, rivaroxaban, and apixaban, are available alternative anticoagulant therapy to vitamin K antagonists. The US Food and Drug Administration (FDA) has approved dabigatran, rivaroxaban, and apixaban for the treatment of appropriate patients for specific clinical indications. Therapeutic advantages of prescribing the new OACs are related to their predictable pharmacokinetic and pharmacodynamic properties. Dabigatran, rivaroxaban, and apixaban have all been shown to be noninferior to warfarin treatment for stroke prevention in respective phase 3 clinical trials; dabigatran and apixaban were shown to be superior to warfarin as preventive therapy. Dabigatran, rivaroxaban, and apixaban are all approved agents for stroke prevention in patients with nonvalvular atrial fibrillation in the United States and Europe. Among these agents, rivaroxaban is the only FDA-approved drug for the treatment of venous thromboembolism. This article reviews the major clinical trials that investigated the efficacy and safety of the new OACs and the use of these agents in special clinical situations.


The complete mitochondrial genome of Asiotmethis jubatus (Uvarov, 1926) (Orthoptera: Acridoidea: Pamphagidae).
The complete mitochondrial genome of Asiotmethis jubatus (Uvarov, 1926), which was collected from the Xinjiang Uygur Autonomous Region of China, is reported here. It is 15,669 bp in length and contains 72.3% AT. All Asiotmethis jubatus protein-coding sequences start with a typical ATN codon, excluding cox1 and nad6. The usual termination codon (TAN) and incomplete stop codons (T) were found from 13 protein-coding genes. All tRNA genes could be folded into the typical cloverleaf secondary structure, excluding trnS(AGN) which forms another structure. The sizes of the large and small ribosomal RNA genes are 1315 and 852 bp, respectively. The AT content of the A + T-rich region is 81.9%.


Recognition and treatment of venous malformations of the rectum.
Venous malformations of the rectum are uncommon lesions that present complex management problems (1-6). The vast majority of these lesions present with rectal bleeding in infancy or childhood. Many cases have been treated as colitis for years before the correct diagnosis was made. The correct diagnosis has generally been based on gross appearance, confirmed subsequently by plain radiographs and angiography. Heroic surgical intervention has been the only repeatedly reported "cure" in the literature. One patient has been reported who did well for 20 years with sclerosis of the hemorrhoidal vein at surgery followed by intermittent transrectal sclerotherapy (7,8). Another patient would appear to have had longterm success with radiation therapy (9-11). We report four new cases of venous malformations of the rectum and results to date of a new therapeutic option with transcutaneous ethanol sclerotherapy in two of these patients. A discussion of alternate methods of treatment is included.


Prospective Biomarkers from Plasma Metabolomics of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Implicate Redox Imbalance in Disease Symptomatology.
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disease of enigmatic origin with no established cure. Its constellation of symptoms has silently ruined the lives of millions of people around the world. A plethora of hypotheses have been vainly investigated over the past few decades, so that the biological basis of this debilitating condition remains a mystery. In this study, we investigate whether there is a disturbance in homeostasis of metabolic networks in the plasma of a female 32-patient cohort compared to 19 healthy female controls. Extensive analysis of the 832-metabolite dataset generated by Metabolon®, covering eight biological classes, generated important insight into metabolic disruptions that occur in ME/CFS. We report on 14 metabolites with differences in abundance, allowing us to develop a theory of broad redox imbalance in ME/CFS patients, which is consistent with findings of prior work in the ME/CFS field. Moreover, exploration of enrichment analysis using www.MetaboAnalyst.ca provides information concerning similarities between metabolite disruptions in ME/CFS and those that occur in other diseases, while its biomarker analysis unit yielded prospective plasma biomarkers for ME/CFS. This work contributes key elements to the development of ME/CFS diagnostics, a crucial step required for discovering a therapy for any disease of unknown origin.


Proton magnetic resonance spectroscopy in oncology: the fingerprints of cancer?
Abnormal metabolism is a key tumor hallmark. Proton magnetic resonance spectroscopy (1H-MRS) allows measurement of metabolite concentration that can be utilized to characterize tumor metabolic changes. 1H-MRS measurements of specific metabolites have been implemented in the clinic. This article performs a systematic review of image acquisition and interpretation of 1H-MRS for cancer evaluation, evaluates its strengths and limitations, and correlates metabolite peaks at 1H-MRS with diagnostic and prognostic parameters of cancer in different tumor types.


[Interaction analysis of the influence of different factors and benzene exposure on workers' alanine aminotransferase].
Objective: To investigate the main factors that influence ALT abnormalities in workers exposed to benzene. Methods: In June 2022, data of 613 enterprises with benzene hazards and 585 enterprises with non-benzene hazards in Tianjin in 2021 were collected, and occupational health examination data of 13018 workers with benzene exposure and 13018 workers with non-benzene exposure were collected, and the region, enterprise type, industry classification and enterprise scale of the employer were analyzed. And occupational health examination data of workers with benzene exposure and non-benzene exposure. The effects of personal general situation, occupational history, enterprise information and benzene exposure on alanine aminotransferase were evaluated by additive interaction. Results: Compared with the group of non-benzene-exposed workers, the personal general conditions, occupational history, company information were higher in the benzene-exposed workers, and the differences were statistically significant (P<0.05). The quantitative analysis of additive interaction found that gender (RERI=2.632, 95%CI: 1.966-3.297; AP=0.383, 95%CI: 0.311-0.456; S=1.813, 95%CI: 1.530-2.149), age (RERI=1.142, 95%CI: 0.928-1.356; AP=0.462, 95% CI: 0.371-0.552; S=4.461, 95%CI: 1.800-11.053), length of service (RERI=-1.199, 95%CI: -1.653--0.745; AP=-0.456, 95%CI: -0.640--0.271; S=0.576, 95%CI: 0.479-0.693), region (RERI=0.421, 95% CI: 0.148-0.694; AP=0.161, 95%CI: 0.053-0.268; S=1.350, 95%CI: 1.057-1.726), industry classification (RERI=0.627, 95%CI: 0.345-0.910; AP=0.232, 95%CI: 0.132-0.332; S=1.584, 95%CI: 1.233-2.035) and benzene exposure had a statistically significant additive interaction with abnormal serum ALT. Conclusion: Emphasis should be placed on male workers under the age of 40 in the petrochemical industry, oil storage and transportation, and power production, so as to protect the health of workers more specifically and reduce the risk of disability due to disease.


Neutrophil collagenase in rheumatoid interstitial lung disease.
Ten patients with rheumatoid arthritis were evaluated by bronchoalveolar lavage. Five patients (group I) had interstitial lung disease by physiological and radiographic criteria, whereas five (group II) had no evidence of lung disease. Lavage fluid from four of the five group I patients contained an active collagenase which by inhibitory profile and substrate specificity appeared to be of neutrophil origin. None of the group II patients demonstrated lavage fluid collagenase. Treatment of lavage fluid with trypsin failed to uncover latent collagenase activity in either group, suggesting that the collagenase is present entirely in an active form. These findings parallel those observed in idiopathic pulmonary fibrosis and suggest a potential pathogenetic role for collagenase in rheumatoid interstitial lung disease.


