[Radiotherapy for Alleviation of Paraparesis due to Leptomeningeal and Cauda Equina Metastasis of HER2-Positive Breast Cancer: A Case Report].
Leptomeningeal metastasis is a rare entity and its diagnosis is often difficult. Moreover, evidence-based therapeutic strategies have not yet been established. A 52-year-old woman presented with high fever and was diagnosed with bacterial meningitis at first examination;although her fever was alleviated, she experienced motor weakness in both of her lower extremities. Ga scintigraphy highlighted the hot-spot areas of the disease in the cranial bone. She was then transferred to our department. Open biopsy of the skull showed metastasis of the cancer. Chest CT results indicated right breast cancer and Gd-DTPA imaging showed obvious enhancement of the pia mater around the conus medullaris and cauda equina. However, cerebrospinal fluid(CSF)cytological examination did not show the presence of any positive cells;consequently, mastectomy was performed in the thoracic surgical department. The severity of paraparesis and pain in her legs increased;however, repeat MRI 1 month later showed no evidence of any change. Therefore, we performed biopsy of the cauda equina and arachnoid lesions. The pathological diagnosis was metastasis of breast cancer with positive human epidermal growth factor receptor 2(HER2)immunological staining. The results of a repeat cytological examination of the CSF during the surgery were negative. Local radiotherapy(25 Gy/5 Fr)as a monotherapy was selected for the patient, because her family did not approve of the combination of radiotherapy and chemotherapy. The severity of both paraparesis and limb pain decreased immediately after the radiotherapy.


A novel, nonclassical MHC class I molecule specific to the common chimpanzee.
All expressed human MHC class I genes (HLA-A, -B, -C, -E, -F, and -G) have functional orthologues in the MHC of the common chimpanzee (Pan troglodytes). In contrast, a nonclassical MHC class I gene discovered in the chimpanzee is not present in humans or the other African ape species. In exons and more so in introns, this Patr-AL gene is similar to the expressed A locus in the orangutan, Popy-A, suggesting they are orthologous. Patr-AL/Popy-A last shared a common ancestor with the classical MHC-A locus >20 million years ago. Population analysis revealed little Patr-AL polymorphism: just three allotypes differing only at residues 52 and 91. Patr-AL is expressed in PBMC and B cell lines, but at low level compared with classical MHC class I. The Patr-AL polypeptide is unusually basic, but its glycosylation, association with beta(2)-microglobulin, and antigenicity at the cell surface are like other MHC class I. No Patr-AL-mediated inhibition of polyclonal chimpanzee NK cells was detected. The Patr-AL gene is present in 50% of chimpanzee MHC haplotypes, correlating with presence of a 9.8-kb band in Southern blots. The flanking regions of Patr-AL contain repetitive/retroviral elements not flanking other class I genes. In sequenced HLA class I haplotypes, a similar element is present in the A*2901 haplotype but not the A*0201 or A*0301 haplotypes. This element, 6 kb downstream of A*2901, appears to be the relic of a human gene related to Patr-AL. Patr-AL has characteristics of a class I molecule of innate immunity with potential to provide common chimpanzees with responses unavailable to humans.


Near infrared spectroscopic analysis of single malt Scotch whisky on an optofluidic chip.
Standardization and quality monitoring of alcoholic beverages is an important issue in the liquor production industry. Various spectroscopic techniques have proved useful for tackling this problem. An ideal sensing device for alcoholic beverages should be able to detect the quality of alcohol with a small amount of sample at a low acquisition time using a portable and easy to use device. We propose the use of near infra-red spectroscopy on an optofluidic chip for quality monitoring of single malt Scotch whisky. This is chip upon which we have previously realized waveguide confined Raman spectroscopy. Analysis on this alignment-free, portable chip may be performed in only 2 seconds with a sample volume of only 20 µl. Using a partial least square (PLS) calibration, we demonstrate that the alcohol content in the beverage may be predicted to within a 1% prediction error. Principal component analysis (PCA) was employed for successful classification of whiskies based upon their age, type and cask. The prospect of implementing an optofluidic analogue of a conventional fiber based spectroscopic probe allows a rapid analysis of alcoholic beverages with dramatically reduced sample volumes.


Development of high performance liquid chromatography-ultraviolet detection method for screening mebendazole, clorsulon, diaveridine, and tolfenamic acid in animal-based food samples.
This study focused on the detection and validation of the residues of the four veterinary drugs, mebendazole, clorsulon, diaveridine, and tolfenamic acid, using high performance liquid chromatography (HPLC) and an ultraviolet (UV) detector. Utilizing C18 column as a stationary phase and applying appropriate mobile phases to each analysis according to the properties of the analytes, target compounds in food samples were successfully detected and separated within 15-50 min. Additionally, in order to optimize detection, liquid-liquid extraction (LLE) and purification steps were established to minimize the endogenous peaks and their interferences. The method was validated through testing of linearity, accuracy, precision, the limit of detection (LOD) and the limit of quantification (LOQ). The LOQ levels of the four drugs were lower than the maximum residual limit, and the coefficient of determination (R(2) ) was over 0.99. The recovery results ranged from 82.3-105.2%, 79.3-83.3%, 79.4-86.0%, and 81.7-88.5% with relative standard deviations lower than 20% for mebendazole, clorsulon, diaveridine, and tolfenamic acid, respectively, corresponding to the CODEX guideline. This proposed method reduces costs and enables easier application in rural or remote areas where testing facilities or instruments often are unavailable.


Application of a new portable microscopic somatic cell counter with disposable plastic chip for milk analysis.
The somatic cell count (SCC) is one of the international standards for monitoring milk quality, and it is a useful indicator of mastitis. The current reference method for determining the SCC in raw milk is direct microscopic analysis, but this method requires well-trained staff to maintain its accuracy and reproducibility. To overcome these inconveniences, we developed a portable system (the C-reader system) that utilizes the capillary flow of a microfluidic chamber by surface modification of the hydrophilicity. The microfluidic technology of disposable microchips allows for low consumption of reagents, and a combination of ready-to-use reagents makes the daily work easier. The repeatability test of the C-reader using 10 composite bovine milk samples satisfied the recommended values for SCC equipment. In addition, an acceptable accuracy level of the natural logarithmic-transformed SCC [ln(SCC/1,000): +/- 0.059 to 0.112] was achieved using composite raw milk samples and various somatic cell standard solutions from the American Eastern Laboratory and the Korean National Veterinary Research and Quarantine Service. After testing 875 composite milk samples, the C-reader showed a high correlation coefficient (R2 = 0.935 to 0.964) and a low mean difference value in log-transformed SCC (-0.088 to 0.004) compared with 3 automatic commercialized somatic cell counters (Fossomatic 4000, Somacount 150, and Somascope). In conclusion, the C-reader system is a new, easy-to-use automatic on-farm method with acceptable repeatability and accuracy for measuring SCC in large dairies and smaller laboratories.


Direct diagnostic testing of SARS-CoV-2 without the need for prior RNA extraction.
The COVID-19 pandemic has resulted in an urgent global need for rapid, point-of-care diagnostic testing. Existing methods for nucleic acid amplification testing (NAAT) require an RNA extraction step prior to amplification of the viral RNA. This step necessitates the use of a centralized laboratory or complex and costly proprietary cartridges and equipment, and thereby prevents low-cost, scalable, point-of-care testing. We report the development of a highly sensitive and robust, easy-to-implement, SARS-CoV-2 test that utilizes isothermal amplification and can be run directly on viral transport media following a nasopharyngeal swab without the need for prior RNA extraction. Our assay provides visual results in 30 min with 85% sensitivity, 100% specificity, and a limit of detection (LoD) of 2.5 copies/μl, and can be run using a simple heat block.


Non-ATP competitive protein kinase inhibitors.
Protein kinases represent an attractive target in oncology drug discovery. Most of kinase inhibitors are ATP-competitive and are called type I inhibitors. The ATP-binding pocket is highly conserved among members of the kinase family and it is difficult to find selective agents. Moreover, the ATP-competitive inhibitors must compete with high intracellular ATP levels leading to a discrepancy between IC50s measured by biochemical versus cellular assays. The non-ATP competitive inhibitors, called type II and type III inhibitors, offer the possibility to overcome these problems. These inhibitors act by inducing a conformational shift in the target enzyme such that the kinase is no longer able to function. In the DFG-out form, the phenylalanine side chain moves to a new position. This movement creates a hydrophobic pocket available for occupation by the inhibitor. Some common features are present in these inhibitors. They contain a heterocyclic system that forms one or two hydrogen bonds with the kinase hinge residue. They also contain a hydrophobic moiety that occupies the pocket formed by the shift of phenylalanine from the DFG motif. Moreover, all the inhibitors bear a hydrogen bond donor-acceptor pair, usually urea or amide, that links the hinge-binding portion to the hydrophobic moiety and interacts with the allosteric site. Examples of non ATP-competitive inhibitors are available for various kinases. In this review small molecules capable of inducing the DFG-out conformation are reported, especially focusing on structural feature, SAR and biological properties.


In vivo production and function of IL-12 p40 homodimers.
The bioactivity of IL-12 is mediated by heterodimers of disulfide-linked p35 and p40 protein subunits. Homodimeric p40 competes with heterodimer for binding to the high affinity IL-12R and inhibits IL-12 bioactivity in vitro. However, the production and significance of p40 homodimer as a cytokine antagonist in vivo have not been determined. In these studies, we observed increased amounts of both IL-12 p40 monomer and homodimer in the serum of C57BL/6 mice following injection of 300 microg of Salmonella enteritidis LPS. Homodimer constituted between 20 and 40% of the total circulating p40 in endotoxemic sera, as confirmed by both Sephacryl S-100 gel filtration and p40-specific immunoprecipitation analyses. Similar relative amounts of homodimer and monomer were observed in endotoxemic BALB/c, C57BL/6, IFN-gamma-deficient C57BL/6 mice and C57BL/6 mice previously infected with bacille Calmette-Guérin. To determine whether IL-12 p40 homodimer was capable of antagonizing IL-12-dependent IFN-gamma responses in vivo, we pretreated C57BL/6 mice with purified rIL-12 p40 homodimer before i.p. challenge with endotoxin. Mice treated with 40 to 80 microg of p40 homodimer generated 80 to 82% less circulating IFN-gamma during acute endotoxemia than saline controls (p < 0.01). We conclude that p40 homodimer is produced in vivo, functions as a cytokine antagonist in the context of the mouse model of acute endotoxemia, and may represent a novel form of self-regulating cytokine response.


