Possible role of glial cells in the relationship between thyroid dysfunction and mental disorders.
It is widely accepted that there is a close relationship between the endocrine system and the central nervous system (CNS). Among hormones closely related to the nervous system, thyroid hormones (THs) are critical for the development and function of the CNS; not only for neuronal cells but also for glial development and differentiation. Any impairment of TH supply to the developing CNS causes severe and irreversible changes in the overall architecture and function of the human brain, leading to various neurological dysfunctions. In the adult brain, impairment of THs, such as hypothyroidism and hyperthyroidism, can cause psychiatric disorders such as schizophrenia, bipolar disorder, anxiety and depression. Although impact of hypothyroidism on synaptic transmission and plasticity is known, its effect on glial cells and related cellular mechanisms remain enigmatic. This mini-review article summarizes how THs are transported into the brain, metabolized in astrocytes and affect microglia and oligodendrocytes, demonstrating an example of glioendocrine system. Neuroglial effects may help to understand physiological and/or pathophysiological functions of THs in the CNS and how hypo- and hyper-thyroidism may cause mental disorders.


Noncanonical B Cells: Characteristics of Uncharacteristic B Cells.
B lymphocytes were originally described as a cell type uniquely capable of secreting Abs. The importance of T cell help in Ab production was revealed soon afterward. Following these seminal findings, investigators made great strides in delineating steps in the conventional pathway that B cells follow to produce high-affinity Abs. These studies revealed generalized, or canonical, features of B cells that include their developmental origin and paths to maturation, activation, and differentiation into Ab-producing and memory cells. However, along the way, examples of nonconventional B cell populations with unique origins, age-dependent development, tissue localization, and effector functions have been revealed. In this brief review, features of B-1a, B-1b, marginal zone, regulatory, killer, NK-like, age-associated, and atypical B cells are discussed. Emerging work on these noncanonical B cells and functions, along with the study of their significance for human health and disease, represents an exciting frontier in B cell biology.


In situ hybridization analysis of protein kinase CK2 expression during plant development.
Protein kinase CK2 (EC 126.96.36.199) is a ubiquitous Ser/Thr kinase composed of two subunits, a subunit (catalytic) and a subunit (regulatory). Although CK2 is one of the components of the network that controls the eukaryotic cell cycle, very little is known about the developmental control of its expression, particularly in plants. Using in situ hybridization we have determined the pattern of expression of its two subunits in relation to plant morphogenesis. Our results show a cell-specific mRNA accumulation, equivalent for both subunits, which suggests a co-ordinate regulation during development. The spatial and temporal pattern of expression correlates with the appearance of the meristems, and high levels of transcripts are also present in differentiated tissues with high mitotic activity. These results confirm the transcriptional regulation of CK2 and establish a general correlation with cell proliferation in a developmental context. They also provide suggestive evidence for the requirement of CK2 expression for the initiation and organization of meristem activity.


The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties.
Human retinoblastoma arises from an undefined developing retinal cell after inactivation of RB1. This is emulated in a murine retinoblastoma model by inactivation of pRB by retinal-specific expression of simian virus 40 large T-antigen (TAg-RB). Some mutational events after RB1 loss in humans are recapitulated at the expression level in TAg-RB, supporting preclinical evidence that this model is useful for comparative studies between mouse and human. Here, the characteristics of the TAg-RB cell of origin are defined. TAg-RB mice were killed at ages from embryonic day (E)18 to postnatal day (P)35. Tumors were analyzed by immunostaining, DNA copy number PCR, or real-time quantitative RT-PCR for TAg protein, retinal cell type markers, and retinoblastoma-relevant genes. TAg expression began at P8 in a row of inner nuclear layer cells that increased in number through P21 to P28, when clusters reminiscent of small tumors emerged from cells that escaped a wave of apoptosis. Early TAg-expressing cells coexpressed the developmental marker Chx10 and glial markers CRALBP, clusterin, and carbonic anhydrase II (Car2), but not TuJ1, an early neuronal marker. Emerging tumors retained expression of only Chx10 and carbonic anhydrase II. As with human retinoblastoma, TAg-RB tumors showed decreased Cdh11 DNA copy number and gain of Kif14 and Mycn. It was confirmed that TAg-RB tumors lose expression of tumor suppressor cadherin-11 and overexpress oncogenes Kif14, Dek, and E2f3. TAg-RB tumors displayed molecular similarity to human retinoblastoma and origin in a cell with features of differentiated Müller glia with progenitor properties.


Biomarkers of fatigue related to adjuvant chemotherapy for breast cancer: evaluation of plasma and lymphocyte expression.
Fatigue is common in cancer patients receiving adjuvant chemotherapy. To further understand the mechanism of fatigue and search for potential biomarkers, we conducted this prospective study. Methods We enrolled breast cancer (BC) patients before their first adjuvant Adriamycin-based chemotherapy cycle. Patients responded to the brief fatigue inventory (BFI) and Chalder fatigue questionnaires and had their blood drawn for both plasma evaluation and evaluation of the peripheral mononuclear cell fraction (PMNCF) mRNA expression of various biomarkers. We evaluated FSH, LH, estradiol, DHEA, DHEAS, IL6, IL2, ILIRA, IL1β, CRP, Cortisol in the plasma and IL2, IL10, IL6, TGF-β, KLRC1, TNF, BTP, SNCA, SOD1, BLNK, PTGS2 and INF γ expression in the PMNCF. 11 patients did not exhibit an increase in their BFI scores and served as controls, whereas 32 patients exhibited an increase in their BFI scores compared with the baseline scores. From the biomarkers we evaluated in the PMNCF, the only one significantly associated with fatigue was TGF-β (p = 0.0343), while there was a trend towards significance with KLRC1 (p = 0.0627). We observed no evidence of significant associations of any plasma biomarkers with the development of fatigue. However when we analyzed patients with more severe fatigue, plasma IL1-RA levels correlated directly with higher fatigue scores (p = 0.0136). We conclude that fatigue induced by chemotherapy in BC patients is associated with changes in IL1-ra plasma levels and in TGF-β lymphocyte expression. Its mechanism may be different than that observed in long-term BC survivors or that induced by radiation therapy. NCT02041364 [ClinicalTrials.gov].