Prevalence, detection, and management of the metabolic syndrome in patients with acute myocardial infarction: role of an obesity-centric definition.
Background. We sought to determine and compare the prevalence of the Metabolic Syndrome (MS) in patients with acute myocardial infarction (AMI) utilizing the new International Diabetes Federation (IDF) definition with the older National Cholesterol Education Program (NCEP) definition. We also examined the clinical utility of MS in this context. Methods. A total of 107 consecutive patients with AMI were prospectively evaluated for MS. Fasting lipids obtained at admission and fasting glucose at discharge were used. A postdischarge folder audit verified rates of discharge coding and implementation of specific management strategies for MS. Results. Baseline patient characteristics included: mean age 59 +/- 13 years; males 80%; diabetes 19%; mean BMI 29.7 +/- 8.4 kg/m(2). MS prevalence was 54% by the IDF definition and 49% by the NCEP definition, with good agreement between definitions: kappa = 0.664, P < .001. Factors predictive of MS after multivariate analysis included: hypertension, fasting glucose, waist circumference, and serum HDL (all P < .05). Despite the high prevalence, MS was recognized at discharge in only 1 patient, and referral for exercise and/or weight-loss programs was undertaken in 5 patients. Conclusion. There is a high prevalence of MS utilizing contemporary definitions in patients with AMI: 54% by the IDF definition and 49% by NCEP criteria. Despite the high prevalence, MS was under-recognized and under-treated in this population.


Secretion in yeast: in vitro analysis of the sec53 mutant.
Of central importance to studying protein translocation via a combined genetic and biochemical approach is the in vitro analysis of yeast conditionally-lethal secretory mutants. Analysis of sec53 presented an opportunity not only to see if mutants could be examined in recently developed yeast in vitro translocation systems, but also to characterize further the nature of this mutant originally postulated to be defective in protein translocation. Membranes from sec53 were capable of translocating and glycosylating nascent prepro-alpha-factor in vitro in both sec53 and wild-type lysates at temperatures that were non-permissive for growth of the mutant cells. These results suggested that the Sec53 protein does not function directly in the translocation and glycosylation of prepro-alpha-factor. To examine this point further, we isolated membranes from sec53 cells that had been grown at the non-permissive temperature prior to disruption. In such cases, regardless of assay temperature, membranes from sec53 cells efficiently translocated but failed to glycosylate prepro-alpha-factor in vitro. The in vitro phenotype of sec53 could be mimicked by isolating rough microsomes from wild-type cells that had been grown for 1 h in the presence of tunicamycin. Together, these results demonstrate that sec53 is not defective in translocation, rather in assembly of the dolichol-oligosaccharide substrate needed for N-linked glycosylation.


[Recovery and remission in schizophrenia. Results from a naturalistic 2-year follow-up inpatient study].
Remission in schizophrenia is defined as a period of at least 6 months in which symptom reduction occurs. In comparison, the term recovery is defined to include not only long-term symptomatic improvement but also good psychosocial functioning and improved quality of life. The aim of this naturalistic study is to prospectively investigate all these variables and their interrelationship in a sample of subjects with schizophrenia over a period of two years. Seventy-seven subjects were included into the analysis. Criteria of remission for each domain were assessed using the BPRS (brief psychiatric rating scale, symptomatic remission), GAF (global assessment of functioning, functional remission) and the SWN-K (subjective well-being under neuroleptics, remission of subjective well-being). Subjects were considered to have "recovered" if they remitted in all three domains at discharge (t0), one (t1) and two-year (t2) follow-up assessments. Symptomatic and functional remissions were rare and occurred only in 10 % of the subjects at t0, t1 and t2. Approximately one-third of the individuals had remission with a stable quality of life. Correlations between quality of life and functional and symptomatic remissions were weak. None of the subjects met the criteria for recovery. Compared to previous studies, the rates of remission and recovery in the current sample were quite low. The contrasting results may be due to the naturalistic characteristics of this sample of initially inpatient subjects while previous studies investigated selected samples of schizophrenic individuals. However, despite their functional and symptomatic impairments, the results also indicate that the schizophrenic subjects have a largely satisfying quality of life.


Safety Needs of People With Disabilities During Earthquakes.
The needs of people with disabilities are not taken into account during disasters, and there is no or little preparation for them. Hence, such people are very anxious about their personal safety during disasters. The aim of this study was to explain the safety needs of people with disabilities during earthquakes. This qualitative study was conducted with purposive sampling. A total of 12 people with movement disability, aged between 18 and 60 years, and with an experience of facing earthquakes, participated in semi-structured interviews. Thematic analysis was used. The safety needs of people with disabilities were categorized into three phases: those before an earthquake were considering building codes and resistant construction, building safe and resistant-to-climate-change shelters, and securing the room at the home and workplace; that during an earthquake was the existence of personal protection facilities; and those after an earthquake were adaptation of bathrooms in secure areas, prioritizing conex containers instead of tents, and sheltering in a safe and vermin-free area. The sudden death of people with disabilities during disasters is preventable through proper planning and preparedness of emergency personnel. Hence, identifying the safety needs of these people and inclusion of such plans in disasters management systems can assure safety for people with disabilities during disasters. (Disaster Med Public Health Preparedness. 2018;12:615-621).


Processing of calcitonin and epidermal growth factor after binding to receptors in human breast cancer cells (T 47D).
125I-labelled calcitonin and 125I-labelled epidermal growth factor (EGF) bound to T 47D breast cancer cells at 37 degrees C in a manner that became increasingly resistant to removal by acid pH. Bound 125I-labelled EGF became resistant to acid removal more rapidly than did bound 125I-labelled calcitonin. The shift from acid accessibility to acid inaccessibility was energy-dependent since it was not seen at 4 degrees C and was inhibited in the presence of cell metabolic inhibitors. Radioactivity removed by acid represented intact hormone as assessed by trichloroacetic acid precipitation, whereas radioactivity released spontaneously by the cells was trichloroacetic acid-soluble. Inclusion of 10 mM-NH4Cl in the incubation medium resulted in an accumulation of cell-associated radioactivity without affecting the shift to acid inaccessibility. The accumulated radioactivity was relatively more trichloroacetic acid-precipitable in comparison with that associated with control cells. These data are consistent with internalization of receptor-bound EGF and a similar though slower mechanism of processing for receptor-bound calcitonin. The predominant route of hormone release from cells seems to occur via intracellular degradation rather than dissociation from cell-surface receptors.