Filling the gaps: Preparing nurse practitioners for hospitalist practice.
Over the last 20 years, the emergence of the hospitalist has changed the face of medicine. Hospitalists may serve as either general or specialty-focused providers caring for acutely ill patients in the hospital setting. As the demands and constraints of hospital-specific patient management have continued to grow, an increased need for inclusion of nurse practitioners (NP) into current hospitalist staffing models has occurred. A hospitalist-focused educational model has been developed to better prepare NP students for a variety of hospitalist roles after graduation. A hospitalist focused masters-level curriculum is discussed, as well as opportunities for advanced hospitalist education with post-graduate opportunities.


Steroid receptor RNA activator protein binds to and counteracts SRA RNA-mediated activation of MyoD and muscle differentiation.
The steroid receptor RNA activator (SRA) has the unusual property to function as both a non-coding RNA (ncRNA) and a protein SRAP. SRA ncRNA is known to increase the activity of a range of nuclear receptors as well as the master regulator of muscle differentiation MyoD. The contribution of SRA to either a ncRNA or a protein is influenced by alternative splicing of the first intron, the retention of which disrupts the SRAP open reading frame. We reported here that the ratio between non-coding and coding SRA isoforms increased during myogenic differentiation of human satellite cells but not myotonic dystrophy patient satellite cells, in which differentiation capacity is affected. Using constructs that exclusively produce SRA ncRNA or SRAP, we demonstrated that whereas SRA ncRNA was indeed an enhancer of myogenic differentiation and myogenic conversion of non-muscle cells through the co-activation of MyoD activity, SRAP prevented this SRA RNA-dependant co-activation. Interestingly, the SRAP inhibitory effect is mediated through the interaction of SRAP with its RNA counterpart via its RRM-like domain interacting with the functional sub-structure of SRA RNA, STR7. This study thus provides a new model for SRA-mediated regulation of MyoD transcriptional activity in the promotion of normal muscle differentiation, which takes into account the nature of SRA molecules present.


Mannose antagonizes GSDME-mediated pyroptosis through AMPK activated by metabolite GlcNAc-6P.
Pyroptosis is a type of regulated cell death executed by gasdermin family members. However, how gasdermin-mediated pyroptosis is negatively regulated remains unclear. Here, we demonstrate that mannose, a hexose, inhibits GSDME-mediated pyroptosis by activating AMP-activated protein kinase (AMPK). Mechanistically, mannose metabolism in the hexosamine biosynthetic pathway increases levels of the metabolite N-acetylglucosamine-6-phosphate (GlcNAc-6P), which binds AMPK to facilitate AMPK phosphorylation by LKB1. Activated AMPK then phosphorylates GSDME at Thr6, which leads to blockade of caspase-3-induced GSDME cleavage, thereby repressing pyroptosis. The regulatory role of AMPK-mediated GSDME phosphorylation was further confirmed in AMPK knockout and GSDMET6E or GSDMET6A knock-in mice. In mouse primary cancer models, mannose administration suppressed pyroptosis in small intestine and kidney to alleviate cisplatin- or oxaliplatin-induced tissue toxicity without impairing antitumor effects. The protective effect of mannose was also verified in a small group of patients with gastrointestinal cancer who received normal chemotherapy. Our study reveals a novel mechanism whereby mannose antagonizes GSDME-mediated pyroptosis through GlcNAc-6P-mediated activation of AMPK, and suggests the utility of mannose supplementation in alleviating chemotherapy-induced side effects in clinic applications.


Ma-huang strikes again: ephedrine nephrolithiasis.
Ephedrine and its metabolites are naturally occurring alkaloids that can be derived from evergreens worldwide and have been used as medicinals for hundreds of years. Because they have "real" pharmacological alpha and beta catecholamine effects and are "natural" products, the alternative medicine industry has popularized them for multiple uses, including asthma, weight loss, energy and sexual enhancement, and euphoria. Several recent reviews have documented the dangerous nature of using these "drugs" unsupervised, including multiple deaths, and the FDA is currently reviewing ephedrine's use in the alternative medicine industry. We report a new toxicity, ephedrine nephrolithiasis, in a patient using an energy supplement, Ma-Huang extract, which contains ephedrine. Although previously not reported, the Louis C. Herring and Company kidney stone database show that this is an endemic complication of ephedrine with hundreds of previous episodes. Using gas chromatography (GC) mass spectrometry, we were able to positively identify the chemical structure of our patient's stone, as well as other similar stones from Louis Herring, as containing ephedrine, norephedrine, and pseudoephedrine.


Skewed megakaryopoiesis in human induced pluripotent stem cell-derived haematopoietic progenitor cells harbouring calreticulin mutations.
Somatic mutations in the calreticulin (CALR) gene have been found in most patients with JAK2- and MPL-unmutated Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). It has recently been shown that mutant CALR constitutively activates the thrombopoietin receptor MPL and, thus, plays a causal role in the development of MPNs. However, the roles of mutant CALR in human haematopoietic cell differentiation remain predominantly elusive. To examine the impact of the 5-base insertion mutant CALR gene (Ins5) on haematopoietic cell differentiation, we generated induced pluripotent stem cells from an essential thrombocythaemia (ET) patient harbouring a CALR-Ins5 mutation and from a healthy individual (WT). Megakaryopoiesis was more prominent in Ins5-haematopoietic progenitor cells (Ins5-HPCs) than in WT-HPCs, implying that the system recapitulates megakaryocytosis observed in the bone marrow of CALR-mutant ET patients. Ins5-HPCs exhibited elevated expression levels of GATA1 and GATA2, suggesting a premature commitment to megakaryocytic differentiation in progenitor cells. We also demonstrated that 3-hydroxy anagrelide markedly perturbed megakaryopoiesis, but not erythropoiesis. Collectively, we established an in vitro model system that recapitulates megakaryopoiesis caused by mutant CALR. This system can be used to validate therapeutic compounds for MPN patients harbouring CALR mutations and in detailed studies on mutant CALR in human haematological cell differentiation.


Different processes lead to similar patterns: a test of codivergence and the role of sea level and climate changes in shaping a southern temperate freshwater assemblage.
Understanding how freshwater assemblages have been formed and maintained is a fundamental goal in evolutionary and ecological disciplines. Here we use a historical approach to test the hypothesis of codivergence in three clades of the Chilean freshwater species assemblage. Molecular studies of freshwater crabs (Aegla: Aeglidae: Anomura) and catfish (Trichomycterus arealatus: Trichomycteridae: Teleostei) exhibited similar levels of genetic divergences of mitochondrial lineages between species of crabs and phylogroups of the catfish, suggesting a shared evolutionary history among the three clades in this species assemblage. A phylogeny was constructed for Trichomycterus areolatus under the following best-fit molecular models of evolution GTR + I + R, HKY + I, and HKY for cytochrome b, growth hormone, and rag 1 respectively. A GTR + I + R model provided the best fit for both 28S and mitochondrial loci and was used to construct both Aegla phylogenies. Three different diversification models were observed and the three groups arose during different time periods, from 2.25 to 5.05 million years ago (Ma). Cladogenesis within Trichomycterus areolatus was initiated roughly 2.25 Ma (Late Pliocene-Early Pleistocene) some 1.7-2.8 million years after the basal divergences observed in both Aegla clades. These results reject the hypothesis of codivergence. The similar genetic distances between terminal sister-lineages observed in these select taxa from the freshwater Chilean species assemblage were formed by different processes occurring over the last ~5.0 Ma. Dramatic changes in historic sea levels documented in the region appear to have independently shaped the evolutionary history of each group. Our study illustrates the important role that history plays in shaping a species assemblage and argues against assuming similar patterns equal a shared evolutionary history.


Attitudes Toward Deafness Affect Impressions of Young Adults With Cochlear Implants.
This study continues a project on speech-based impressions of early-implanted cochlear implant (CI) users. It examined relationships between listeners' attitudes or personal traits and how they judged CI users upon hearing their speech. College students with typical hearing (TH) listened to speech samples from CI users and TH young adults and rated the speakers' personalities and attractiveness as friends. CI users varied in speech intelligibility (proportion of words recognized by transcribers in prior work). Overall, listeners rated TH speakers most positively, CI users with high intelligibility (CI-Hi) as intermediate, and CI users with lower intelligibility (CI-Lo) most negatively. Listeners also completed questionnaires about their personalities, values, and attitudes toward deafness. Listeners with more positive attitudes toward deaf people rated both CI user groups more positively, and listeners whose personality and values questionnaires showed more tolerance and openness to interpersonal differences rated CI-Lo speakers more positively. These patterns underline the social importance of CI users' speech intelligibility while bringing to light the role of listeners' pre-existing attitudes in forming negative first impressions, which could impact CI users' friendships with TH peers. Because listeners' attitudes reflected ignorance about deaf people's abilities, this study calls for increased education about deafness for TH students.


Cetuximab and biomarkers in non-small-cell lung carcinoma.
Cancer progression is a highly complex process that is driven by a constellation of deregulated signaling pathways and key molecular events. In non-small-cell lung cancer (NSCLC), as in several other cancer types, the epidermal growth factor receptor (EGFR) and its downstream signaling components represent a key axis that has been found not only to trigger cancer progression but also to support advanced disease leading to metastasis. Two major therapeutic approaches comprising monoclonal antibodies and small molecule tyrosine kinase inhibitors have so far been used to target this pathway, with a combination of positive, negative, and inconsequential results, as judged by patient survival indices. Since these drugs are expensive and not all patients derive benefits from taking them, it has become both pertinent and paramount to identify biomarkers that can predict not only beneficial response but also resistance. This review focuses on the chimeric monoclonal antibody, cetuximab, its application in the treatment of NSCLC, and the biomarkers that may guide its use in the clinical setting. A special emphasis is placed on the EGFR, including its structural and mechanistic attributes.