Physioxia Stimulates Extracellular Matrix Deposition and Increases Mechanical Properties of Human Chondrocyte-Derived Tissue-Engineered Cartilage.
Cartilage tissue has been recalcitrant to tissue engineering approaches. In this study, human chondrocytes were formed into self-assembled cartilage sheets, cultured in physiologic (5%) and atmospheric (20%) oxygen conditions and underwent biochemical, histological and biomechanical analysis at 1- and 2-months. The results indicated that sheets formed at physiological oxygen tension were thicker, contained greater amounts of glycosaminoglycans (GAGs) and type II collagen, and had greater compressive and tensile properties than those cultured in atmospheric oxygen. In all cases, cartilage sheets stained throughout for extracellular matrix components. Type II-IX-XI collagen heteropolymer formed in the neo-cartilage and fibrils were stabilized by trivalent pyridinoline cross-links. Collagen cross-links were not significantly affected by oxygen tension but increased with time in culture. Physiological oxygen tension and longer culture periods both served to increase extracellular matrix components. The foremost correlation was found between compressive stiffness and the GAG to collagen ratio.


Calorie restriction for long-term remission of type 2 diabetes.
Starting with a hypothesis which postulated a simple explanation arising from the basic cause of type 2 diabetes, a series of studies has introduced a paradigm shift in our understanding of the condition. Gradual accumulation of fat in the liver and pancreas leads eventually to beta cell dedifferentiation and loss of specialised function. The consequent hyperglycaemia can be returned to normal by removing the excess fat from liver and pancreas. At present this can be achieved only by substantial weight loss, and a simple practical and efficacious method for this has been developed and applied in a series of studies. For those people who used to have type 2 diabetes, the state of post-diabetes can be long term provided that weight regain is avoided. The implications for personal health and for national health economics are considerable.


Changes in prostacyclin synthase in pregnant sheep myometrium, endometrium, and placenta at spontaneous term labor and regulation by estradiol and progesterone.
Our purpose was to investigate, first, whether there were changes in the abundance of prostacyclin synthase protein in intrauterine tissues of pregnant ewes in association with spontaneous term labor. Second, we examined the effect of either estradiol or progesterone, or both, on regulation of prostacyclin synthase protein abundance in uterine tissues using an ovariectomized nonpregnant sheep model. The abundance of prostacyclin synthase protein was quantified by Western blot analysis in the myometrium, endometrium, and placenta of pregnant ewes in spontaneous term labor (n = 6) and term control ewes not in labor (n = 6). The changes of prostacyclin synthase in the myometrium and endometrium of 20 ovariectomized nonpregnant sheep (n = 5 for each group) were evaluated after treatment with estradiol, progesterone, or both. Prostacyclin synthase protein was present in pregnant and nonpregnant sheep myometrium, endometrium, and placenta at a molecular weight of about 55 kd. At spontaneous term labor the level of prostacyclin synthase decreased in endometrium (P <.05), increased in myometrium (P <.05), and remained unchanged in placenta. Estradiol and progesterone had no effect on prostacyclin synthase protein abundance in nonpregnant ovine endometrium and myometrium. The decrease in prostacyclin synthase in pregnant sheep endometrium during labor may indicate paracrine interactions between the endometrium, the myometrium, fetal membranes, or a combination of these. The significant increase of prostacyclin synthase in pregnant sheep myometrium at spontaneous term labor may contribute to the increased uterine sensitivity to oxytocin or stimulate vasodilatation during labor to increase myometrial blood flow. Neither estradiol nor progesterone at the dosages studied changed prostacyclin synthase expression in the nonpregnant myometrium and endometrium. The molecular mechanism or mechanisms that differentially regulate prostacyclin synthase expression in pregnant uterine tissues merit further study.


Complete genome sequence analysis and genome organization of Dasychira pudibunda nucleopolyhedrovirus (DapuNPV-T1) from Turkey.
The economically important pale tussock moth Dasychira pudibunda L. (Lepidoptera: Lymantriidae), known as a beech pest in Europe, primarily inflicts damage on beech leaves. In the present study, we aim to reveal the genome characteristics of Dasychira pudibunda nucleopolyhedrovirus (DapuNPV-T1), which was detected for the first time in Turkey and compare it with the reference genome and other baculovirus genomes. The DapuNPV-T1 genome was determined to be a circular, double-stranded DNA molecule with 136,920 bp and a nucleotide distribution of 54.4% G + C. Bioinformatics analysis showed that the DapuNPV-T1 genome contains 163 open reading frames with more than 150 nucleotides. Fifty-four ORFs of unknown function, 6 homologous regions (hrs), 1 AC-rich region, and 3 bro genes (bro-a, bro-b, and bro-c) were determined in the genome sequence. Comparative analysis with other baculovirus strains revealed distinctions in the DapuNPV-T1 genome based on ORF. The gene parity plot and phylogenetic analysis confirmed that DapuNPV-T1 belongs to the alphabaculovirus group Ib. In addition, the DapuNPV-T1 isolate was found to be close to the nucleopolyhedrovirus Poland isolate in Dasychira pudibunda and Orgyia pseudotsugata multiple nucleopolyhedrovirus. With this study, the first genome analysis of DapuNPV from Turkey became the second in the world to enter the literature. Comprehensive information on a wide range of isolates will provide a more detailed overview of baculoviruses and help overcome their shortcomings as biocontrol agents.


Prioritization of neurodevelopmental disease genes by discovery of new mutations.
Advances in genome sequencing technologies have begun to revolutionize neurogenetics, allowing the full spectrum of genetic variation to be better understood in relation to disease. Exome sequencing of hundreds to thousands of samples from patients with autism spectrum disorder, intellectual disability, epilepsy and schizophrenia provides strong evidence of the importance of de novo and gene-disruptive events. There are now several hundred new candidate genes and targeted resequencing technologies that allow screening of dozens of genes in tens of thousands of individuals with high specificity and sensitivity. The decision of which genes to pursue depends on many factors, including recurrence, previous evidence of overlap with pathogenic copy number variants, the position of the mutation in the protein, the mutational burden among healthy individuals and membership of the candidate gene in disease-implicated protein networks. We discuss these emerging criteria for gene prioritization and the potential impact on the field of neuroscience.