Diabetes is associated with drug-resistant tuberculosis in Eastern Taiwan.
We assessed the association between diabetes mellitus and drug-resistant tuberculosis (TB). Among new patients, diabetes was significantly associated with any resistance to isoniazid excluding multidrug-resistant TB (MDR-TB; adjusted OR [aOR] 1.88, 95%CI 1.07-3.31), but not with MDR-TB (aOR 0.95, 95%CI 0.34-2.68). Among previously treated patients, diabetes was also significantly associated with INH resistance (aOR 6.76, 95%CI 1.53-29.98) but not with MDR-TB (aOR 1.52, 95%CI 0.59-3.95). We concluded that diabetes was associated with INH resistance and speculated that the sample size of retreatment cases was insufficient to confirm the association between diabetes and MDR-TB.


Ultrathin bronchoscopy for solitary pulmonary lesions in a region endemic for tuberculosis: a randomised pilot trial.
The evaluation of solitary pulmonary lesions (SPL) requires a balance between procedure-related morbidity and diagnostic yield, particularly in areas where tuberculosis (TB) is endemic. Data on ultrathin bronchoscopy (UB) for this purpose is limited. To evaluate feasibility and safety of UB compared to SB for diagnosis of SPL in a TB endemic region. In this prospective randomised trial we compared diagnostic yield and adverse events of UB with standard-size bronchoscopy (SB), both combined with fluoroscopy, in a cohort of patients with SPL located beyond the visible range of SB. We included 40 patients (mean age 55.2 years, 45 % male) with malignant SPL (n = 16; 40 %), tuberculous SPL (n = 11; 27.5 %) and other benign SPL (n = 13; 32.5 %). Mean procedure time in UB and SB was 30.6 and 26.0 min, respectively (p = 0.15). By trend, adverse events were recorded more often with UB than with SB (30.0 vs. 5.0 %, p = 0.091), including extensive coughing (n = 2), blocked working channel (n = 2), and arterial hypertension requiring therapeutic intervention (n = 1), all with UB. The overall diagnostic yield of UB compared to SB was 55.0 % vs. 80.0 %, respectively (p = 0.18). Sensitivity for the diagnosis of malignancy of UB and SB was 50.0 % and 62.5 %, respectively (p = 0.95). UB is not superior to SB for the evaluation of SPL in a region endemic with tuberculosis, when combined with fluoroscopic guidance only. ClinicalTrials.gov (Identifier: NCT02490059 ).


Improving paddling efficiency through raising sitting height in female white water kayakers.
The study compared female white water paddlers over two conditions: with seat raise and with no seat raise. The aim was to determine whether raising the sitting height would improve paddling efficiency. Sitting height of each participant was recorded in order to calculate the seat raise height required and three-dimensional kinematic data was collected for six participants over both conditions. Twelve measures of efficiency were utilised. The efficiency of all participants improved on the seat condition for ≥4 of the measures, with three participants showing improvement for ≥6 of the measures. The stern snaking measure had the highest value of significance (P = 0.1455) and showed an average of 11.98% reduction in movement between no seat and seat conditions. The results indicate that improvements were seen although these were individualistic. Therefore it can be concluded that it is worth experimenting with a seat raise for a female kayaker who is lacking efficiency, noting, however, that improvements might depend on anthropometrics and the seat height selected, and therefore could elicit differing results.


Selective Calcium-Dependent Inhibition of ATP-Gated P2X3 Receptors by Bisphosphonate-Induced Endogenous ATP Analog ApppI.
Pain is the most unbearable symptom accompanying primary bone cancers and bone metastases. Bone resorptive disorders are often associated with hypercalcemia, contributing to the pathologic process. Nitrogen-containing bisphosphonates (NBPs) are efficiently used to treat bone cancers and metastases. Apart from their toxic effect on cancer cells, NBPs also provide analgesia via poorly understood mechanisms. We previously showed that NBPs, by inhibiting the mevalonate pathway, induced formation of novel ATP analogs such as ApppI [1-adenosin-5'-yl ester 3-(3-methylbut-3-enyl) triphosphoric acid diester], which can potentially be involved in NBP analgesia. In this study, we used the patch-clamp technique to explore the action of ApppI on native ATP-gated P2X receptors in rat sensory neurons and rat and human P2X3, P2X2, and P2X7 receptors expressed in human embryonic kidney cells. We found that although ApppI has weak agonist activity, it is a potent inhibitor of P2X3 receptors operating in the nanomolar range. The inhibitory action of ApppI was completely blocked in hypercalcemia-like conditions and was stronger in human than in rat P2X3 receptors. In contrast, P2X2 and P2X7 receptors were insensitive to ApppI, suggesting a high selectivity of ApppI for the P2X3 receptor subtype. NBP, metabolite isopentenyl pyrophosphate, and endogenous AMP did not exert any inhibitory action, indicating that only intact ApppI has inhibitory activity. Ca2+-dependent inhibition was stronger in trigeminal neurons preferentially expressing desensitizing P2X3 subunits than in nodose ganglia neurons, which also express nondesensitizing P2X2 subunits. Altogether, we characterized previously unknown purinergic mechanisms of NBP-induced metabolites and suggest ApppI as the endogenous pain inhibitor contributing to cancer treatment with NBPs.


Polymeric nanomedicines as a promising vehicle for solid tumor therapy and targeting.
Inspite of demanding research that has been undertaken for cancer treatment, cancer is a major cause of mortality. Available conventional treatment options of solid tumor are associated with serious side effects. Nanomedicines mediated fascinating approach may be effectively utilized for efficient tumor targeting by avoiding all the problems associated with conventional chemotherapy. Polymeric nanomedicines such as polymer micelles, polymeric nanoparticles, polymersomes and polymer conjugates currently developed for solid tumor treatment have proved to be efficacious cancer therapeutics. These polymeric nanostructures are able to reach tumor tissue or angiogenic endothelial cells either passively or actively. To date, more advancement in the tumor targeting field includes stimuli sensitive polymeric nanocarriers that pass through the intracellular delivery barriers and release the bioactives in response to the microenvironmental trigger of tumor cell. This review discusses the molecular aspects of solid tumor pathophysiology and its dramatic impact on research for innovative and novel therapeutic approaches linked with tumor-targeting polymeric nanomedicines.