Construction of Baculovirus-Inducible CRISPR/Cas9 Antiviral System Targeting BmNPV in Bombyx mori.
The silkworm Bombyx mori is an economically important insect. The sericulture industry is seriously affected by pathogen infections. Of these pathogens, Bombyx mori nucleopolyhedrovirus (BmNPV) causes approximately 80% of the total economic losses due to pathogen infections. We previously constructed a BmNPV-specific CRISPR/Cas9 silkworm line with significantly enhanced resistance to BmNPV. In order to optimize the resistance properties and minimize its impact on economic traits, we constructed an inducible CRISPR/Cas9 system for use in transgenic silkworms. We used the 39k promoter, which is induced by viral infection, to express Cas9 and the U6 promoter to express four small guide RNA targeting the genes encoding BmNPV late expression factors 1 and 3 (lef-1 and lef-3, respectively), which are essential for viral DNA replication. The system was rapidly activated when the silkworm was infected and showed considerably higher resistance to BmNPV infection than the wild-type silkworm. The inducible system significantly reduced the development effects due to the constitutive expression of Cas9. No obvious differences in developmental processes or economically important characteristics were observed between the resulting transgenic silkworms and wild-type silkworms. Adoption of this accurate and highly efficient inducible CRISPR/Cas9 system targeting BmNPV DNA replication will result in enhanced antivirus measures during sericulture, and our work also provides insights into the broader application of the CRISPR/Cas9 system in the control of infectious diseases and insect pests.


The coherent organization of mental life depends on mechanisms for context-sensitive gain-control that are impaired in schizophrenia.
There is rapidly growing evidence that schizophrenia involves changes in context-sensitive gain-control and probabilistic inference. In addition to the well-known cognitive disorganization to which these changes lead, basic aspects of vision are also impaired, as discussed by other papers on this Frontiers Research Topic. The aim of this paper is to contribute to our understanding of such findings by examining five central hypotheses. First, context-sensitive gain-control is fundamental to brain function and mental life. Second, it occurs in many different regions of the cerebral cortex of many different mammalian species. Third, it has several computational functions, each with wide generality. Fourth, it is implemented by several neural mechanisms at cellular and circuit levels. Fifth, impairments of context-sensitive gain-control produce many of the well-known symptoms of schizophrenia and change basic processes of visual perception. These hypotheses suggest why disorders of vision in schizophrenia may provide insights into the nature and mechanisms of impaired reality testing and thought disorder in psychosis. They may also cast light on normal mental function and its neural bases. Limitations of these hypotheses, and ways in which they need further testing and development, are outlined.


[Miniinvasive interventions in treatments of pancreatic cysts].
The article presents the results of surgical treatment of 58 patients with pancreatic cysts. An analysis of efficiency of various current miniinvasive surgical methods of treatment is given. Criteria of differential approach to the choice of the kind of miniinvasive intervention in pancreatic and parapancreatic cysts were formulated.


Viral enteritis in calves.
A complex community of bacteria, viruses, fungi, protists, and other microorganisms inhabit the gastrointestinal tract of calves and play important roles in gut health and disease. The viral component of the microbiome (the virome) is receiving increasing attention for its role in neonatal calf diarrhea (NCD). Rotavirus and coronavirus have for a long time been associated with NCD and commercial vaccines have been produced against these agents. Recently, several other viruses which may play a role in diarrhea have been discovered in calf fecal samples, mostly by sequence-based methods. These viruses include torovirus, norovirus, nebovirus, astrovirus, kobuvirus, and enterovirus. Most studies have involved epidemiologic investigations seeking to show association with diarrhea for each virus alone or in combination with potential pathogens. However, determining the contribution of these viruses to calf diarrhea has been challenging and much uncertainty remains concerning their roles as primary pathogens, co-infection agents, or commensals.


Rotating night shift work and nutrition of nurses and midwives.
Previous research points to some inappropriate nutritional habits among nurses working night shifts. However, the knowledge of specific nutritional components of their diet has been limited. In the present study, we aimed to investigate the association between rotating night shifts of nurses and midwives and their usual dietary intake of energy and nutrients. A cross-sectional study was conducted among 522 Polish nurses and midwives: 251 working rotating night shifts (i.e. working night shift followed by a day off on a subsequent day) and 271 day workers. Polish adaptation of the Food Frequency Questionnaire, regarding 151 food items, was used to assess the usual dietary energy and nutrient intake. Data on occupational history and potential confounders were collected via face-to-face interviews. Body weight, height, waist and hip circumference were measured. Linear regression models: univariate (crude) and multivariate (adjusted) were run, with the nutrient intake as dependent variables, night work characteristics, and important confounders. Among nurses and midwives working rotating night shifts, a significantly higher adjusted mean intake was found for the total energy (2005 kcal vs 1850 kcal) and total fatty acids (77.9 g vs 70.4 g) when compared to day workers, as well as for cholesterol (277 mg vs 258 mg), carbohydrates (266 g vs 244 g) and sucrose (55.8 g vs 48.6 g). Night shift work duration was inversely related to the consumption of calcium, phosphorus, vitamin A, vitamin C and % energy from proteins. The higher energy consumption may contribute to increase risk of overweight and obesity among nurses working night shifts.


[Experimental study on xenogenic acellular dermal matrix incorporated with silver].
To investigate the biological characteristics of xenogenic acellular dermal matrix( Xeno-ADM) incorporated with silver, and to observe its effect in grafting. Xeno-ADM was prepared with 0. 25% trypsin and 0. 5% triton X-100 , and then it was immersed in 2 g/L silver nitrate solution to prepare xeno-ADM incorporated with silver. The bacterial inhibitory effect of two kinds of xeno-ADM on burn wound was determined, and the histological characteristic of the wounds was observed with optical microscope, transmission electron microscope and scanning electron microscope. The Ag+ content in the xeno-ADM incorporated with silver was measured with atomic absorption spectrometer. Twenty-seven rabbits with full-thickness skin defects on the back were randomly divided into three groups, i. e. split-thickness skin autograft only( group A, n = 9) , xeno-ADM with overlying split-thickness skin autograft( group B, n = 9) , xeno-ADM incorporated with silver with overlying split-thickness skin autograft ( group C, n = 9). The skin specimens from grafted area in each group were harvested at 2,4 and 6 post-operation weeks( POW) and examined under light microscope and transmission electron microscope. The condition of the graft, the contraction degree of the grafts and the historical changes in grafting area were observed at 2,4,6 POW. The survival rate of the grafts was calculated and the proliferative activity of the lymphocyte in each group was determined at 2 POW. 1. Compared with xeno-ADM, the anti-bacterial effect of xeno-ADM incorporated with silver was much better ( P < 0. 05). No epidermis was seen in both types of xenografts ,and the collagen fibers were even in size and arranged regularly, with no obvious degeneration, and the dermis was also devoid of cells and cellular components. The Ag + content in xeno-ADM incorporated with silver measured (2. 7+/-0. 7) mg/g. 2. The grafts in B and C groups presented similar color to that of normal skin at 6 POW, and it was smooth, with fine texture and no scarring. The collagen fibers was arranged regularly, and conjunction between epidermis and dermis, the structure of basal cell desmosome and semi-desmosome were well reconstructed. The grafts in A group was in dark red color, with obvious contraction, and easily broken. The contraction rate in A group at 2,4 and 6 POW were obviously higher than those in B and C groups( P < 0. 05), while no obvious difference was observed between B and C groups. ( P >0. 05). The overall survival rate of the grafts in C group at 2 POW was 91.7% , which was evidently higher than that in A (77.8%) and B (80. 6% ) groups. The lymphocyte proliferative activity exhibited no difference among A, B and C groups( P >0.05). The xeno-ADM incorporated with silver has good anti-bacterial effect. In addition, it preserves the basic tissue structure and integral collagen fiber scaffold, without cells to induce rejection, so that it can be used as an ideal dermal substitute.


[Orbital involvement in acute sinusitis in children].
We review the literature on orbital involvement in acute sinusitis in children. Because of the potential severity of the disease which may be life threatening a vigorous treatment is required. Hemophilus Influenzae is a major cause of orbital cellulitis followed by Staphylococcus Aureus and group A streptococcus. Because of the emergence of Ampicillin-Resistant H. Influenzae strains in Belgium, chloramphenicol should be included in the initial therapy in combination with a penicillinase resistant semisynthetic penicillin. Therapy is adjusted as soon as the results of bacterial culture are known. Surgical establishment of sinus or abscess drainage is required if the child is severely ill or failed to respond to medical treatment. A treatment protocol is proposed.


[Hopf's acrokeratosis verruciformis. Communication of a non-familial case].
A 46-years-old man with non familial acrokeratosis verruciformis of Hopf is described. We comment on the clinical and histopathological features of this rare dermatosis and the unsuccessful therapy with etretinate.


Microsurgical anatomy and insular connectivity of the cerebral opercula.
Radiological, anatomical, and electrophysiological studies have shown the insula and cerebral opercula to have extremely high functionality. Because of this complexity, interventions in this region cause higher morbidity compared to those in other areas of the brain. In most early studies of the insula and white matter pathways, insular dissection was begun after the opercula were removed. In this study, the authors examined the insula and deep white matter pathways to evaluate the insula as a whole with the surrounding opercula. Twenty formalin-fixed adult cerebral hemispheres were studied using fiber microdissection techniques and examination of sectional anatomy. Dissections were performed from lateral to medial, medial to lateral, inferior to superior, and superior to inferior. A silicone brain model was used to show the normal gyral anatomy. Sections and fibers found at every stage of dissection were photographed with a professional camera. MRI tractography studies were used to aid understanding of the dissections. The relationships between the insula and cerebral opercula were investigated in detail through multiple dissections and sections. The relationship of the extreme and external capsules with the surrounding opercula and the fronto-occipital fasciculus with the fronto-orbital operculum was demonstrated. These findings were correlated with the tractography studies. Fibers of the extreme capsule connect the medial aspect of the opercula with the insula through the peri-insular sulcus. Medial to lateral dissections were followed with the removal of the central core structures, and in the last step, the medial surface of the cerebral opercula was evaluated in detail. This anatomical study clarifies our understanding of the insula and cerebral opercula, which have complex anatomical and functional networks. This study also brings a new perspective to the connection of the insula and cerebral opercula via the extreme and external capsules.


Emotional responses in Papua New Guinea show negligible evidence for a universal effect of major versus minor music.
Music is a vital part of most cultures and has a strong impact on emotions [1-5]. In Western cultures, emotive valence is strongly influenced by major and minor melodies and harmony (chords and their progressions) [6-13]. Yet, how pitch and harmony affect our emotions, and to what extent these effects are culturally mediated or universal, is hotly debated [2, 5, 14-20]. Here, we report an experiment conducted in a remote cloud forest region of Papua New Guinea, across several communities with similar traditional music but differing levels of exposure to Western-influenced tonal music. One hundred and seventy participants were presented with pairs of major and minor cadences (chord progressions) and melodies, and chose which of them made them happier. The experiment was repeated by 60 non-musicians and 19 musicians in Sydney, Australia. Bayesian analyses show that, for cadences, there is strong evidence that greater happiness was reported for major than minor in every community except one: the community with minimal exposure to Western-like music. For melodies, there is strong evidence that greater happiness was reported for those with higher mean pitch (major melodies) than those with lower mean pitch (minor melodies) in only one of the three PNG communities and in both Sydney groups. The results show that the emotive valence of major and minor is strongly associated with exposure to Western-influenced music and culture, although we cannot exclude the possibility of universality.