Triazole-Based Half-Sandwich Ruthenium(II) Compounds: From In Vitro Antiproliferative Potential to In Vivo Toxicity Evaluation.
A new series of half-sandwich ruthenium(II) compounds [(η6-arene)Ru(L)Cl][CF3SO3] bearing 1,2,3-triazole ligands (arene = p-cymene, L = L1 (1); arene = p-cymene, L = L2 (2); arene = benzene, L = L1 (3); arene = benzene, L2 (4); L1 = 2-[1-(p-tolyl)-1H-1,2,3-triazol-4-yl]pyridine and L2 = 1,1'-di-p-tolyl-1H,1'H-4,4'-bi(1,2,3-triazole) have been synthesized and fully characterized by 1H and 13C NMR and IR spectroscopy, mass spectrometry, and elemental analysis. The molecular structures of 1, 2, and 4 have been determined by single-crystal X-ray diffraction. The cytotoxic activity of 1-4 was evaluated using the MTS assay against human tumor cells, namely ovarian carcinoma (A2780), colorectal carcinoma (HCT116), and colorectal carcinoma resistant to doxorubicin (HCT116dox), and against normal primary fibroblasts. Whereas compounds 2 and 4 showed no cytotoxic activity toward tumor cell lines, compounds 1 and 3 were active in A2780, while showing no antiproliferative effect in human normal dermal fibroblasts at the IC50 concentrations of the A2780 cell line. Exposure of ovarian carcinoma cells to IC50 concentrations of compound 1 or 3 led to an accumulation of reactive oxygen species and an increase of apoptotic and autophagic cells. While compound 3 displayed low levels of angiogenesis induction, compound 1 showed an ability to induce cell cycle delay and to interfere with cell migration. When the in vivo toxicity studies using zebrafish and chicken embryos are considered, compounds 1 and 3, which were not lethal, are promising candidates as anticancer agents against ovarian cancer due to their good cytotoxic activity in tumor cells and their low toxicity both in vitro and in vivo.


The history of the prolonged depolarizing afterpotential (PDA) and its role in genetic dissection of Drosophila phototransduction.
In invertebrate photoreceptors, the photopigment exhibits a long-lived and physiologically active photoproduct, called metarhodopsin (M). The long life of invertebrate M implies that under physiological conditions, M and the original pigment state rhodopsin, R, are in photoequilibrium. In many invertebrates, the absorption spectra of R and M states are different, allowing large photopigment conversion between R and M states. These net pigment molecules conversions between R and M are the basis of the prolonged depolarizing afterpotential (PDA) phenomenology, which is the main subject of this review. A large net conversion of R to M disrupts phototransduction termination at the photopigment level, which in turn results in sustained excitation long after the light is turned off. Throughout this period, the photoreceptors are partially desensitized and are insensitive (or less sensitive) to subsequent test lights. In Drosophila, the PDA tests the maximal capacity of the photoreceptor cell to maintain excitation for an extended period and is strictly dependent on the presence of high concentrations of rhodopsin and the transient receptor potential (TRP) channels. Therefore, it detects even minor defects in rhodopsin or TRP biogenesis and easily scores deficient replenishment of phototransduction components, which results in temporary desensitization of the phototransduction process. Indeed, the introduction and use of PDA to screen for phototransduction-defective Drosophila mutants by Pak and colleagues yielded a plethora of new and most interesting visual mutants. Remarkably, to this day, the PDA mutants that Pak and his colleagues isolated are the main source of mutants for analysis of the Drosophila visual system.


Molokai fracture zone: continuation west of the hawaiian ridge.
The Molokai Fracture Zone is one of the principal east-west (striking) fracture zones between California and the mid-Pacific. On the basis of bathymetry alone, it has been assumed that the zone ended abruptly east of the Hawaiian Islands. Use of correlation techniques between bathymetric features and their magnetic anomalies in the vicinity of the islands now show that structural elements of the zone cross the islands and continue westward for at least 130 kilometers. Recent volcanism and deep rift zones of the islands parallel the zone, suggesting structural correlation between the strike of the zone and the origin of recent volcanism in the islands.


Inhibition of IFN-gamma signaling by glucocorticoids.
Recent reports suggest that a novel mechanism of glucocorticoid (GC) immunosuppressive action is inhibition of signaling by IL-2 and IL-12, cytokines that use the Janus kinase-STAT signaling pathway. We investigated whether GCs could also block activation of Janus kinase-STAT signaling by IFN-gamma, a potent proinflammatory cytokine. Addition of dexamethasone to PBMC cultures resulted in a dramatic inhibition of IFN-gamma activation of STAT1. Several days of exposure to GCs were required for inhibition of IFN-gamma signaling to become apparent, and the underlying mechanism was down-regulation of STAT1 expression. GCs suppressed the expression of STAT1 mRNA, but did not affect STAT1 protein stability. STAT1 expression and IFN-gamma signaling were preferentially suppressed in macrophages. GCs did not act directly on macrophages, but worked indirectly by regulating macrophage-lymphocyte interactions that control STAT1 expression. GCs inhibited IFN-gamma-inducible gene expression, thus demonstrating the physiological significance of inhibition of signal transduction. Our results identify a novel level of regulation of IFN-gamma signaling, whereby GCs control the amplitude of IFN-gamma signaling by regulating STAT1 expression. These results suggest that inhibition of IFN-gamma signaling contributes to the immunosuppressive action of GCs.


Substituting carbamazepine with oxcarbazepine increases citalopram levels. A report on two cases.
The combination of antiepileptic and psychotropic medications is not uncommon. The widely used anticonvulsant carbamazepine, however, has been found to induce the degradation of many psychiatric drugs. On the contrary, its 10-keto analog oxcarbazepine does not have a significant effect on the metabolism of concomitant drugs. Consequently, when carbamazepine medication is changed to oxcarbazepine, the serum concentrations of various concurrently used drugs may increase, resulting in alterations in the therapeutic and toxic response. In this paper we describe two patients with comorbid epilepsy, major depression, and panic disorder, whose serum citalopram levels increased and antidepressant response changed when concurrent carbamazepine treatment was substituted with oxcarbazepine.