Effect of Early Everolimus-Facilitated Reduction of Tacrolimus on Efficacy and Renal Function in De Novo Liver Transplant Recipients: 24-Month Results for the North American Subpopulation.
A recent randomized phase III study of 719 de novo liver transplant recipients showed that early everolimus plus reduced-dose tacrolimus (EVR + rTAC) led to significantly better kidney function than standard TAC (TAC-C), without compromising efficacy. In that study, patients from North America (n = 211) had increased risk factors for posttransplant renal insufficiency at study start, relative to patients from Europe and rest of world (eg, worse renal function, more diabetes, older age). A post hoc analysis was performed to assess whether these regional disparities affected study outcomes in North American patients. In this subpopulation, estimated glomerular filtration rates at randomization were higher in TAC-C over EVR + rTAC (76.4 vs 69.3 mL/min per 1.73 m). Mean changes in estimated glomerular filtration rate values (mL/min per 1.73 m) favored EVR + rTAC over TAC-C at months 12 (+3.7 vs -4.5; P = 0.032), 24 (+2.7 vs -6.6; P = 0.042), and 36 (+4.3 vs -8.1; P = 0.059). The composite efficacy endpoint of treated biopsy-proven acute rejection, graft loss, or death was 10.9%, 14.1%, and 14.1% for EVR + rTAC and 13.1%, 17.2%, and 19.3% for TAC-C at months 12, 24, and 36, respectively. Although the North American cohort had more comorbidities, results were consistent with the overall population for efficacy and renal function.


The beneficial effect of family meals on obesity differs by race, sex, and household education: the national survey of children's health, 2003-2004.
Studies have indicated that family meals may be a protective factor for childhood obesity; however, limited evidence is available in children with different racial, socioeconomic, and individual characteristics. The purpose of this study was to examine family meal frequency as a protective factor for obesity in a US-based sample of non-Hispanic white, non-Hispanic black, and Hispanic children age 6 to 11 years, and to identify individual, familial, and socioeconomic factors that moderate this association. Data were from the 2003 National Survey of Children's Health (n=16,770). Multinomial logistic regression analyses were used to test the association between family meal frequency and weight status, and the moderating effects of household structure, education, poverty level, and sex, by racial group. Non-Hispanic white children who consumed family meals every day were less likely to be obese than those eating family meals zero or a few days per week. A moderating effect for sex was observed in non-Hispanic black children such that family meal frequency was marginally protective in boys but not in girls. Higher family meal frequency was a marginal risk factor for obesity in Hispanic boys from low-education households, but not in girls from similar households. In conclusion, family meals seem to be protective of obesity in non-Hispanic white children and non-Hispanic black boys, whereas they may put Hispanic boys living in low-education households at risk. Greater emphasis is needed in future research on assessing why this association differs among different race/ethnic groups, and evaluating the influence of the quality and quantity of family meals on child obesity.


Nucleotide composition and codon usage bias of SRY gene.
The SRY gene is present within the sex-determining region of the Y chromosome which is responsible for maleness in mammals. The nonuniform usage of synonymous codons in the mRNA transcript for encoding a particular amino acid is the codon usage bias (CUB). Analysis of codon usage pattern is important to understand the genetic and molecular organisation of a gene. It also helps in heterologous gene expression, design of primer and synthetic gene. However, the analysis of codon usage bias of SRY gene was not yet studied. We have used bioinformatic tools to analyse codon usage bias of SRY gene across mammals. Codon bias index (CBI) indicated that the overall extent of codon usage bias was weak. The relative synonymous codon usage (RSCU) analysis suggested that most frequently used codons had an A or C at the third codon position. Compositional constraint played an important role in codon usage pattern as evident from correspondence analysis (CA). Significant correlation among nucleotides constraints indicated that both mutation pressure and natural selection affect the codon usage pattern. Neutrality plot suggested that natural selection might play a major role, while mutation pressure might play a minor role in codon usage pattern in SRY gene in different species of mammals.


Intergovernmental Relations in the UK: Time for a Radical Overhaul?
Brexit and the coronavirus pandemic have put relationships between the UK government and its devolved counterparts under growing strain. Tensions generated by both of these developments have exposed the inadequacies of the existing, under-developed system for bringing governments together in the UK. The limitations of the current system include the ad hoc nature of intergovernmental meetings, and their consultative rather than decision-making character. Drawing upon an analysis of how intergovernmental relationships are structured in five other countries, the authors offer a number of suggestions for the reconfiguration of the UK model. They explore different ways of enabling joint decision making by its governments, and argue against the assumption that England can be represented adequately by the UK administration. Without a serious attempt to address this dysfunctional part of the UK's territorial constitution, there is every prospect that relations between these different governments will continue to deteriorate.


Pedigree analysis of 5 swine breeds in the United States and the implications for genetic conservation.
Globally, genetic diversity of livestock populations is contracting. Knowing the true extent of the contraction is needed to develop effective conservation strategies. Although contractions of genetic diversity have been documented at the breed level, little within breed documentation has occurred. This situation is no different for US swine breeds. Therefore, the objective of this study was to establish an inbreeding baseline for 5 pig breeds via pedigree records extracted from purebred registrations to each breed association for Berkshire (n = 116,758), Duroc (n = 878,480), Hampshire (n = 744,270), Landrace (n = 126,566), and Yorkshire (n = 727,268). For all breeds the number of registrations peaked after 1990 and declined since that time. The breeder structure was analyzed for Berkshire and Duroc; the average breeder registered pigs for 4.0 yr for both breeds. Breeders were grouped by longevity and herd size, and the inbreeding levels for the current population (pigs born 2006 and later) were evaluated. Presently, more than 99% of all pigs are inbred with the majority having inbreeding less than 10%. The range for percentage of animals that are more than 25% inbred ranged from 1.16% for Yorkshire to 6.09% for Berkshire. The greatest inbreeding for all animals within a breed ranged from 51% for Landrace and 65% for Yorkshire. Sires were grouped into 10 percentiles based on number of great-grandprogeny (GGP) produced; for all breeds, the top 10 percentile accounted for more than 75% of all GGP. Sixty percent of all sires produced less than 1% of all GGP, indicating few males are contributing to future generations. Generations ranged from 17 to 19 per breed with a generation interval ranging from 1.65 yr for Berkshire to 2.21 yr for Yorkshire. Mean inbreeding (%) at generation 17 (the most generations computed across breeds), rate of inbreeding per generation, and effective population size were 12.3, 0.0065, and 77 for Berkshire; 11.8, 0.0044, and 113 for Duroc; 6.8, 0.0046, and 109 for Hampshire; 17.9, 0.0067, and 74 for Landrace; and 8.0, 0.0044, and 113 for Yorkshire, respectively. The 2 breeds with fewest registrations, Berkshire and Landrace, had greater inbreeding rates and smaller effective population sizes, suggesting a need for more immediate conservation efforts. This analysis provides a basis for future monitoring of the genetic diversity of pig breeds and serves as a basis for planning conservation activities.