Variation in fetal hemoglobin parameters and predicted hemoglobin S polymerization in sickle cell children in the first two years of life: Parisian Prospective Study on Sickle Cell Disease.
Intracellular hemoglobin S (HbS) polymerization is most likely to be the primary determinant of the clinical and biologic manifestations of sickle cell disease (SCD). Fetal hemoglobin (HbF) does not enter the HbS polymer and its intracellular expression in sickle erythrocytes inhibits polymerization. HbF levels, high at birth but decreasing thereafter, protect the newborn from the clinical manifestations of this hemoglobinopathy. We have measured the sequential changes in HbF, F reticulocytes, and F cells in the first 2 years of life in 25 children with SCD and compared the results with those obtained in 30 normal children (AA). We have also calculated HbF per F cell (F/F cell), the preferential survival of F cells versus non-F cells, as measured by the ratio F cells versus F reticulocytes (FC/FR) and polymer tendency at 40% and 70% oxygen saturation. HbF levels decreased from about 80.4% +/- 4.0% at birth to 9.2% +/- 2.9% at 24 months. During this time, we observed a regular decrease of the F reticulocytes and the F cells. The kinetics of the decline of F/F cell was comparable with the decline of HbF, rapid from birth (mean, 27.0 +/- 3.6 pg) to 12 months of age (mean, 8.5 +/- 1.5 pg) and then slower from 12 to 24 months of age (mean, 6.2 +/- 1.0 pg) in the SCD children. In the AA children, the decrease in HbF, due to changes in both numbers of F cells and F/F cell, was more precipitous, reaching steady-state levels by 10 months of age. Calculated values for mean polymer tendency in the F-cell population showed that polymerization should begin to occur at 40% oxygen saturation at about 3 months and increase progressively with age, whereas polymerization at 70% oxygen saturation would not occur until about 24 months. These values correspond to HbF levels of 50.8% +/- 10.8% and 9.2% +/- 2.9%, respectively, and F/F cell levels of 15.6 +/- 4.5 pg and 6.2 +/- 1.0 pg, respectively. In the non--F-cell population, polymerization was expected at birth at both oxygen saturation values. Three individuals had significantly greater predicted polymerization tendency than the remainder of the group because of early decreases in HbF. These individuals in particular, the remainder of the cohort, as well as other recruited newborns, will be studied prospectively to ascertain the relationship among hematologic parameters, which determine polymerization tendency and the various clinical manifestations of SCD.


Free choice access to multipoint wellness education and related services positively impacts employee wellness: a randomized and controlled trial.
Examine effects of voluntary participation in employer-sponsored, multipoint wellness education programming on employee wellness. A randomized and controlled design was used to organize 96 participants into an education + access group; an access-only group, and control group. Outcome measures were made at start and end of a 12-week intervention period. Education + access improved wellness knowledge, which, in turn, enhanced life satisfaction, employee morale, and energy, and nearly improved stress level. Those who received facility access without educational programming did not reap health benefits. Employees voluntarily used the fitness facility and healthy meal cards only 1.3 and 1.5 times per week, respectively. Participants made limited and likely inadequate use of wellness opportunities. As a result, physical health benefits (eg, blood pressure, fitness parameters) were not seen in the present study. However, multipoint wellness education resulted in psychosocial health benefits in 12 weeks.


Pulmonary thromboembolism in 29 dogs: 1985-1995.
Pulmonary thromboembolism (PTE) occurs as a complication to a number of commonly encountered clinical diseases. Antemortem recognition of this life-threatening disorder is hampered by nonspecificity of clinical signs. This retrospective study was performed to analyze clinical features, laboratory findings, imaging abnormalities, and concurrent postmortem diagnoses in 29 dogs with confirmed pulmonary embolism. A variety of clinicopathologic and radiographic abnormalities were noted but there were no pathognomonic findings for PTE. Arterial blood gas analyses were performed in 15 (52%) of 29 dogs; 12 (80%) of 15 exhibited hypoxemia and 15 (100%) of 15 had increased alveolar-arterial oxygen gradients. Response to supplemental O2 was variable and did not correlate with the presence or absence of additional pulmonary pathology on postmortem. At postmortem, 25 (86%) of 29 dogs had grossly visible emboli, 17 (59%) of 29 dogs had multiple disease processes, and 16 (55%) of 29 dogs had additional pulmonary pathology. PTE was suspected antemortem in 11 (38%) of 29 dogs. In dogs with respiratory signs consistent with PTE, the condition was a differential diagnosis in 11 of 17 animals; all had diseases previously reported to be associated with PTE. Neoplasia, systemic bacterial disease, and immune-mediated hemolytic anemia were diagnosed most frequently.


Far-red Sensitive Dark Processes Essential for Light- and Gibberellin-induced Germination of Lettuce Seed.
The action of prolonged far-red on seed germination was studied in Lactuca sativa L. var. Grand Rapids. Exposure of imbibed seeds to 6 hours far-red before the application of gibberellic acid (GA(3)) and thiourea completely prevented germination. Using GA(3), this far-red was effective after the sixth hour of imbibition. At 6, 12, and 18 hours of imbibition equal durations of far-red had equal effects. The kinetics of far-red action was investigated: it was found that although far-red for several hours, irrespective of the energy level, was needed for maximum inhibition, shorter durations (15 and 30 mins) were also appreciably effective provided they were followed by several hours darkness before the supply of GA(3). This is taken to indicate the existence of labile product(s) of the action of a far-red sensitive pigment. Evidence is provided for the existence of promotive dark processes controlled by this pigment, which are essential for germination whether triggered by GA(3), thiourea or red-light. A model for the operation of the pigment system is proposed and its role in the germination mechanism of this seed is discussed.


Studies on some specific Ap4A-degrading enzymes with the use of various methylene analogues of P1P4-bis-(5',5'''-adenosyl) tetraphosphate.
Six new methylenephosphonate analogues of P1P4-bis-(5',5'''-adenosyl) tetraphosphate, Ap4A, having P2-P3 carbon bridges CF2, CCl2 and CH2CH2 or P1-P2 and P3-P4 carbon bridges CF2, CCl2 and CH2CH2 in the tetraphosphate chain, were examined as substrates or inhibitors for two specific Ap4A-degrading enzymes: (asymmetrical) Ap4A hydrolase (EC 184.108.40.206) from yellow-lupin seeds and (symmetrical) Ap4A hydrolase (EC 220.127.116.11) from Escherichia coli. All analogues in which the central oxygen atom was replaced by a stable carbon bridge were hydrolysed by the asymmetrical hydrolase (CF2 greater than CCl2 greater than O greater than CHBr greater than CH2 greater than CH2CH2). As expected, these analogues were not hydrolysed by the symmetrical hydrolase, which was also unable to act on analogues having P1-P2 and P3-P4 carbon bridges.


Evidence for inhibitory deficits in the prefrontal cortex in schizophrenia.
Abnormal gamma-aminobutyric acid inhibitory neurotransmission is a key pathophysiological mechanism underlying schizophrenia. Transcranial magnetic stimulation can be combined with electroencephalography to index long-interval cortical inhibition, a measure of GABAergic receptor-mediated inhibitory neurotransmission from the frontal and motor cortex. In previous studies we have reported that schizophrenia is associated with inhibitory deficits in the dorsolateral prefrontal cortex compared to healthy subjects and patients with bipolar disorder. The main objective of the current study was to replicate and extend these initial findings by evaluating long-interval cortical inhibition from the dorsolateral prefrontal cortex in patients with schizophrenia compared to patients with obsessive-compulsive disorder. A total of 111 participants were assessed: 38 patients with schizophrenia (average age: 35.71 years, 25 males, 13 females), 27 patients with obsessive-compulsive disorder (average age: 36.15 years, 11 males, 16 females) and 46 healthy subjects (average age: 33.63 years, 23 females, 23 males). Long-interval cortical inhibition was measured from the dorsolateral prefrontal cortex and motor cortex through combined transcranial magnetic stimulation and electroencephalography. In the dorsolateral prefrontal cortex, long-interval cortical inhibition was significantly reduced in patients with schizophrenia compared to healthy subjects (P = 0.004) and not significantly different between patients with obsessive-compulsive disorder and healthy subjects (P = 0.5445). Long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex were also significantly greater in patients with schizophrenia compared to patients with obsessive-compulsive disorder (P = 0.0465). There were no significant differences in long-interval cortical inhibition across all three groups in the motor cortex. These results demonstrate that long-interval cortical inhibition deficits in the dorsolateral prefrontal cortex are specific to patients with schizophrenia and are not a generalized deficit that is shared by disorders of severe psychopathology.


Selective up-regulation of LXR-regulated genes ABCA1, ABCG1, and APOE in macrophages through increased endogenous synthesis of 24(S),25-epoxycholesterol.
Liver X receptor (LXR) activation represents a mechanism to prevent macrophage foam cell formation. Previously, we demonstrated that partial inhibition of oxidosqualene:lanosterol cyclase (OSC) stimulated synthesis of the LXR agonist 24(S),25-epoxycholesterol (24(S),25-epoxy) and enhanced ABCA1-mediated cholesterol efflux. In contrast to a synthetic, nonsteroidal LXR activator, TO-901317, triglyceride accumulation was not observed. In the present study, we determined whether endogenous 24(S),25-epoxy synthesis selectively enhanced expression of macrophage LXR-regulated cholesterol efflux genes but not genes that regulate fatty acid metabolism. THP-1 human macrophages incubated with the OSC inhibitor (OSCi) RO0714565 (15 nM) significantly reduced cholesterol synthesis and maximized synthesis of 24(S),25-epoxy. Endogenous 24(S),25-epoxy increased ABCA1, ABCG1, and APOE mRNA abundance and consequently increased cholesterol efflux to apoAI. In contrast, OSCi had no effect on LXR-regulated genes LPL (lipoprotein lipase) and FAS (fatty acid synthase). TO-901317 (>or=10 nM) significantly enhanced expression of all genes examined. OSCi and TO-901317 increased the mRNA and precursor form of SREBP-1c, a major regulator of fatty acid and triglyceride synthesis. However, conversion of the precursor to the active form (nSREBP-1c) was blocked by OSCi-induced 24(S),25-epoxy but not by TO-901317 (>or=10 nm), which instead markedly increased nSREBP-1c. Disruption of nSREBP-1c formation by 24(S),25-epoxy accounted for diminished FAS and LPL expression. In summary, endogenous synthesis of 24(S),25-epoxy selectively up-regulates expression of macrophage LXR-regulated cholesterol efflux genes without stimulating genes linked to fatty acid and triglyceride synthesis.