Examination of sexually abused children.
The approach to the examination of sexually abused children differs from that of normal for sick children and also from that of adults who have been the victims of rape. While the physical and psychological welfare of the patient must be the prime concern, medico-legal aspects are equally important. In the interests of the patient the initial examination and subsequent management and follow-up should be done by those with specific skills and with the support of members of disciplines essential to the total management of the complex and not uncommon problem of sexual abuse in children.


[Quality of pharma rep meetings in general practice].
For many general practitioners (GPs), visits from pharmaceutical representatives (reps) are common settings for receiving updated drug information. We here aim to describe the content and assess the quality of information provided by reps visiting Norwegian GPs. Medical students filled in a questionnaire addressing one pharma rep visit they had experienced during their 6-week general practice period in their fifth year at medical school in Oslo (2001 and 2002). Students from three classes participated and 144/241 (60 %) of them returned completed questionnaires. The 144 pharma rep meetings addressed 64 different and mostly new drugs, most commonly cardiovascular and pulmonary preparations. The visit was most commonly conducted during a free lunch (90 %) for the entire practice staff (81 %). The representatives offered the GPs free drug samples (41 %), and small presents (44 %). Four of five visits were characterized by incomplete or lacking information about side effects, interactions, contraindications or precautions for using the drug. The students scored their educational benefit from the session on a visual analogue scale from 0 (poor) to 10 (excellent), which revealed a mean score of less than neutral, 4.2. The systematic omittance of important safety information, emphasizes the need for industry unbiased continuing medical drug education in general practice.


Transformation of bisphenol A and alkylphenols by ammonia-oxidizing bacteria through nitration.
Transformation of bisphenol A (BPA) by ammonia-oxidizing bacteria (AOB) Nitrosomonas europaea ATCC 19718 was investigated. On the basis of the ultraperformance liquid chromatography (UPLC) coupled to quadrupole time-of-flight mass spectrometry (Q-TOF MS) and nuclear magnetic resonance analysis, we found N. europaea could transform BPA into nitro- and dinitro-BPA, suggesting that abiotic nitration between the biogenic nitrite and BPA played a major role in the transformation of BPA in the batch AOB system. Nitrite concentrations, temperature, and pH values were the major factors to influence the reaction rate. Furthermore, the yeast estrogenic screening assay showed that the formed nitro- and dinitro-BPA had much less estrogenic activity as compared with its parent compound BPA. Similar reactions of abiotic nitration were considered for 4-n-nonylphenol (nNP) and 4-n-octylphenol (nOP) since nitro-nNP and nitro-nOP were detected by UPLC-Q-TOF MS. In addition, results from the local wastewater treatment plant (WWTP) showed the occurrence of nitro-BPA and dinitro-BPA during the biological treatment process and in the effluent, indicating that nitration of BPA is also a pathway for removal of BPA. Results of this study provided implication that AOB in the WWTPs might contribute to removal of selected endocrine-disrupting compounds (EDCs) through abiotic nitritation.


Hypoxia up-regulates the activity of a novel erythropoietin mRNA binding protein.
The mechanisms which control the production of erythropoietin (Epo) remain enigmatic. Recent data suggest that the half-time of Epo messenger RNA (mRNA) is increased by hypoxia in Hep 3B cells, a human hepatoma line. The post-transcriptional regulation of other rapidly degraded mRNAs is mediated by sequence-specific mRNA binding proteins. In order to determine if Epo mRNA specific binding proteins exist, we probed cytosolic lysates from Hep 3B cells and mouse tissues with radiolabeled Epo RNA. A cytosolic protein that binds specifically to Epo RNA was identified in the Epo-producing, hepatoblastoma Hep 3B cell line by gel mobility shift assay. This protein was identified in both normoxic and hypoxic cells and bound specifically to a 120-base fragment of the 3'-untranslated region (3'-UTR) of Epo mRNA. Binding was completed with unlabeled Epo RNA, but not with granulocyte-macrophage colony-stimulating factor RNA. Ultraviolet light cross-linked Epo RNA-protein complexes migrated as two bands of 70 and 135-140 kD on sodium dodecyl sulfate-polyacrylamide gels. Binding activity was markedly increased in brain and spleen lysates from mice subjected to 24 h of hypoxia. Therefore, the post-transcriptional regulation of Epo expression in response to hypoxia may in part be due to the interaction of Epo RNA with its specific binding protein.


Interorgan synthesis of arginine is down-regulated in tumor-bearing mice undergoing surgical trauma.
Renal de novo arginine production has been suggested to be crucial for regulation of arginine production in disease. We investigated how the interorgan pathway for de novo arginine production is affected by the presence of malignant tumor and/or surgical trauma. Controls and methylcholanthrene-sarcoma-bearing mice were studied, both with and without undergoing laparotomy (n = 9-13 per group). One day after laparotomy, amino acid fluxes across the hindquarter, intestine, liver, and kidney were studied. In contrast to healthy mice, the liver of tumor-bearing mice took up citrulline (9 +/- 3 vs 1 +/- 2 nmol/[10 g min], P < .05), simultaneous with attenuated renal arginine output (4 +/- 3 vs 12 +/- 2 nmol/[10 g min], P < .05), despite increased intestinal conversion of glutamine to citrulline (15 +/- 3 vs 8 +/- 1 nmol/[10 g min], P < .05). In tumor-bearing mice undergoing surgery, intestinal citrulline output decreased (from 15 +/- 3 to 8 +/- 2 nmol/[10 g min], P < .05) and renal arginine output remained close to zero despite increased renal citrulline uptake (from 6 +/- 2 to 12 +/- 2 nmol/[10 g min], P < .05). In conclusion, the interorgan pathway for de novo arginine production was differently regulated depending on the pathophysiological situation. In methylcholanthrene-sarcoma-bearing mice, decreased de novo arginine production was accompanied by the presence of hepatic citrulline uptake, whereas tumor-bearing mice subjected to surgical trauma showed concomitant decreased intestinal citrulline output.