Association of serotonin transporter promoter gene polymorphism (5-HTTLPR) with depression in Costa Rican schizophrenic patients.
Depression and suicidal behavior are frequently observed in patients with schizophrenia. The serotonin transporter protein regulates serotonergic signaling at synapses and is encoded by a single gene (SLC6A4; Locus Link ID: 6532), located at 17q11.1-q12 with two polymorphic variants (the short and the long allele). The short allele of serotonin transporter gene has been associated with depression and suicidality in individuals who suffered negative life events and with depression in individuals with chronic psychosis.. Subjects were recruited from a genetic study of schizophrenia conducted in Costa Rica. The authors replicated their previous research, using a more narrow phenotype (only schizophrenic subjects) and a more ethnically homogenous sample (only Costa Rican schizophrenic individuals who were not included in the previous study). The authors hypothesized that subjects with at least one copy of the serotonin transporter promoter gene polymorphism (5-HTTLPR) "s" allele would have a greater history of lifetime depression and suicidability rate than those who had an "l/l" genotype. The authors analyzed 155 subjects with a DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) diagnosis of schizophrenia (73% male, age at interview 38.3, SD = 11.23). The genotype distribution was "ss" 58 (37%), "sl" 69 (45%), and "ll" 28 (18%). In the secondary analysis, the authors explored association of the "s" allele with lifetime history of suicide behavior in 173 subjects (18 more subjects than primary analysis because schizophrenic individuals were included regardless of history of depression). The authors found that subjects carrying at least one short allele had a significant increased lifetime risk for depressive syndromes (chi(2) = 5.4, df = 1, P = 0.02; odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.15-6.3). No association was found for suicidal behavior in the same sample (chi(2) = 0.928, P = 0.629). In conclusion, the genotype at the 5-HTTLPR promoter polymorphic locus increases the risk of developing major depression but not suicidal behavior during the course of the schizophrenia in these patients. Due to the small sample size, these results should be followed by definitive replication.


Efficacy and toxicity of the antisense oligonucleotide aprinocarsen directed against protein kinase C-alpha delivered as a 21-day continuous intravenous infusion in patients with recurrent high-grade astrocytomas.
Protein kinase C alpha (PKC-alpha) is a cytoplasmic serine threonine kinase involved in regulating cell differentiation and proliferation. Aprinocarsen is an antisense oligonucleotide against PKC-alpha that reduces PKC-alphain human cell lines and inhibits a human glioblastoma tumor cell line in athymic mice. In this phase 2 study, aprinocarsen was administered to patients with recurrent high-grade gliomas by continuous intravenous infusion (2.0 mg/kg/day for 21 days per month). Twenty-one patients entered this trial. Their median age was 46 years (range, 28-68 years), median Karnofsky performance status was 80 (range, 60-100), median tumor volume was 58 cm3 (range, 16-254 cm3), and histology included glioblastoma multiforme (n = 16), anaplastic oligodendroglioma (n = 4), and anaplastic astrocytoma (n = 1). The number of prior chemotherapy regimens included none (n = 3), one (n = 10), and two (n = 8). No tumor responses were observed. Patients on this therapy rapidly developed symptoms of increased intracranial pressure with increased edema, enhancement, and mass effect on neuroimaging. The median time to progression was 36 days, and median survival was 3.4 months. The observed toxicities were mild, reversible, and uncommon (grade 3 thrombocytopenia [n = 3] and grade 4 AST [n = 1]), and no coagulopathy or CNS bleeding resulted from this therapy. Plasma concentrations of aprinocarsen during the infusion exhibited significant interpatient variability (mean = 1.06 mug/ml; range, 0.34-6.08 mug/ml). This is the first study to use an antisense oligonucleotide or a specific PKC-alpha inhibitor in patients with high-grade gliomas. No clinical benefit was seen. The rapid deterioration seen in these patients could result from tumor growth or an effect of aprinocarsen on bloodbrain barrier integrity.


Quantification in clinical fluorodeoxyglucose positron emission tomography.
Positron emission tomography (PET) is increasingly used clinically to provide functional information on disease processes, especially in oncology using the glucose analogue 2-[18F]fluoro-2-deoxy-D-glucose (F-FDG). In the clinical setting it has become standard practice to use simplified imaging protocols compared to the often complex methods developed for research using PET. This is partly due to scarcity of resources but also for reasons of patient comfort and compliance, and not least expense and patient throughput. Fortunately the resulting loss in information can be justified to some extent on the grounds that in clinical PET it is usually relative rather than absolute metabolic rates that are of interest. Nonetheless, there remain unresolved questions of how best to perform quantification in clinical PET.


Sustained expression of miR-26a promotes chromosomal instability and tumorigenesis through regulation of CHFR.
MicroRNA 26a (miR-26a) reduces cell viability in several cancers, indicating that miR-26a could be used as a therapeutic option in patients. We demonstrate that miR-26a not only inhibits G1-S cell cycle transition and promotes apoptosis, as previously described, but also regulates multiple cell cycle checkpoints. We show that sustained miR-26a over-expression in both breast cancer (BC) cell lines and mouse embryonic fibroblasts (MEFs) induces oversized cells containing either a single-large nucleus or two nuclei, indicating defects in mitosis and cytokinesis. Additionally, we demonstrate that miR-26a induces aneuploidy and centrosome defects and enhances tumorigenesis. Mechanistically, it acts by targeting G1-S transition genes as well as genes involved in mitosis and cytokinesis such as CHFR, LARP1 and YWHAE. Importantly, we show that only the re-expression of CHFR in miR-26a over-expressing cells partially rescues normal mitosis and impairs the tumorigenesis exerted by miR-26a, indicating that CHFR represents an important miR-26a target in the regulation of such phenotypes. We propose that miR-26a delivery might not be a viable therapeutic strategy due to the potential deleterious oncogenic activity of this miRNA.


Self-administration of agonists selective for dopamine D2, D3, and D4 receptors by rhesus monkeys.
Dopamine receptor mechanisms are believed to play a role in the reinforcing effects of cocaine and other drugs of abuse. The lack of receptor-selective agonists has made it difficult to determine the role of the individual dopamine receptors in mediating these reinforcing effects. In this study, rhesus monkeys with a history of intravenous cocaine self-administration were tested for the reinforcing effects of several D(3)-preferring agonists, a D(2)-preferring agonist, and a D(4) agonist. The D(2)-preferring agonist did not maintain responding in any monkeys, and the D(4) agonist was self-administered at low rates, just above those maintained by saline, in one monkey. The D(3)-preferring agonists were self-administered by approximately half of the animals, although at lower rates than cocaine. These results indicate that the apparent limited reinforcing effectiveness of D(2)-like agonists requires activity at D(3) receptors. Previous data from this laboratory and others also suggest that these drugs may not serve as reinforcers directly; the behavior may be maintained by response-contingent delivery of stimuli previously paired with cocaine. The ability of drug-related stimuli to maintain responding apparently differs among monkeys and other organisms, and may be related to individual differences in drug-taking behavior in humans.