Type I and II endometrial cancers: have they different risk factors?
Endometrial cancers have long been divided into estrogen-dependent type I and the less common clinically aggressive estrogen-independent type II. Little is known about risk factors for type II tumors because most studies lack sufficient cases to study these much less common tumors separately. We examined whether so-called classical endometrial cancer risk factors also influence the risk of type II tumors. Individual-level data from 10 cohort and 14 case-control studies from the Epidemiology of Endometrial Cancer Consortium were pooled. A total of 14,069 endometrial cancer cases and 35,312 controls were included. We classified endometrioid (n = 7,246), adenocarcinoma not otherwise specified (n = 4,830), and adenocarcinoma with squamous differentiation (n = 777) as type I tumors and serous (n = 508) and mixed cell (n = 346) as type II tumors. Parity, oral contraceptive use, cigarette smoking, age at menarche, and diabetes were associated with type I and type II tumors to similar extents. Body mass index, however, had a greater effect on type I tumors than on type II tumors: odds ratio (OR) per 2 kg/m(2) increase was 1.20 (95% CI, 1.19 to 1.21) for type I and 1.12 (95% CI, 1.09 to 1.14) for type II tumors (P heterogeneity < .0001). Risk factor patterns for high-grade endometrioid tumors and type II tumors were similar. The results of this pooled analysis suggest that the two endometrial cancer types share many common etiologic factors. The etiology of type II tumors may, therefore, not be completely estrogen independent, as previously believed.


Nanostructure-Mediated Phase Evolution in Lithiation/Delithiation of Co3O4.
Nanostructured transition-metal oxides have been under intensive investigation for their tantalizing potential as anodes of next-generation lithium-ion batteries (LIBs). However, the exact mechanism for nanostructures to influence the LIB performance remains largely elusive. In this work, we discover the nanostructure-mediated lithiation mechanism in Co3O4 anodes using ex situ transmission electron microscopy (TEM) and X-ray diffractometry: while Co3O4 nanosheets exhibit a typical two-step conversion reaction (from Co3O4 to CoO and then to Co0), Co3O4 nanoarrays can go through a direct conversion from Co3O4 to Co0 at a high discharge rate. Such nanostructure-dependent lithiation can be rationalized by the slow lithiation kinetics intrinsic to Co3O4 nanoarrays, which at a high discharge rate may cause local accumulation of lithium to initiate a one-step Co3O4-to-Co0 conversion. Combined with the larger volume change observed in Co3O4 nanoarrays, the slow lithiation kinetics can lead to inhomogeneous expansion with large stress developed at the reaction front, which can eventually cause structure failure and irreversible capacity loss, as explicitly observed by in situ TEM as well as galvanostatic discharge-charge measurement. Our observation resolves the nanostructure-dependent lithiation mechanism of Co3O4 and provides important insights into the interplay among lithiation kinetics, phase evolution, and lithium-storage performance, which can be translated into electrode design strategies for next-generation LIBs.


Making sense of differences in pneumococcal serotype replacement.
Serotype replacement in invasive pneumococcal disease threatens to undermine the most costly vaccination programme currently undertaken. However, the effects of replacement on public health have varied geographically. Striking differences have emerged between the UK and USA, countries that otherwise often resemble each other epidemiologically. Similar to other European settings, the UK has had rising non-vaccine serotype invasive pneumococcal disease, most notably in older adults, since introducing a 13-valent pneumococcal conjugate vaccine to the paediatric immunisation schedule. Such impacts of serotype replacement have not been reported in the USA, where incidence of non-vaccine serotype invasive pneumococcal disease in young children and older people has been stable since the introduction of the same vaccine. Here, we explore factors that have been suggested to account for these differences, including surveillance practices, transmission dynamics, population risk factors, and pathogen evolution. We contend that none of these factors individually appears sufficient to account for the observed differences. Assessing the existing evidence, we define priorities for research and data collection to discern causes and inform future pneumococcal vaccine policy.


Predictors of body mass index change in Australian primary school children.
To assess associations between multiple potential predictors and change in child body mass index (BMI). In the 1997 Health of Young Victorians Study, children in Grades preparatory to three (aged 5-10 years) had their height and weight measured. Parents provided information on potential predictors of childhood overweight across six domains (children's diet, children's activity level, family composition, sociodemographic factors, prenatal factors and parental adiposity). Measures were repeated three years later in 2000/1. BMI was transformed to standardised (z) scores using the US 2000 Growth Chart data and children were classified as non-overweight or overweight according to international cut-points. Regression analyses, including baseline BMI z-score as a covariate, assessed the contribution of each potential predictor to change in BMI z-score, development of overweight and spontaneous resolution of overweight in 1,373 children. BMI z-score change was positively associated with frequency of take-away food, food quantity, total weekly screen time, non-Australian paternal country of birth, maternal smoking during pregnancy, and maternal and paternal BMI. Inverse associations were noted for the presence of siblings and rural residence (all p<0.05). Predictors of categorical change (development and resolution of overweight) were less clearly identified, apart from an association between maternal BMI and overweight development (p=0.02). Multivariable models suggested individual determinants have a cumulative effect on BMI change. Strong short-term tracking of BMI makes it difficult to identify predictors of change. Nonetheless, putative determinants across all domains assessed were independently associated with adiposity change. Multi-faceted solutions are likely to be required to successfully deal with the complexities of childhood overweight.


Dedifferentiated and undifferentiated neoplasms: A conceptual approach.
This review provides a conceptual approach to dedifferentiation across a variety of tumor types, with particular attention to genetic events that tie together morphologically disparate areas of these neoplasms. First, working definitions of the terms differentiated, undifferentiated, and dedifferentiated are developed. Then, specific examples of tumors with a particular propensity for undergoing dedifferentiation are highlighted, with emphasis on both immunohistochemical studies and molecular lesions that enable surgical pathologists to establish diagnostic clarity in morphologically vexing situations. Throughout this review, the historical arc of the literature is followed, and therefore the discussion of specific tumor types begins with dedifferentiated chondrosarcoma, the neoplasm that inspired the terminology regarding dedifferentiation that remains in use today. Selected other sarcomas with well-established pathways of dedifferentiation are subsequently discussed, followed by descriptions of this process in subtypes of carcinoma and melanoma.


Effect of annealing treatment on electroluminescence from GaN/Si nanoheterostructure array.
A GaN/Si nanoheterostructure array was prepared by growing GaN nanostructures on silicon nanoporous pillar array (Si-NPA). Based on as-grown and annealed GaN/Si-NPA, two light-emitting diodes (LEDs) were fabricated. It was found that after the annealing treatment, both the turn-on voltage and the leakage current density of the nanoheterostructure varied greatly, together with the electroluminescence (EL) changed from a yellow band to a near infrared band. The EL variation was attributed to the radiative transition being transformed from a defect-related recombination in GaN to an interfacial recombination of GaN/Si-NPA. Ours might have provided an effective approach for fabricating GaN/Si-based LEDs with different emission wavelengths.


Identical peptides recognized by MHC class I- and II-restricted T cells.
Previous data from many groups show that both class I and class II-restricted T cells recognize short synthetic peptides in the context of their respective MHC molecules (9-18), all of the peptides described to date are restricted to only a single class of MHC molecules; however, structural homology between the class I and II MHC molecules and the use of similar TCRs by class I and II-restricted T cells suggest that antigen recognition mechanisms are similar in both systems. To directly compare antigen recognition in the two systems, we analyzed peptides for the ability to function in both a class I and II-restricted system and found that seven of seven individual peptides tested stimulate both class I and II-restricted T cell responses. In addition, two of the peptides can function in different species stimulating both human class I and murine class II T cell responses. Thus, the process of T cell recognition of antigen in the context of MHC molecules was highly conserved in evolution not only between the class I and class II MHC systems, but also between the murine and human species.


Deep Geodesic Learning for Segmentation and Anatomical Landmarking.
In this paper, we propose a novel deep learning framework for anatomy segmentation and automatic landmarking. Specifically, we focus on the challenging problem of mandible segmentation from cone-beam computed tomography (CBCT) scans and identification of 9 anatomical landmarks of the mandible on the geodesic space. The overall approach employs three inter-related steps. In the first step, we propose a deep neural network architecture with carefully designed regularization, and network hyper-parameters to perform image segmentation without the need for data augmentation and complex post-processing refinement. In the second step, we formulate the landmark localization problem directly on the geodesic space for sparsely-spaced anatomical landmarks. In the third step, we utilize a long short-term memory network to identify the closely-spaced landmarks, which is rather difficult to obtain using other standard networks. The proposed fully automated method showed superior efficacy compared to the state-of-the-art mandible segmentation and landmarking approaches in craniofacial anomalies and diseased states. We used a very challenging CBCT data set of 50 patients with a high-degree of craniomaxillofacial variability that is realistic in clinical practice. The qualitative visual inspection was conducted for distinct CBCT scans from 250 patients with high anatomical variability. We have also shown the state-of-the-art performance in an independent data set from the MICCAI Head-Neck Challenge (2015).


Conservation of Salmonella typhimurium virulence plasmid maintenance regions among Salmonella serovars as a basis for plasmid curing.
The association of large plasmids with virulence in invasive Salmonella serovars has led to a number of studies designed to uncover the role of these plasmids in virulence. This study addresses two aspects of virulence-associated plasmids. The first is the distribution of the replication and maintenance regions among the plasmids of different Salmonella serovars, and the second is the use of the conserved virulence plasmid par region to provide a rapid method for eliminating the virulence plasmids specifically. Colony blots revealed that the par and repB regions of the S. typhimurium virulence plasmid hybridized with 80% of the isolates of S. choleraesuis, S. dublin, S. enteritidis, S. gallinarum, S. pullorum, and S. typhimurium, while the repC region was not detected in any of the isolates of S. dublin, S. gallinarum, or S. pullorum. None of these maintenance regions was found in any of the 30 additional serovars tested. The large plasmids of those serovars that hybridized with par were labeled with a Kmr insert within parA via P22HTint or P1L4 transduction, which destabilized the plasmids and allowed the rapid isolation of plasmid-free derivatives for all of the serovars, except for S. dublin, which exhibited weak homology with par.