Diabetes and hypertension increases in a society with abdominal obesity: results of the Mexican National Health Survey 2000.
To determine the prevalences of overweight, obesity, type 2 diabetes mellitus (DM) and hypertension (HT) in the Mexican population and compare them with those of a previous Mexican urban survey and an American survey. A structured, randomised, nationally representative Mexican sample was compared with a 1993 Mexican urban survey and the US Third National Health and Nutrition Examination Survey (NHANES III) of non-Hispanic Whites. The Mexican National Health Survey 2000. SUBJECTS were 12,856 men and 28,332 women, aged 20-69 years, who had their body weight, height, waist circumference (WC), blood pressure and fasting capillary blood glucose measured. Mexican adult men and women had a high prevalence of overweight (41.3 and 36.3%, respectively) and obesity (19.4 and 29.0%, respectively), similar to those in the USA in 1988-1992 and exceeding those of the 1993 Mexican survey. The prevalence of HT was 33.3% in men and 25.6% in women, with inferred DM rates of 5.6 and 9.7%, respectively. Abdominal obesity affected 46.3% of men (WC>or=94 cm) and 81.4% of women (WC>or=80 cm). There was a high prevalence of abdominal obesity in normal-weight women, with co-morbidities relating better to WC than to body mass index (BMI) in both sexes. Rates of DM and HT exceeded US rates on a comparable BMI or WC basis in adults aged <50 years. The high prevalence of obesity and abdominal obesity in Mexicans is associated with markedly increased prevalences of DM and HT to levels comparable with, or even higher than, those in NHANES III of non-Hispanic Whites.


Activation of IL-27 signalling promotes development of postinfluenza pneumococcal pneumonia.
Postinfluenza pneumococcal pneumonia is a common cause of death in humans. However, the role of IL-27 in the pathogenesis of secondary pneumococcal pneumonia after influenza is unknown. We now report that influenza infection induced pulmonary IL-27 production in a type I IFN-α/β receptor (IFNAR) signalling-dependent manner, which sensitized mice to secondary pneumococcal infection downstream of IFNAR pathway. Mice deficient in IL-27 receptor were resistant to secondary pneumococcal infection and generated more IL-17A-producing γδ T cells but not αβ T cells, thereby leading to enhanced neutrophil response during the early phase of host defence. IL-27 treatment could suppress the development of IL-17A-producing γδ T cells activated by Streptococcus pneumoniae and dendritic cells. This suppressive activity of IL-27 on γδ T cells was dependent on transcription factor STAT1. Finally, neutralization of IL-27 or administration of IL-17A restored the role of γδ T cells in combating secondary pneumococcal infection. Our study defines what we believe to be a novel role of IL-27 in impairing host innate immunity against pneumococcal infection.


Secure Outsourced Matrix Computation and Application to Neural Networks.
Homomorphic Encryption (HE) is a powerful cryptographic primitive to address privacy and security issues in outsourcing computation on sensitive data to an untrusted computation environment. Comparing to secure Multi-Party Computation (MPC), HE has advantages in supporting non-interactive operations and saving on communication costs. However, it has not come up with an optimal solution for modern learning frameworks, partially due to a lack of efficient matrix computation mechanisms. In this work, we present a practical solution to encrypt a matrix homomorphically and perform arithmetic operations on encrypted matrices. Our solution includes a novel matrix encoding method and an efficient evaluation strategy for basic matrix operations such as addition, multiplication, and transposition. We also explain how to encrypt more than one matrix in a single ciphertext, yielding better amortized performance. Our solution is generic in the sense that it can be applied to most of the existing HE schemes. It also achieves reasonable performance for practical use; for example, our implementation takes 9.21 seconds to multiply two encrypted square matrices of order 64 and 2.56 seconds to transpose a square matrix of order 64. Our secure matrix computation mechanism has a wide applicability to our new framework E2DM, which stands for encrypted data and encrypted model. To the best of our knowledge, this is the first work that supports secure evaluation of the prediction phase based on both encrypted data and encrypted model, whereas previous work only supported applying a plain model to encrypted data. As a benchmark, we report an experimental result to classify handwritten images using convolutional neural networks (CNN). Our implementation on the MNIST dataset takes 28.59 seconds to compute ten likelihoods of 64 input images simultaneously, yielding an amortized rate of 0.45 seconds per image.


Designing rites to re-enchant secularized society: new varieties of spiritualized therapy in contemporary Sweden.
Detraditionalization in late modernity in Western society has affected the domains of both traditional religion and clinical psychotherapy. Sweden, which is said to be one of the most secularized societies in the world, instead, has allowed the public domain to be colonized by new, spiritualized practices. Sold as therapy, the services of new spiritual leaders offer anti-stress techniques to prevent burnout, or leaders are trained to develop their leadership in coaching activities. New varieties of spiritualized therapy are rapidly increasing in contemporary Sweden, typical of which is to have added healing rhetoric to their agenda, such as "find your inner self" or "develop your inner potential." Four common denominators seem to guide these practices: self-appointed leaders, individual-centered rites, realization of one's Self, and intense emotions. We might also add a fifth aspect: profit. Rites have become a commodity and are sold as liberating practices for burnt-out souls or for people in pursuit of self-realization.


Hyperchloraemic acidosis: another misnomer?
To review the term hyperchloraemic acidosis. Articles and reviews from peer reviewed journals on acid-base physiology. The concept of hyperchloraemic acidosis is well established in medicine and regularly taught to medical students. Unfortunately, it is yet another medical misnomer. Hyperchloraemic acidosis is only likely to exist with normal plasma sodium concentrations. This is because the acidosis is due to a decreased strong-ion-difference rather than the hyperchloraemia alone. If hyponatraemia is present, an identical acidosis can exist without hyperchloraemia; or if hypernatraemia is present there may be hyperchloraemia without acidosis. Even those who cling to the bicarbonate centred approach to acid-base physiology should recognise that describing acid-base changes in terms of chloride alone is less meaningful than considering both the strong cations and the strong anions. For those clinicians, using the Stewart approach the value of the terms "strong ion acidosis" and "strong ion alkalosis" should be readily apparent. The use of the term hyperchloraemic acidosis is a misnomer as the chloride ion may be elevated or depressed in the absence of an acid bade abnormality.