A Delphi study to identify the core components of nurse to nurse handoff.
The aim of this study was to identify the core components of nurse-nurse handoffs. Patient handoffs involve a process of passing information, responsibility and control from one caregiver to the next during care transitions. Around the globe, ineffective handoffs have serious consequences resulting in wrong treatments, delays in diagnosis, longer stays, medication errors, patient falls and patient deaths. To date, the core components of nurse-nurse handoff have not been identified. This lack of identification is a significant gap in moving towards a standardized approach for nurse-nurse handoff. Mixed methods design using the Delphi technique. From May 2016 - October 2016, using a series of iterative steps, a panel of handoff experts gave feedback on the nurse-nurse handoff core components and the content in each component to be passed from one nurse to the next during a typical unit-based shift handoff. Consensus was defined as 80% agreement or higher. After three rounds of participant review, 17 handoff experts with backgrounds in clinical nursing practice, academia and handoff research came to consensus on the core components of handoff: patient summary, action plan and nurse-nurse synthesis. This is the first study to identify the core components of nurse-nurse handoff. Subsequent testing of the core components will involve evaluating the handoff approach in a simulated and then actual patient care environment. Our long-term goal is to improve patient safety outcomes by validating an evidence-based handoff framework and handoff curriculum for pre-licensure nursing programmes that strengthen the quality of their handoff communication as they enter clinical practice.


Structure of a thyroid hormone receptor DNA-binding domain homodimer bound to an inverted palindrome DNA response element.
Thyroid hormone receptor (TR), as a member of the nuclear hormone receptor family, can recognize and bind different classes of DNA response element targets as either a monomer, a homooligomer, or a heterooligomer. We report here the first crystal structure of a homodimer TR DNA-binding domain (DBD) in complex with an inverted repeat class of thyroid response element (TRE). The structure shows a nearly symmetric structure of the TR DBD assembled on the F2 TRE where the base recognition contacts in the homodimer DNA complex are conserved relative to the previously published structure of a TR-9-cis-retinoic acid receptor heterodimer DNA complex. The new structure also reveals that the T-box region of the DBD can function as a structural hinge that enables a large degree of flexibility in the position of the C-terminal extension helix that connects the DBD to the ligand-binding domain. Although the isolated TR DBDs exist as monomers in solution, we have measured highly cooperative binding of the two TR DBD subunits onto the inverted repeat DNA sequence. This suggests that elements of the DBD can influence the specific TR oligomerization at target genes, and it is not just interactions between the ligand-binding domains that are responsible for TR oligomerization at target genes. Mutational analysis shows that intersubunit contacts at the DBD C terminus account for some, but not all, of the cooperative homodimer TR binding to the inverted repeat class TRE.


ACOG Committee Opinion no. 599: Committee on Adoscent Health Care: Adolescent confidentiality and electronic health records.
Confidentiality concerns are heightened during adolescence, and these concerns can be a critical barrier to adolescents in receiving appropriate health care. Health care providers caring for minors should be aware of federal and state laws that affect confidentiality. State statutes on the rights of minors to consent to health care services vary by state, and health care providers should be familiar with the regulations that apply to their practice. Parents and adolescents should be informed, both separately and together, that the information each of them shares with the health care provider will be treated as confidential, and of any restrictions to the confidential nature of the relationship. Health care providers and institutions establishing an electronic health record (EHR) system should consider systems with adolescent-specific modules that can be customized to accommodate the confidentiality needs related to minor adolescents and comply with the requirements of state and federal laws. If the EHR system does not allow for procedures to maintain adolescent confidentiality, the health care provider or staff should inform the patient that parents will have access to the records, and the patient should be given the option for referral to a health care provider who is required to provide confidential care, such as one who participates in the Title X family planning program.


Absence of dysplasia in the excised cervix by a loop electrosurgical excision procedure in the treatment of cervical intraepithelial neoplasia.
Absence of dysplasia in the excised specimen following loop electrosurgical excision procedure (LEEP) for treatment of cervical intraepithelial neoplasia (CIN) 2/3 is an occasional finding of uncertain clinical significance. We evaluated several factors including age, liquid-based Pap (LBP) test, human papillomavirus (HPV) load before treatment, and HPV typing as predictors for absence of dysplasia. Absence of dysplasia in LEEP specimens was analyzed in terms of factors for recurrent disease after LEEP conization In total, 192 women (mean age, 39.3+/-8.4 years; range, 24 to 70 years) with biopsy-proven CIN 2/3 were treated by LEEP conization. Age, LBP test, histological grade, HPV load, and HPV DNA typing were evaluated as possible predictors of the absence of residual dysplasia or recurrent disease. Of the LEEP specimens, 34 (17.7%) showed no dysplasia in preoperative biopsies from patients with proven CIN 2/3. Low HPV load (<100 relative light units [RLU]) was significantly related to the absence of dysplasia in LEEP specimens, using logistic regression. Margin involvement and high HPV load (>/=400 RLU) were significant factors for recurrence. Absence of dysplasia in LEEP specimens occurred in 17.7% of our specimens. Prediction of the absence of dysplasia in LEEP specimens was associated with low HPV load. Residual/recurrent disease after LEEP was associated with a positive resection margin and high viral load, and was not associated with absence of dysplasia in LEEP specimens. Even if there is no dysplasia in conization specimens, close follow-up for residual/recurrent disease is needed.


Clinical significance of VEGF-A, -C and -D expression in esophageal malignancies.
Vascular endothelial growth factors (VEGF)-A, -C and -D are members of the proangiogenic VEGF family of glycoproteins. VEGF-A is known to be the most important angiogenic factor under physiological and pathological conditions, while VEGF-C and VEGF-D are implicated in the development and sprouting of lymphatic vessels, so called lymphangiogenesis. Local tumor progression, lymph node metastases and hematogenous tumor spread are important prognostic factors for esophageal carcinoma (EC), one of the most lethal malignancies throughout the world. We found solid evidence in the literature that VEGF expression contributes to tumor angiogenesis, tumor progression and lymph node metastasis in esophageal squamous cell carcinoma (SCC), and many authors could show a prognostic value for VEGF-assessment. In adenocarcinoma (AC) of the esophagus angiogenic properties are acquired in early stages, particularly in precancerous lesions like Barrett's dysplasia. However, VEGF expression fails to give prognostic information in AC of the esophagus. VEGF-C and -D were detected in SCC and dysplastic lesions, but not in normal mucosa of the esophagus. VEGF-C expression might be associated with lymphatic tumor invasion, lymph node metastases and advanced disease in esophageal SCC and AC. Therapeutic interference with VEGF signaling may prove to be a promising way of anti-angiogenic co-treatment in esophageal carcinoma. However, concrete clinical data are still pending.


[Animal echinococcosis in Italy: epidemiological update].
Cystic Echinococcosis (CE) is one of the most widespread parasitoses in the Mediterranean Region (MR). This is due to various factors, the most important being the close association between man, sheep and dogs in areas where open farming is practised. Although this disease has been known for several years and many studies have been carried out, nowadays in Italy there are no complete epidemiological data on its diffusion and distribution. The available data show that CE is mainly diffused in those districts where the sheep-dog cycle can be perpetuated, such as central and southern Italy, and the islands. Furthermore, no data are available on biomolecular characterisation of the strains of Echinococcus granulosus in Italy, apart form those in Sardinia, where the G1 (sheep-dog) and G7 (pig-dog) strains were recently isolated. One of the reasons why CE is a problem with no easy solution is undoubtedly the difficulty of making a certain diagnosis in the dog, the principal definitive host of E. granulosus.