Intratunical bupivacaine and methylprednisolone instillation for scrotal pain after testicular sperm retrieval procedures.
To investigate the effect of intratunical instillation of bupivacaine and methylprednisolone for scrotal pain, swelling and peritesticular fibrosis due to testicular sperm retrieval procedures. A total of 65 patients were randomly divided into two groups. In the instillation group (GI), 34 patients were administered 2.5 mL of 0.5 % bupivacaine combined with 10 mg/ml methylprednisolone before closure of the tunica vaginalis. In the control group (GC), 31 patients only received analgesics postoperatively by intramuscular route. The pain (by visual analogue scale, VAS) and duration of pain-free period after surgery between the two groups were evaluated at 2 and 4 h and at days 2 and 7 postoperatively. The mean pain scores were significantly lower in the GI than in the GC group at 2 and 4 h after surgery (P<0.05 and P<0.01, respectively). The mean duration of pain free interval after the procedure was 47.8 +/-16.9 (12-72) h in GI, which was significantly longer than that in GC [(9.9 +/-3.6; 4-20) h]. Besides, in the GI, 29 % of patients were completely free from pain and 67 % had no scrotal swelling, but in the GC, all the patients required additional NSAID injection due to pain and only 3 % had no scrotal swelling. This study confirms that direct intratunical instillation of bupivacaine and methylprednisolone around the testis reduces the postoperative pain, scrotal swelling and peritesticular fibrosis.


WDR5 is required for DUX4 expression and its pathological effects in FSHD muscular dystrophy.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent neuromuscular disorders. The disease is linked to copy number reduction and/or epigenetic alterations of the D4Z4 macrosatellite on chromosome 4q35 and associated with aberrant gain of expression of the transcription factor DUX4, which triggers a pro-apoptotic transcriptional program leading to muscle wasting. As today, no cure or therapeutic option is available to FSHD patients. Given its centrality in FSHD, blocking DUX4 expression with small molecule drugs is an attractive option. We previously showed that the long non protein-coding RNA DBE-T is required for aberrant DUX4 expression in FSHD. Using affinity purification followed by proteomics, here we identified the chromatin remodeling protein WDR5 as a novel DBE-T interactor and a key player required for the biological activity of the lncRNA. We found that WDR5 is required for the expression of DUX4 and its targets in primary FSHD muscle cells. Moreover, targeting WDR5 rescues both cell viability and myogenic differentiation of FSHD patient cells. Notably, comparable results were obtained by pharmacological inhibition of WDR5. Importantly, WDR5 targeting was safe to healthy donor muscle cells. Our results support a pivotal role of WDR5 in the activation of DUX4 expression identifying a druggable target for an innovative therapeutic approach for FSHD.


Augmenter of liver regeneration (alr) promotes liver outgrowth during zebrafish hepatogenesis.
Augmenter of Liver Regeneration (ALR) is a sulfhydryl oxidase carrying out fundamental functions facilitating protein disulfide bond formation. In mammals, it also functions as a hepatotrophic growth factor that specifically stimulates hepatocyte proliferation and promotes liver regeneration after liver damage or partial hepatectomy. Whether ALR also plays a role during vertebrate hepatogenesis is unknown. In this work, we investigated the function of alr in liver organogenesis in zebrafish model. We showed that alr is expressed in liver throughout hepatogenesis. Knockdown of alr through morpholino antisense oligonucleotide (MO) leads to suppression of liver outgrowth while overexpression of alr promotes liver growth. The small-liver phenotype in alr morphants results from a reduction of hepatocyte proliferation without affecting apoptosis. When expressed in cultured cells, zebrafish Alr exists as dimer and is localized in mitochondria as well as cytosol but not in nucleus or secreted outside of the cell. Similar to mammalian ALR, zebrafish Alr is a flavin-linked sulfhydryl oxidase and mutation of the conserved cysteine in the CxxC motif abolishes its enzymatic activity. Interestingly, overexpression of either wild type Alr or enzyme-inactive Alr(C131S) mutant promoted liver growth and rescued the liver growth defect of alr morphants. Nevertheless, alr(C131S) is less efficacious in both functions. Meantime, high doses of alr MOs lead to widespread developmental defects and early embryonic death in an alr sequence-dependent manner. These results suggest that alr promotes zebrafish liver outgrowth using mechanisms that are dependent as well as independent of its sulfhydryl oxidase activity. This is the first demonstration of a developmental role of alr in vertebrate. It exemplifies that a low-level sulfhydryl oxidase activity of Alr is essential for embryonic development and cellular survival. The dose-dependent and partial suppression of alr expression through MO-mediated knockdown allows the identification of its late developmental role in vertebrate liver organogenesis.


[Clinical course of herpes zoster in middle-aged and elderly persons].
The clinical progress of herpes zoster (HZ) was studied in 216 patients under 60 years and in elderly and senile persons. A clear relationship was revealed between the gravity of the clinical progress of HZ and the patients' age. The number of patients with grave HZ patterns and with HZ of medium gravity was found to be increasing in elderly and senile persons. It was also established that HZ took a graver course in patients aggravated with concomitant pathology. The concomitant diseases are demonstrated to have a multifactorial aggravating effect on the progress of HZ.


Human T-cell leukemia-lymphoma virus type 1 and adult T-cell leukemia-lymphoma in Okinawa.
A serological survey for the presence of antibodies against the human T-cell leukemia virus, type 1 (HTLV-1) in patients seen at the Chubu Hospital in Okinawa was undertaken. All patients with the clinicopathological diagnosis of adult T-cell leukemia-lymphoma were positive. These cases had the characteristic features of adult T-cell leukemia-lymphoma: diffuse histology, often mixed cell or pleomorphic, and a high frequency of hypercalcemia, leukemic phase, diffuse visceral involvement, and opportunistic infections. The median survival of these patients was short, being only 18 weeks. Of the other patients with cancers screened, two of five other non-Hodgkin's lymphoma patients were positive and three of eight patients with other hematological cancers were positive. In addition, three of the four immediate family members of one adult T-cell leukemia-lymphoma case had antibodies. Of the other persons (both in- and outpatients) without hematological cancers, those under the age of 50 had a much lower antibody prevalence (4%) than those over 50 (30%). There was no significant difference in antibody prevalence between the two sexes in either the younger or older age group. These findings further document that Okinawa is an endemic area for HTLV-1. None of the 157 individuals screened for antibodies to HTLV-3 were positive, consistent with the fact that no cases of the acquired immune deficiency syndrome have been reported from Okinawa.


Practical hardware for evolvable robots.
The evolutionary robotics field offers the possibility of autonomously generating robots that are adapted to desired tasks by iteratively optimising across successive generations of robots with varying configurations until a high-performing candidate is found. The prohibitive time and cost of actually building this many robots means that most evolutionary robotics work is conducted in simulation, but to apply evolved robots to real-world problems, they must be implemented in hardware, which brings new challenges. This paper explores in detail the design of an example system for realising diverse evolved robot bodies, and specifically how this interacts with the evolutionary process. We discover that every aspect of the hardware implementation introduces constraints that change the evolutionary space, and exploring this interplay between hardware constraints and evolution is the key contribution of this paper. In simulation, any robot that can be defined by a suitable genetic representation can be implemented and evaluated, but in hardware, real-world limitations like manufacturing/assembly constraints and electrical power delivery mean that many of these robots cannot be built, or will malfunction in operation. This presents the novel challenge of how to constrain an evolutionary process within the space of evolvable phenotypes to only those regions that are practically feasible: the viable phenotype space. Methods of phenotype filtering and repair were introduced to address this, and found to degrade the diversity of the robot population and impede traversal of the exploration space. Furthermore, the degrees of freedom permitted by the hardware constraints were found to be poorly matched to the types of morphological variation that would be the most useful in the target environment. Consequently, the ability of the evolutionary process to generate robots with effective adaptations was greatly reduced. The conclusions from this are twofold. 1) Designing a hardware platform for evolving robots requires different thinking, in which all design decisions should be made with reference to their impact on the viable phenotype space. 2) It is insufficient to just evolve robots in simulation without detailed consideration of how they will be implemented in hardware, because the hardware constraints have a profound impact on the evolutionary space.


Trenbolone acetate: experiences with bound residues in cattle tissues.
Two heifers were implanted with 300 mg of the radiolabeled anabolic steroid, trenbolone acetate (TBA). After a 60 day slaughter and a 60 day removal followed by 76 day slaughter, total 3H-content in various tissues was 0.5--25 ng/g equivalents of TBA. Radioimmunoassay of the tissues showed that only 1--5% of the total residue present was TBA, its main metabolite trenbolone (TBOH), and TBOH glucuronide, plus up to 5% of other organic-soluble material. Of the radioactivity remaining about half was directly water-soluble, and the insoluble residue could be made water-soluble by treatment with the proteolytic enzymes pepsin and trypsin. These 2 portions were purified with Sephadex G-25 to give a low and high molecular weight fraction. Raney nickel reduction of sulfur bonds in either fraction released up to 50% of radioactivity into the organic phase. TLC showed that the latter contained 2 components which had characteristics similar to TBOH and its metabolites, and thus were at least partly drug-related metabolites. In vitro experiments with bovine liver also showed a small but definite protein binding. It is proposed that in dealing with these covalently bound residues, priority be given to the reactive drug intermediate and the type of binding to macromolecules rather than to the presence of the bound residue itself.


Determinants of observed confidant support for divorced mothers.
Marital separation can be a time of extreme stress and can significantly disrupt support networks and support processes when they are needed most. The purpose of this investigation was to test mechanisms of support erosion in a multimethod study of 138 divorced mothers and their confidants. Previous work was extended by using observational measures of confidant support in a process model including (a) maternal characteristics over time, (b) support person characteristics, and (c) relationship characteristics (intimacy and confidant relationship type). A hypothesized mechanism of erosion was supported in which ongoing maternal distress was positively associated with levels of confidant negativity, which in turn was related to lower levels of observed support. Having a partner was related to more intimacy than was having family and friends. Contrary to expectation, however, having a partner was related to lower levels of support, and intimacy was not related to observed support.