[Mesenchymal stem cells as perspective method of fibrosis/cirrhosis treatment].
THE PURPOSE OF THE REVIEW: Discuss the background and available results of transplantation of bone marrow stem cells as a promising treatment of hepatic fibrosis. KEY PROVISIONS: Actuality of the problem of chronic hepatitis is present due to their progressive course with the formation of liver cirrhosis and a high level of mortality. Conservative treatment of patients with decompensated process requires a liver transplantation that is compounded by the high percentage of graft reinfection in infectious hepatology. It is necessary to study the use of bone marrow-derived stem cells transplantation, because MSCs have certain therapeutic potential, low immunogenicity and the capacity for directional migration. In experimental models MSCs mechanisms of action are shown to limit the progression of liver fibrosis and stimulation of regeneration processes. In clinical studies good tolerability and relative safety of administration of autologous MSCs have reported as well as the positive effects on liver synthetic function, a decrease in the severity of cirrhosis on class Child-Pugh and MELD, reduction in overall mortality are shown. The results of our own prospective pilot study using autologous MSCs from bone marrow in patients with HCV-associated liver cirrhosis are described. MSCs can exert multiple synergistic effects on the hepatic stellate cells, reduce inflammation in the liver tissue remodeling processes and fibrogenesis. For objective evidence of the clinical benefits of the method, evaluation of long-term efficacy and safety of MSCs, as well as developing rational strategies, further clinical studies are required.


Epidermal growth factor receptor activation: an upstream signal for transition of quiescent astrocytes into reactive astrocytes after neural injury.
Modulating the behaviors of reactive astrocytes is a potential therapeutic strategy for neurodegenerative diseases. We found that upregulation and activation of the epidermal growth factor receptor (EGFR) occur in astrocytes after different injuries in optic nerves in vivo. Activation of EGFR regulates genes and cellular processes representing most major markers of reactive astrocytes and genes related with glaucomatous optic neuropathy and other neural disorders. These results suggest that activation of EGFR is a common, regulatory pathway that triggers quiescent astrocytes into reactive astrocytes in response to neural injuries in the optic nerve, and perhaps other parts of the CNS. Targeting EGFR activation using an EGFR tyrosine kinase inhibitor prevents the loss of retinal ganglion cells in a model of glaucomatous optic neuropathy. Because these inhibitors are currently used clinically, our results present an approach to reactive astrocytes as a potential new target for the treatment of neurodegenerations.


An international analysis of the price and affordability of beer.
To apply methods for measuring the affordability of beer in a large cross section of countries, and to investigate trends in affordability of beer over time. We use the Relative Income Price (RIP), which uses per capita GDP, to measure the affordability of beer in up to 92 countries from 1990 to 2016 (69 countries were included in 1990, however the survey has since grown to include 92 countries). In addition to affordability, we also investigate trends in the price of beer. While beer is, on average, similarly priced in high-income (HICs) and low- and middle-income countries (LMICs), it is significantly more affordable in HICs. There is significant variation in both price and affordability in HICs and in LMICs. Beer has become cheaper in real terms in 49% (18/37) of HICs and 43% (20/46) of LMICs. Beer became more affordable in most HICs (RIP: 30/37 or 81%) and LMICs (RIP: 42/44 or 95%). The increased affordability over time of beer in most countries raises concerns about public health. Governments need to increase taxes on beer so that it becomes less affordable over time, in an effort to improve public health.


A Retrospective Study of 158 Cases on the Risk Factors for Recurrence in Ameloblastoma.
Background: Ameloblastoma is an odontogenic tumor occurring in jaws, with local aggressiveness and postoperative recurrence. This study was aim to investigate the clinical and radiographic risk factors for recurrence in ameloblastoma. Methods: Patients diagnosed with ameloblastoma between March 2009 and March 2019 were retrospectively analyzed. Clinical and Radiological data and follow-up records were collected. Survival analyses were performed by Kaplan-Meier and log-rank tests, as well as Cox proportional hazards model. Results: One hundred and fifty-eight patients (104 males and 54 females were enrolled. The overall recurrence rate for ameloblastoma was 13.29%, and 10.76% recurred within 5 years. Most of the tumors were located in mandible (86.71%), while the rest 21 cases were in maxilla (13.29%). More than half cases (55.06%) showed multilocular radiolucency, 61 cases (38.61%) showed unilocular radiolucency. Significant differences were found with amelobastoma recurrence rate related to treatment modality, impacted tooth and root resorption (P =0.002, 0.022 and 0.007 respectively). Conclusions: Treatment modality, impacted tooth and root resorption all showed statistically significant associations with the recurrence rate in ameloblastoma. However, due to the limitation of this study, further studies are needed to reveal the true mechanism of ameloblastoma recurrence.


Genomic and phenotypic response of hornyhead turbot exposed to municipal wastewater effluents.
Laboratory tests with marine flatfish were conducted to investigate associations among gene expression, higher biological responses and wastewater effluent exposure. In the present study, male hornyhead turbot (Pleuronichthys verticalis) were exposed to environmentally realistic (0.5%) and higher (5%) concentrations of chemically enhanced advanced-primary (PL) and full-secondary treated (HTP) effluents from two southern California wastewater treatment plants (WWTP). Hepatic gene expression was examined using a custom low-density microarray. Alterations in gene expression (vs. controls) were observed in fish exposed to both effluent types. Fish exposed to 0.5% PL effluent showed changes in genes involved in the metabolism of xenobiotics, steroids, and lipids, among other processes. Fish exposed to 5% PL effluent showed expression changes in genes involved in carbohydrate metabolism, stress responses, xenobiotic metabolism, and steroid synthesis, among others. Exposure to 5% HTP effluent changed the expression of genes involved in lipid, glutathione and xenobiotic metabolism, as well as immune responses. Although no concentration-dependent patterns of response to effluent exposure were found, significant Spearman correlations were observed between the expression of 22 genes and molecular and/or higher biological responses. These results indicate that microarray gene expression data correspond to higher biological responses and should be incorporated in studies assessing fish health after exposure to complex environmental mixtures.