Interactive Associations between PPARγ and PPARGC1A and Bisphosphonate-Related Osteonecrosis of the Jaw in Patients with Osteoporosis.
Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a rare but severe adverse effect that can occur as a result of bisphosphonate treatment. This study aimed to examine the relationship between PPARγ and PPARGC1A polymorphisms and the BRONJ development in female osteoporosis patients undergoing bisphosphonate treatment. We prospectively conducted this nested case-control study at the Ewha Womans University Mokdong Hospital between 2014 and 2018. We assessed five single-nucleotide polymorphisms (SNPs) of PPARγ and six SNPs of PPARGC1A and performed a multivariable logistic regression analysis to determine the independent risk factors for developing BRONJ. There were a total of 123 patients included in this study and 56 patients (45.5%) developed BRONJ. In the univariate analysis, PPARGC1A rs2946385 and rs10020457 polymorphisms were significantly associated with BRONJ (p = 0.034, p = 0.020, respectively), although the results were not statistically significant in the multivariable analysis. Patients with the combined genotypes of GG in both PPARγ rs1151999 and PPARGC1A rs2946385 showed a 3.03-fold higher risk of BRONJ compared to individuals with other genotype combinations after adjusting for confounders (95% confidence interval (CI): 1.01-9.11). Old age (≥70 years) and duration of bisphosphonate use (≥60 months) increased the risk of BRONJ. The area under the receiver operating characteristic curve for the predicted probability was 0.78 (95% CI: 0.69-0.87, p < 0.001), demonstrating a satisfactory level of discriminatory power. Our study elucidated that PPARγ and PPARGC1A polymorphisms were interactively associated with BRONJ development. These results have potential implications for tailoring personalized treatments for females undergoing bisphosphonate therapy for osteoporosis.


Multiset canonical correlations analysis and multispectral, truly multitemporal remote sensing data.
This paper describes two- and multiset canonical correlations analysis (CCA) for data fusion, multisource, multiset, or multitemporal exploratory data analysis. These techniques transform multivariate multiset data into new orthogonal variables called canonical variates (CVs) which, when applied in remote sensing, exhibit ever-decreasing similarity (as expressed by correlation measures) over sets consisting of 1) spectral variables at fixed points in time (R-mode analysis), or 2) temporal variables with fixed wavelengths (T-mode analysis). The CVs are invariant to linear and affine transformations of the original variables within sets which means, for example, that the R-mode CVs are insensitive to changes over time in offset and gain in a measuring device. In a case study, CVs are calculated from Landsat Thematic Mapper (TM) data with six spectral bands over six consecutive years. Both Rand T-mode CVs clearly exhibit the desired characteristic: they show maximum similarity for the low-order canonical variates and minimum similarity for the high-order canonical variates. These characteristics are seen both visually and in objective measures. The results from the multiset CCA R- and T-mode analyses are very different. This difference is ascribed to the noise structure in the data. The CCA methods are related to partial least squares (PLS) methods. This paper very briefly describes multiset CCA-based multiset PLS. Also, the CCA methods can be applied as multivariate extensions to empirical orthogonal functions (EOF) techniques. Multiset CCA is well-suited for inclusion in geographical information systems (GIS).


Immediate implants and immediate loading in periodontally compromised patients-a 3-year prospective clinical study.
To avoid the necessity of a removable provisional prosthesis, and therefore preserve the patient's functional outcome, esthetics, and quality of life, a clinical protocol was developed to approach periodontally compromised patients presenting a full-arch irreversibly lost dentition: full-arch extraction and immediate replacement with a provisional acrylic resin implant-supported fixed partial denture (FPD). A total of 23 periodontally compromised patients (11 women, 12 men; 4 smokers, 4 controlled diabetics) were included in this study. Pretreatment casts were taken and vertical dimension of occlusion was determined. In most patients, 6 Straumann implants were distributed along the arch according to the surgical guide or bone availability, with the most distal ones in the maxilla slightly tilted so they could emerge more distally. A total of 168 implants (146 Straumann, 10 Nobel Biocare, 8 Biomet 3i, and 4 Lifecore) were placed (83 in the maxilla, 85 in the mandible). Of those in the maxilla, 74 were loaded immediately (implant stability quotient mentor [ISQm] > 70) and 9 placed with delayed loading (ISQm =/< 70). Of the 85 implants placed in the mandible, all were loaded immediately (ISQm > 70). If an FPD had not been fabricated already, impressions were taken during surgery to do so. The prosthesis was then adapted (cemented or screwed) to the 6 implants within the first 48 hours postsurgery. After 2 months, definitive impressions were taken, and a definitive porcelain-fused-to-metal implant-supported 12-element FPD was fabricated and cemented or screwed to all 6 implants. Of the 168 implants, 108 were immediate implants and 159 immediately loaded. Only 2 implants (1 in the mandible, 1 in the maxilla) did not osseointegrate. This yields a 3-year cumulative survival rate of 98.74% (98.65% in the maxilla, 98.82% in the mandible). From a total of 26 immediately loaded prostheses (12 in the maxilla, 14 in the mandible), 6 were cemented and 20 screw-retained. The 3-year cumulative survival rate was 100%. Immediate loading in mandibular and maxillary periodontally compromised patients presents itself as a predictable technique with a 100% cumulative survival rate for provisional and definitive prosthetic rehabilitations.