[Academic medicine and complementary medicine differ from each other in reasoning and evaluation but not in goals].
The principal objective of all medical activity is to prevent deterioration of health, but also its recuperation, when it has been lost, by mobilisation of inner, natural resources and the commitment of practical knowledge about ill-health. This is less true not for individuals with regard to their proper care, than for practitioners of the arts and sciences of healing towards those who seek their help, regardless of the 'school' to which they may belong. If such objectives are generally accepted, the way to their accomplishment is open. However relevant and justifiable differing intentions may be, they become difficult to materialize if energy is squandered in futile disputes over territorial rights. It is the purpose of the Swiss National Science Foundation's 'Komplementärmedizin' Programme (NFP 34) to build bridges between different territories. (See the Table of Projects currently being undertaken at the end of this article.)


Artificial Intelligence for the Future Radiology Diagnostic Service.
Radiology historically has been a leader of digital transformation in healthcare. The introduction of digital imaging systems, picture archiving and communication systems (PACS), and teleradiology transformed radiology services over the past 30 years. Radiology is again at the crossroad for the next generation of transformation, possibly evolving as a one-stop integrated diagnostic service. Artificial intelligence and machine learning promise to offer radiology new powerful new digital tools to facilitate the next transformation. The radiology community has been developing computer-aided diagnosis (CAD) tools based on machine learning (ML) over the past 20 years. Among various AI techniques, deep-learning convolutional neural networks (CNN) and its variants have been widely used in medical image pattern recognition. Since the 1990s, many CAD tools and products have been developed. However, clinical adoption has been slow due to a lack of substantial clinical advantages, difficulties integrating into existing workflow, and uncertain business models. This paper proposes three pathways for AI's role in radiology beyond current CNN based capabilities 1) improve the performance of CAD, 2) improve the productivity of radiology service by AI-assisted workflow, and 3) develop radiomics that integrate the data from radiology, pathology, and genomics to facilitate the emergence of a new integrated diagnostic service.


Bortezomib, liposomal doxorubicin and dexamethasone followed by thalidomide and dexamethasone is an effective treatment for patients with newly diagnosed multiple myeloma with Internatinal Staging System stage II or III, or extramedullary disease.
We evaluated sequential bortezomib, liposomal doxorubicin and dexamethasone (BDD) followed by thalidomide and dexamethasone (TD) if ≥ partial response (PR) or bortezomib and TD (BTD) if < PR in untreated patients with multiple myeloma with International Staging System stage II/III or extramedullary disease. Of the 42 patients enrolled, two-thirds had cytogenetic abnormalities including high-risk findings [del(13q) by karyotype, t(4;14), loss of p53 or gain 1q] in one-third. After the planned three cycles of BDD, the overall response rate (ORR) was 81% with 40% ≥ very good partial response (VGPR), including 26% near complete and complete responses (nCR/CR). After the additional two cycles of TD or BTD, ORR was 83% with 60% ≥ VGPR including 43% nCR/CR, indicating deeper responses following sequential therapy (p = 0.008). Two-thirds of patients who presented with significant renal impairment had improved renal function. All patients undergoing stem cell harvest had a successful collection. BDD followed by TD or BTD is effective initial therapy for this population with higher-risk myeloma and results in rapid disease control and a high response rate.


External CO2 and water supplies for enhancing electrical power generation of air-cathode microbial fuel cells.
Alkalization on the cathode electrode limits the electrical power generation of air-cathode microbial fuel cells (MFCs), and thus external proton supply to the cathode electrode is essential to enhance the electrical power generation. In this study, the effects of external CO2 and water supplies to the cathode electrode on the electrical power generation were investigated, and then the relative contributions of CO2 and water supplies to the total proton consumption were experimentally evaluated. The CO2 supply decreased the cathode pH and consequently increased the power generation. Carbonate dissolution was the main proton source under ambient air conditions, which provides about 67% of total protons consumed for the cathode reaction. It is also critical to adequately control the water content on the cathode electrode of air-cathode MFCs because the carbonate dissolution was highly dependent on water content. On the basis of these experimental results, the power density was increased by 400% (143.0 ± 3.5 mW/m(2) to 575.0 ± 36.0 mW/m(2)) by supplying a humid gas containing 50% CO2 to the cathode chamber. This study demonstrates that the simultaneous CO2 and water supplies to the cathode electrode were effective to increase the electrical power generation of air-cathode MFCs for the first time.


Low dose of methylmercury (MeHg) exposure induces caspase mediated-apoptosis in cultured neural progenitor cells.
Methylmercury (MeHg) is an environmental pollutant known to cause neurobehavioral defects, and it is especially toxic to the developing brain. In contrast to the adult, the developing brain consists of a large number of dividing neural progenitor cells (NPCs), which are vulnerable targets for MeHg toxicity. In a previous study, we showed that the embryonic NPCs from the telencephalon are more sensitive to MeHg than other neural cells. Here, we investigated the mechanism of cell death underlying MeHg toxicity. We observed that exposure of NPCs to MeHg caused DNA laddering in a dose- and time-dependent manner. Decreased pro-caspase3 and increased cleaved-caspase3 protein was observed 3-12 hours after incubation of NPCs with MeHg. Moreover, the caspase-inhibitor Z-VAD FMK significantly suppressed MeHg-induced cell death in a dose-dependent manner. These results suggest that environmentally relevant levels of MeHg exposure induce apoptosis in NPCs.


Insulin-like growth factor-1 and lean body mass in HIV-infected children.
To describe insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-1-binding protein-1 (IGFBP-1) and IGFBP-3 in HIV+ children before and after initiating or changing antiretroviral therapy and to evaluate association of growth and body composition to growth factors at baseline and over time. Ninety-seven prepubertal HIV+ children aged 1 month to younger than 13 years were observed over 48 weeks after beginning or changing antiretroviral therapy. Serum IGF-1, IGFBP-1, and IGFBP-3 were measured and compared with age- and sex-specific norms. Anthropometric measures were compared as follows: subjects vs matched children from (a) the National Health and Nutrition Examination Survey to generate z scores and (b) HIV-exposed, uninfected children from Women and Infants Transmission Study; and subjects with normal vs abnormal IGF-1 and IGFBP concentrations at baseline. Anthropometric changes were compared for children whose IGF-1 level normalized vs remaining subjects. Multivariate analysis adjusting for sex, race, and baseline age evaluated associations between anthropometry and IGF-1 and IGFBP concentrations. In multivariate analysis, lower baseline IGF-1 and IGFBP-3 were associated with lower mean weight, height, mid-arm muscle circumference, and mid-thigh circumference z scores. Twenty-four percent of children had a low IGF-1 level at baseline, 50% of whom normalized IGF-1 on study. Children whose IGF-1 normalized had greater increases in mean mid-arm muscle circumference z score (1.00 vs -0.03, P = 0.029), but a trend toward lesser mean height increase (P = 0.082) than remaining subjects. Likewise, in comparison to controls from Women and Infants Transmission Study, mean mid-arm muscle circumference also increased more in children whose IGF-1 normalized (P = 0.024) but mean height changed less (P = 0.003). Fifty-five percent of children had elevated IGFBP-1 at baseline, 69% of whom normalized. IGF-1 increases and IGFBP-1 decreases in HIV-infected children upon initiation or change in antiretroviral therapy. Improved muscle mass, but not linear growth, is associated with normalized IGF-1 concentration. These findings suggest that IGF-1 may merit evaluation as a potential therapeutic strategy to improve lean body mass in HIV-infected children.


Resistance of Chinese Meishan, Fengjing, and Minzhu pigs to the K88ac+ strain of Escherichia coli.
The microscopic brush border membrane adherence assay was used to determine resistance (nonadherence) and susceptibility (adherence) of Chinese pigs (n = 289) to the K88ac+ strain of Escherichia coli-mediated disease. This study estimates prevalence of resistance to diarrheal disease in multiple family lines (no common ancestry for a minimum of 3 generations) for the Chinese Meishan, Fengjing, and Minzhu breeds. Results of in vitro assays indicate that pigs of the Meishan breed are highly resistant (nonadherent) to K88ac+ E coli-mediated disease. The gene conferring susceptibility to K88ac+ E coli-mediated disease exists at low frequency in pigs of the Minzhu breed. Minzhu-type (crossbred) pigs of both phenotypes (susceptible and resistant) were identified in ratios consistent with a 1-locus gene model. Given that all susceptible pigs were from 1 site, frequency of susceptibility within this Minzhu population is estimated at 8%. Inheritance within the Fengjing breed is still unclear because a weakly adherent phenotype, as well as the resistant phenotype, was identified. The weakly adherent phenotype was observed in pigs derived from multiple family lines. Expression of the weakly adherent phenotype in terms of susceptibility to disease is not known at this time.


Comparative activation of aflatoxin B1 by mammalian pulmonary tissues.
Occupational exposures to respirable dusts contaminated with the mycotoxin aflatoxin B1 (AFB1) have been associated with an increased incidence of upper airway tumors. To investigate this possible etiology we compared the abilities of tracheal and lung S9 from rabbit, hamster and rat to activate AFB1 to mutagens in Salmonella typhimurium TA 98. The activation of AFB1 was compared to that of benzo[a]pyrene (B[a]P), a known respiratory carcinogen. These species differ in airway morphology with respect to numbers of metabolically-active non-ciliated tracheal epithelial cells. Tracheas from hamster and rabbit and lung from rabbit were active in converting AFB1 to bacterial mutagens. Trachea from hamster was more efficient in activating AFB1 to mutagens than lung, while rabbit lung was over 4 times more active in converting AFB1 to mutagens than that from trachea. In all cases, AFB1 was more mutagenic than B[a]P. The relative capabilities of trachea to activate AFB1 were in agreement with the ability of cultured tracheas from these species to form to AFB1-DNA adducts. These results demonstrate that AFB1 is activated more efficiently than B[a]P in the lung, and that the metabolic capabilities of airway epithelium to activate AFB1 are not predictable by airway morphology.