Inhibition of Stearoyl-CoA Desaturase Induces the Unfolded Protein Response in Pancreatic Tumors and Suppresses Their Growth.
Pancreatic ductal adenocarcinoma is the fourth-leading cause of cancer death in the United States, and there is an urgent need for effective therapies. Stearoyl-CoA desaturase (SCD) is an enzyme localized in the endoplasmic reticulum and generates monounsaturated fatty acid from saturated fatty acid. In this study, we examined the role of SCD in pancreatic cancer. We isolated epithelial cell adhesion molecule-positive pancreatic tumors from the Pdx1Cre;LSL-KrasG12D mouse and formed organoids in Matrigel. Using a SCD inhibitor, A939572, we tested its effects on growth and cell death in tumor organoids, tumors developed in the Pdx1Cre;LSL-KrasG12D mouse, and a human pancreatic ductal adenocarcinoma cell line, PANC-1. A939572 treatment rapidly induced degeneration of mouse tumor organoids and activated the unfolded protein response (UPR). Cotreatment of oleic acid, but not stearic acid, reduced the UPR in the organoids and rescued the inhibitory effect of the SCD inhibitor on their growth. Administration of A939572 to Pdx1Cre;LSL-KrasG12D mice caused cell death in early pancreatic tumors, but not in acini or islets. The SCD inhibitor induced the UPR in PANC-1 and suppressed their growth but did not induce cell death. The inhibition of the SCD enzyme causes an UPR and cell death in early pancreatic tumors.


Future directions of paclitaxel-based therapy of breast cancer.
In the past 15 years, substantial progress has been made in the treatment of breast cancer, but management of women with breast cancer is still not curative in many patients. One important goal of new treatment strategies is that of defining criteria to specifically indicate therapies so that therapeutic benefit will no longer result from the indiscriminate application of treatment to all patients within a broad category of risk. This approach could be applied to paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ). The taxane is one of the most active new drugs developed for women with breast cancer. A number of conventional comparative trials are ongoing to assess its role in different stages of the disease. Some of its features, however, are suitable to explore more specific and relevant questions. Possibly because of paclitaxel's documented antiangiogenic properties, its high efficacy in combination could also provide an as yet unproven survival advantage in advanced breast cancer, with the drug being administered for adequately prolonged periods of time as a single agent after initial induction of response. In addition, available evidence suggests that patients with poor prognosis associated with overexpression of c-erb B2 (HER2) have a higher probability of responding to paclitaxel than patients with HER2-negative tumors. The clarification of this possibility is a priority. Should HER2 status be a predictor of response to paclitaxel and paclitaxel-based therapy, the use of the drug could be tailored to specific patient characteristics. The ability to discriminate between paclitaxel as a therapeutic option or a therapeutic indication is one of the challenges of the future development of this important drug.


Mass mortality of Eurasian Tree Sparrows (Passer montanus) from Salmonella Typhimurium dt40 in Japan, winter 2008-09.
An outbreak of salmonellosis in wild passerines caused mass mortality of Eurasian Tree Sparrows (Passer montanus) in Hokkaido, Japan, 2005-06; however, the etiology was poorly understood. In winter 2008-09, sparrow mortality again occurred in Hokkaido, and 202 deaths in 100 incidents at 94 sites were reported. We conducted a comprehensive investigation to evaluate the cause and impact on sparrow populations. We collected 26 carcasses at 13 sites, including a zoological park. In addition, Salmonella screening of zoo animals was conducted as a biosecurity measure. Salmonella Typhimurium was isolated from multiple organs in all examined sparrows; they were diagnosed with septicemic salmonellosis. Eleven sites (85%) were related to wild bird feeding and six of eight sparrow fecal samples, including from the zoo, were S. Typhimurium-positive. No infection was detected in zoo animals. Isolates belonged to three phage types: DT40 (88%), DT110 (8%), and DT120 (4%). Pulsed-field gel electrophoresis patterns were the same in all isolates, regardless of phage type. Biochemical characteristics and antibiotic-resistance profiles of DT40 were similar in all isolates, indicating a single origin. The mortality was likely associated with that in 2005-06 because the isolates had the same profiles. Tissue levels of sodium, calcium, and magnesium (the main components of chemical deicer suspected to be the major cause of poisoning deaths in 2005-06 mortality) were not higher in the affected sparrows. We conclude that an emerging epidemic infection with S. Typhimurium DT40 related to bird feeding was the cause of sparrow mortality in 2008-09 and suggest that this causative strain is host-adapted to sparrows in Japan. The mortality might have had some impact on the local population, but its influence was limited.


Gastrointestinal Stromal Tumor: An Uncommon but Serious Cause of Gastrointestinal Bleeding.
Gastrointestinal stromal tumors (GISTs) are rare tumors of the GI tract that can sometimes present as a gastrointestinal bleeding source. This report describes a patient presented with upper GI bleeding secondary to a gastric GIST, which was initially detected on endoscopy. The patient underwent surgical resection of the tumor and was started on adjuvant chemotherapy with imatinib. The patient's postoperative course was complicated by an esophageal leak requiring re-exploratory laparotomy and esophageal stent placement. The stent was removed 5 weeks later and the patient remained stable for discharge after 60 days of inpatient care.


Centrally induced cardiovascular and sympathetic responses to hydrocortisone in rats.
Central effects of hydrocortisone were investigated by injecting it intracerebroventricularly (icv) while recording blood pressure and heart rate in awake rats. Dose-dependent increases in both blood pressure and heart rate occurred following injections of hydrocortisone. Pretreatment by icv injections of the angiotensin II antagonist, [Sar1-Ile8]angiotensin II, completely abolished vasopressor responses to subsequent injections of hydrocortisone. When rats were later anesthetized with urethan to allow recording of abdominal sympathetic nerve activity, hydrocortisone produced vasopressor responses accompanied by corresponding increases in sympathetic nerve firing, which were also abolished by central pretreatment with either [Sar1-Ile8]angiotensin II or angiotensin I converting-enzyme inhibitor, captopril. These results indicate that centrally administered hydrocortisone stimulates the brain renin-angiotensin system to produce vasopressor responses by increasing sympathetic nerve firing.