Bacillus licheniformis in geogenic dust induces inflammation in respiratory epithelium.
Exposure to environmental geogenic (or earth-derived) dust can lead to more frequent and severe infections in the human airway. Particulate matter < 10 µm (PM10) is the component of air pollution that is commonly associated with the exacerbation of respiratory diseases. We have previously demonstrated that mice exposed to geogenic dust PM10 experienced an exacerbation of inflammatory responses to influenza A virus. Whether geogenic dust PM10 also exacerbates respiratory bacterial infection is not yet known, nor are the components of the dust that drive these responses. We treated airway bronchial epithelial cells (NuLi-1) with UV-irradiated geogenic dust PM10 from six remote Western Australian towns. High levels of IL-6 and IL-8 production were observed, as well as persistent microbial growth. 16 S rRNA sequencing of the growth identified the microbe as Bacillus licheniformis, a spore-forming, environmentally abundant bacterium. We next investigated the interaction of B. licheniformis with respiratory epithelium in vitro to determine whether this exacerbated infection with a bacterial respiratory pathogen (non-typeable Haemophilus influenzae, NTHi). Heat treatment (100 °C) of all PM10 samples eliminated B. licheniformis contamination and reduced epithelial inflammatory responses, suggesting that heat-labile and/or microbial factors were involved in the host response to geogenic dust PM10. We then exposed NuLi-1 epithelium to increasing doses of the isolated Bacillus licheniformis (multiplicity of infection of 10:1, 1:1 or 0.1:1 bacteria: cells) for 1, 3, and 24 h. B. licheniformis and NTHi infection (association and invasion) was assessed using a standard gentamicin survival assay, and epithelial release of IL-6 and IL-8 was measured using a bead based immunoassay. B. licheniformis was cytotoxic to NuLi-1 cells at 24 h. At 3 h post-challenge, B. licheniformis elicited high IL-6 and IL-8 inflammatory responses from NuLi-1 cells compared with cells treated with heat-treated geogenic dust PM10 (p < 0.0001). Whilst treatment of cells with B. licheniformis increased inflammation, this did not make the cells more susceptible to NTHi infection. This study highlights that geogenic dust PM10 can harbour viable bacterial spores that induce inflammation in respiratory epithelium. The impact on respiratory health from inhalation of bacterial spores in PM10 in arid environments may be underestimated. Further investigation into the contribution of B. licheniformis and the wider dust microbiome to respiratory infection is warranted.


Is Oxytocin Application for Autism Spectrum Disorder Evidence-Based?
Autism spectrum disorder (ASD) is characterized by persistent deficits within two core symptom domains: social communication and restricted, repetitive behaviors. Although numerous studies have reported psychopharmacological treatment outcomes for the core symptom domains of ASD, there are not enough studies on fundamental treatments based on the etiological pathology of ASD. Studies on candidate medications related to the pathogenesis of ASD, such as naltrexone and secretin, were conducted, but the results were inconclusive. Oxytocin has been identified as having an important role in maternal behavior and attachment, and it has been recognized as a key factor in the social developmental deficit seen in ASD. Genetic studies have also identified associations between ASD and the oxytocin pathway. As ASD has its onset in infancy, parents are willing to try even experimental or unapproved treatments in an effort to avoid missing the critical period for diagnosis and treatment, which can place their child in an irreversible state. While therapeutic application of oxytocin for ASD is in its early stages, we have concluded that oxytocin would be a promising therapeutic substance via a thorough literature review focusing on the following: the relationship between oxytocin and sociality; single nucleotide polymorphisms as a biological marker of ASD; and validity verification of oxytocin treatment in humans. We also reviewed materials related to the mechanism of oxytocin action that may support its potential application in treating ASD.


Molecular insights into hypomineralized enamel.
Hypomineralized enamel may be found in connection with the condition molar incisor hypomineralization (MIH), which has a prevalence of around 15% in most parts of the world. Molar incisor hypomineralization is associated with extensive objective and subjective problems, such as hypersensitivity of the affected teeth, enamel breakdown, and problems with retention of restorations. The etiology behind MIH has not yet been elucidated, but a number of possible factors, which affect the same or different functions of ameloblasts during their different stages of maturation, have been suggested. The aim of this study was to utilize multi-nuclear, solid-state nuclear magnetic resonance (ss-NMR) and time-of-flight secondary ion mass spectroscopy (ToF-SIMS) to elucidate any differences, at a molecular level, between enamel powder prepared from normal, healthy teeth and enamel powder prepared from teeth diagnosed with MIH. 31 P and 23 Na ss-NMR confirmed the presence of HPO42- and two different Na+ sites in hypomineralized enamel, suggesting a heterogeneous chemical composition. The content of organic components was higher in hypomineralized enamel, as shown by both 13 C ss-NMR and ToF-SIMS, indicating the presence of higher numbers of proteins and phospholipids. The interplay between both is necessary for the formation and mineralization of enamel, which might be disturbed or halted in hypomineralized enamel.


Molecular characterization of new natural hybrids of Saccharomyces cerevisiae and S. kudriavzevii in brewing.
We analyzed 24 beer strains from different origins by using PCR-restriction fragment length polymorphism analysis of different gene regions, and six new Saccharomyces cerevisiae x Saccharomyces kudriavzevii hybrid strains were found. This is the first time that the presence in brewing of this new type of hybrid has been demonstrated. From the comparative molecular analysis of these natural hybrids with respect to those described in wines, it can be concluded that these originated from at least two hybridization events and that some brewing hybrids share a common origin with wine hybrids. Finally, a reduction of the S. kudriavzevii fraction of the hybrid genomes was observed, but this reduction was found to vary among hybrids regardless of the source of isolation. The fact that 25% of the strains analyzed were discovered to be S. cerevisiae x S. kudriavzevii hybrids suggests that an important fraction of brewing strains classified as S. cerevisiae may correspond to hybrids, contributing to the complexity of Saccharomyces diversity in brewing environments. The present study raises new questions about the prevalence of these new hybrids in brewing as well as their contribution to the properties of the final product.


Pearls and pitfalls in clinical neuroradiology.
Imaging technology continues to advance at a rapid pace. Central nervous system imaging, in particular, is an invaluable tool for the practicing clinical neurologist. Although computed tomography (CT) was once the procedure of choice for neuroimaging, CT has been surpassed by magnetic resonance imaging (MRI) because of the latter's greater sensitivity. MRI exquisitely demonstrates brain and spine pathology by means of its multiplanar capability and its ability to generate different tissue contrast with various pulse sequences. However, artifacts as well as normal anatomic variants can mimic significant CNS pathology. An understanding of the technology involved in producing and interpreting these images is necessary in order that protocols can be tailored for each individual patient and that unimportant findings are not misinterpreted as being pathologic. This article will present cases illustrating some of the common neuroimaging artifacts and normal variants as well as important differential diagnoses of certain imaging findings.


Category-specific naming deficit identified by intraoperative stimulation mapping and postoperative neuropsychological testing. Case report.
Category-specific naming deficits and differential brain activation patterns have been reported in patients naming living as opposed to nonliving objects. The authors report on a case in which they used preoperative functional magnetic resonance (fMR) imaging, intraoperative electrocortical stimulation mapping (ESM), and postoperative neuropsychological testing to map language function. Using the latter two modalities, the authors identified a specific locus for category-specific naming in the posterior inferior temporal lobe, presumably a part of the basal temporal language area. Preoperative fMR imaging findings revealed the presence of a language area in the inferior temporal lobe; intraoperative ESM results indicated that this cortical area may be category specific for living objects; and after resection of the area, the results of postoperative neuropsychological testing confirmed that the patient made significantly more errors while naming living objects compared with nonliving ones (p < 0.001), independent of the effects of word frequency and with an intact system of object recognition and comprehension. These authors are the first to identify a specific and well-localized area of category-specific naming in the inferior temporal lobe and to demonstrate congruence of intraoperative and postoperative category-specific naming deficits. They also emphasize the roles of preoperative and intraoperative testing in predicting clinical outcomes.