Prevalence, risk factors and outcomes of patients coming from the community with sepsis due to multidrug resistant bacteria.
Although previous studies showed an increasing prevalence of infections due to multi-drug resistant (MDR) bacteria in the community, specific data on sepsis are lacking. We aimed to assess prevalence, risk factors and outcomes of patients with sepsis due to MDR bacteria. An observational, retrospective study was conducted on consecutive adult patients coming from the community and admitted to the Policlinico Hospital, Milan, Italy, with a diagnosis of sepsis between January 2011 and December 2015. Primary study outcome was in-hospital mortality. Among 518 patients, at least one MDR bacteria was isolated in 88 (17%). ESBL+ Enterobacteriaceae were the most prevalent MDR bacteria (9.7%) followed by MRSA (3.9%). Independent risk factors for sepsis due to MDR bacteria were septic shock (OR: 2.2; p = 0.002) and hospitalization in the previous 90 days (OR: 2.3; p = 0.003). Independent risk factors for sepsis due to ESBL+ bacteria were hospitalization in the previous 90 days (OR: 2.1; p = 0.02) and stroke (OR: 2.1; p = 0.04). A significantly higher mortality was detected among patients with vs. without MDR bacteria (40.2% vs. 23.1% respectively, p = 0.001). Independent risk factors for mortality among patients with sepsis were coagulation dysfunction (OR: 3.2; p = 0.03), septic shock (OR: 3.2; p = 0.003), and isolation of a MDR bacteria (OR: 4.6; p < 0.001). In light of the prevalence and impact of MDR bacteria causing sepsis in patients coming from the community, physicians should consider ESBL coverage when starting an empiric antibiotic therapy in patients with specific risk factors, especially in the presence of septic shock.


Longitudinal growth and emotional and behavioral problems at age 7 in moderate and late preterms.
Moderately and late preterm children (MLPs, 32.0-36.9 weeks gestational age) have a greater risk of poorer growth. This seems to be associated with poorer neuropsychological functioning. Evidence is limited on whether this also holds for emotional and behavioral (EB) problems. Therefore, we assessed whether longitudinal growth from birth until age 7 was associated with EB problems at age 7 in MLPs. This study was part of the Longitudinal Preterm Outcome Project, a prospective cohort study. Data on growth (height, weight, head circumference, and extent of catch-up growth) were obtained from assessments from birth until age 7. EB problems were assessed at age 7 with the Child Behavior Checklist. We assessed whether growth and EB problems were associated using logistic regression analyses, adjusting for multiple birth, parity, and socioeconomic status. We included 248 MLPs. Median gestational age was 34 weeks (interquartile range: 33-35 weeks). Mean birth weight was 2.2 kg (standard deviation: 0.5 kg). Postnatal growth measures were below the Dutch reference norm. EB problems were more prevalent in MLPs than in the general Dutch population. Generally, we found no associations between growth and EB problems; odds ratios ranged from 0.20 to 2.72. In MLPs, postnatal growth from birth until age 7 was not associated with EB problems at age 7. Poorer growth thus seems to relate to neuropsychological problems, but not to EB problems. This suggests that the etiologies of these problems differ at least partially.


[Effect of heat shock on cells of phytopathogenic mycoplasma Acholeplasma laidlawii PG-8A].
Heat shock caused a more active formation of the "dormant" forms (minibodies), as well as increased production of extracellular membrane vesicles by Acholeplasma laidlawii PG-8A cells. Raise of the amount of the minibodies that have increased resistance to biogenic and abiogenic stress factors and pathogenicity may lead to more successful persistence of mycoplasmas in their hosts. Increased production of the extracellular membrane vesicles containing virulence factors by Acholeplasma laidlawii cells during stress may be an additional burden for the infected organism. It has been recently revealed that the vesicles of A. laidlawii contain appreciable quantities of small heat shock protein IbpA (Hsp20). In this paper, using immune-electron microscopy, have shown that at elevated temperature IbpA is associated with A. laidlawii minibodies. Perhaps, IbpA contributes to increased resistance and pathogenicity of the minibodies, keeping their proteins and polypeptides, including protein virulence factors in the folding-competent state.


[On methodological aspects of ecological experiments (comments on M. V. Kozlov publication)].
The meaning of conception of pseudoreplication in ecological experiments is discussed. The replications are found to be pseudo if factors causing random variation act on such replications as on one unit. For example, preudoreplications could appear if a single flipped coin would be split up. The absence of random spatial distribution of experimental and control fields could be considered as a mistake because the experimental results could interfere with spatial heterogeneity. However, there are no pseudoreplications in this case, because the variations of ecological systems are produced by factors that are different in different places and each organism responds to these factors individually. The pseudoreplication should be created by multiple determination of a response of an individual organism. Also recommendations for applications of randomized block design and analysis of covariance for field trials in plant communities are proposed. Randomized blocks unite the experimental and control fields occupying the identical place in the series of spatial heterogeneity. The influence of such heterogeneity on random variation of determined parameters could be excluded by this approach. The heterogeneity considered only at the scale of used blocks. As far as control and experimental fields belongs to a single set, the series of heterogeneities, that comprises the range of their parameters, is identical. The random sorting of the large amount of experimental and control samples consisting of the same number of replications will produces replications in the same place of the series of general heterogeneity of investigated set. The replications occupying the same places of the sorted series form "virtual block". The population of such blocks includes the majority of random variation and allows one to reveal even very weak experimental effects by variance analysis.


Rank- and sex-specific differences in the neuroendocrine regulation of glucocorticoids in a wild group-living fish.
Individuals that live in groups experience different challenges based on their social rank and sex. Glucocorticoids have a well-established role in coordinating responses to challenges and glucocorticoid levels often vary between ranks and sexes. However, the neuroendocrine mechanisms regulating glucocorticoid dynamics in wild groups are poorly understood, making it difficult to determine the functional consequences of differences in glucocorticoid levels. Therefore, we observed wild social groups of a cooperatively breeding fish (Neolamprologus pulcher) and evaluated how scale cortisol content (an emerging method to evaluate cortisol dynamics in fishes) and expression of glucocorticoid-related genes varied across group members. Scale cortisol was detectable in ~50% of dominant males (7/17) and females (7/15)-but not in any subordinates (0/16)-suggesting that glucocorticoid levels were higher in dominants. However, the apparent behavioural and neuroendocrine factors regulating cortisol levels varied between dominant sexes. In dominant females, higher cortisol was associated with greater rates of territory defense and increased expression of corticotropin-releasing factor in the preoptic and hypothalamic regions of the brain, but these patterns were not observed in dominant males. Additionally, transcriptional differences in the liver suggest that dominant sexes may use different mechanisms to cope with elevated cortisol levels. While dominant females appeared to reduce the relative sensitivity of their liver to cortisol (fewer corticosteroid receptor transcripts), dominant males appeared to increase hepatic cortisol breakdown (more catabolic enzyme transcripts). Overall, our results offer valuable insights on the mechanisms regulating rank- and sex-based glucocorticoid dynamics, as well as the potential functional outcomes of these differences.


Nonadiabatic semiclassical dynamics in the mixed quantum-classical initial value representation.
We extend the Mixed Quantum-Classical Initial Value Representation (MQC-IVR), a semiclassical method for computing real-time correlation functions, to electronically nonadiabatic systems using the Meyer-Miller-Stock-Thoss (MMST) Hamiltonian in order to treat electronic and nuclear degrees of freedom (dofs) within a consistent dynamic framework. We introduce an efficient symplectic integration scheme, the MInt algorithm, for numerical time evolution of the phase space variables and monodromy matrix under the non-separable MMST Hamiltonian. We then calculate the probability of transmission through a curve crossing in model two-level systems and show that MQC-IVR reproduces quantum-limit semiclassical results in good agreement with exact quantum methods in one limit, and in the other limit yields results that are in keeping with classical limit semiclassical methods like linearized IVR. Finally, exploiting the ability of the MQC-IVR to quantize different dofs to different extents, we present a detailed study of the extents to which quantizing the nuclear and electronic dofs improves numerical convergence properties without significant loss of accuracy.


Apixaban-Associated Diffuse Alveolar Hemorrhage in an Elderly Man with Multiple Complications.
BACKGROUND Diffuse alveolar hemorrhage (DAH) caused by direct oral anticoagulants (DOACs) has increased in recent years with the increase in prescriptions of DOACs. Generally, DOACs are considered to have a lower bleeding risk than the traditional anticoagulant, warfarin. However, major bleeding, including DAH, due to DOACs can be seen in clinical practice, and there are few reports to elucidate when DOAC-associated alveolar hemorrhage occurs and whether DOAC-induced DAH has a trigger. CASE REPORT An 80-year-old man diagnosed and treated for atrial fibrillation with apixaban 2.5 mg twice daily for 1 year before admission, underwent 2 invasive medical procedures over a short period of time. Hemoptysis began after the procedures. He experienced shortness of breath and rapidly progressive hypoxic respiratory failure. His postsurgical oxygen saturation level dropped rapidly. Chest radiography and computed tomography images showed pulmonary infiltration and ground-glass opacity in both lungs. Apixaban treatment was discontinued, and mechanical ventilation was initiated. Bronchoalveolar lavage cytology revealed hemosiderin-laden macrophages. A diagnosis of diffuse alveolar hemorrhage (DAH) was made. In previous reports about DAH caused by DOACs, most patients had bleeding triggers; drug interactions in patients taking DOACs are one of such triggers. Although DOACs are relatively safe for elderly patients, DAH can occur in patients receiving either early-stage or long-term treatment. CONCLUSIONS The onset of DOAC-associated DAH is not limited to the early stages of medication initiation. Various triggers can induce DAH in patients receiving DOACs.


An approach to preimplantation diagnosis of beta-thalassaemia.
Using the polymerase chain reaction (PCR), it was possible to amplify a single copy fragment of the beta-globin gene from 2-32 human embryonic cells obtained from arrested preimplantation embryos. For the detection of beta-thalassaemia mutations, allele specific priming of the PCR using nested primers was employed using approximately 10 pg of DNA from individuals known to carry these mutations. This approach was successful in detecting the presence or absence of five Asian Indian beta-thalassaemia mutations that were selected for this study. In spite of meticulous precautions against contamination, false-positive amplification was observed, a problem that will have to be overcome before this approach can be used in clinical practice.


TT-seq maps the human transient transcriptome.
Pervasive transcription of the genome produces both stable and transient RNAs. We developed transient transcriptome sequencing (TT-seq), a protocol that uniformly maps the entire range of RNA-producing units and estimates rates of RNA synthesis and degradation. Application of TT-seq to human K562 cells recovers stable messenger RNAs and long intergenic noncoding RNAs and additionally maps transient enhancer, antisense, and promoter-associated RNAs. TT-seq analysis shows that enhancer RNAs are short-lived and lack U1 motifs and secondary structure. TT-seq also maps transient RNA downstream of polyadenylation sites and uncovers sites of transcription termination; we found, on average, four transcription termination sites, distributed in a window with a median width of ~3300 base pairs. Termination sites coincide with a DNA motif associated with pausing of RNA polymerase before its release from the genome.