Crystal structure of interleukin-6 in complex with a modified nucleic acid ligand.
IL-6 is a secreted cytokine that functions through binding two cell surface receptors, IL-6Rα and gp130. Because of its involvement in the progression of several chronic inflammatory diseases, IL-6 is a target of pharmacologic interest. We have recently identified a novel class of ligands called SOMAmers (S low Off-rate Modified Aptamers) that bind IL-6 and inhibit its biologic activity. SOMAmers exploit the chemical diversity of protein-like side chains assembled on flexible nucleic acid scaffolds, resulting in an expanded repertoire of intra- and intermolecular interactions not achievable with conventional aptamers. Here, we report the co-crystal structure of a high affinity SOMAmer (Kd = 0.20 nm) modified at the 5-position of deoxyuridine in a complex with IL-6. The SOMAmer, comprised of a G-quartet domain and a stem-loop domain, engages IL-6 in a clamp-like manner over an extended surface exhibiting close shape complementarity with the protein. The interface is characterized by substantial hydrophobic interactions overlapping the binding surfaces of the IL-6Rα and gp130 receptors. The G-quartet domain retains considerable binding activity as a disconnected autonomous fragment (Kd = 270 nm). A single substitution from our diversely modified nucleotide library leads to a 37-fold enhancement in binding affinity of the G-quartet fragment (Kd = 7.4 nm). The ability to probe ligand surfaces in this manner is a powerful tool in the development of new therapeutic reagents with improved pharmacologic properties. The SOMAmer·IL-6 structure also expands our understanding of the diverse structural motifs achievable with modified nucleic acid libraries and elucidates the nature with which these unique ligands interact with their protein targets.


Neural Reorganization Due to Neonatal Amygdala Lesions in the Rhesus Monkey: Changes in Morphology and Network Structure.
It is generally believed that neural damage that occurs early in development is associated with greater adaptive capacity relative to similar damage in an older individual. However, few studies have surveyed whole brain changes following early focal damage. In this report, we employed multimodal magnetic resonance imaging analyses of adult rhesus macaque monkeys who had previously undergone bilateral, neurotoxic lesions of the amygdala at about 2 weeks of age. A deformation-based morphometric approach demonstrated reduction of the volumes of the anterior temporal lobe, anterior commissure, basal ganglia, and pulvinar in animals with early amygdala lesions compared to controls. In contrast, animals with early amygdala lesions had an enlarged cingulate cortex, medial superior frontal gyrus, and medial parietal cortex. Diffusion-weighted imaging tractography and network analysis were also used to compare connectivity patterns and higher-level measures of communication across the brain. Using the communicability metric, which integrates direct and indirect paths between regions, lesioned animals showed extensive degradation of network integrity in the temporal and orbitofrontal cortices. This work demonstrates both degenerative as well as progressive large-scale neural changes following long-term recovery from neonatal focal brain damage.


Sound-driven fluid dynamics in pressurized carbon dioxide.
Using high-speed visualization we demonstrate that ultrasound irradiation of pressurized carbon dioxide (CO(2)) induces phenomena that do not occur in ordinary liquids at ambient conditions. For a near-critical mixture of CO(2) and argon, sonication leads to extremely fast local phase separation, in which the system enters and leaves the two-phase region with the frequency of the imposed sound field. This phase transition can propagate with the speed of sound, but can also be located at fixed positions in the case of a standing sound wave. Sonication of a vapor-liquid interface creates a fine dispersion of liquid and vapor, irrespective whether the ultrasound horn is placed in the liquid or the vapor phase. In the absence of an interface, sonication of the liquid leads to ejection of a macroscopic vapor phase from the ultrasound horn with a velocity of several meters per second in the direction of wave propagation. The findings reported here potentially provide a tunable and noninvasive means for enhancing mass and heat transfer in high-pressure fluids.


Epigenome-450K-wide methylation signatures of active cigarette smoking: The Young Finns Study.
Smoking as a major risk factor for morbidity affects numerous regulatory systems of the human body including DNA methylation. Most of the previous studies with genome-wide methylation data are based on conventional association analysis and earliest threshold-based gene set analysis that lacks sensitivity to be able to reveal all the relevant effects of smoking. The aim of the present study was to investigate the impact of active smoking on DNA methylation at three biological levels: 5'-C-phosphate-G-3' (CpG) sites, genes and functionally related genes (gene sets). Gene set analysis was done with mGSZ, a modern threshold-free method previously developed by us that utilizes all the genes in the experiment and their differential methylation scores. Application of such method in DNA methylation study is novel. Epigenome-wide methylation levels were profiled from Young Finns Study (YFS) participants' whole blood from 2011 follow-up using Illumina Infinium HumanMethylation450 BeadChips. We identified three novel smoking related CpG sites and replicated 57 of the previously identified ones. We found that smoking is associated with hypomethylation in shore (genomic regions 0-2 kilobases from CpG island). We identified smoking related methylation changes in 13 gene sets with false discovery rate (FDR) ≤ 0.05, among which is olfactory receptor activity, the flagship novel finding of the present study. Overall, we extended the current knowledge by identifying: (i) three novel smoking related CpG sites, (ii) similar effects as aging on average methylation in shore, and (iii) a novel finding that olfactory receptor activity pathway responds to tobacco smoke and toxin exposure through epigenetic mechanisms.


Current concepts in diagnosis of unusual salivary gland tumors.
Salivary gland tumors are relatively uncommon and account for approximately 3-6% of all neoplasms of the head and neck. Tumors mostly involve the major salivary glands, 42.9-90% of which occur in the parotid glands and 8-19.5% in the sub-mandibular glands; tumors in the sub-lingual glands being uncommon. Despite the plethora of different malignant salivary gland tumor presented to pathologists for diagnosis, there is consensus on a limited number of pathologic observations that determine treatment and outcome. There are few absolutes in salivary gland tumor diagnosis given the marked spectrum and overlap of differentiated cell types that participate in the numerous benign and malignant tumors. Thus, there are enumerating antibodies that may be helpful in resolving difficult differential diagnoses when applied with astute morphologic correlation. In general, immunohistochemistry as an ancillary diagnostic tool should be used sparingly and wisely as a morphologic adjunct because of the lack of specificity of many markers for specific histologic tumor types. The aim of this review is to discuss the molecular profiling of salivary gland neoplasms and correlate this with histogenesis of salivary gland neoplasms. We have elected to discuss and illustrate some of the unusual salivary gland tumors that the practicing pathologist find difficult to diagnose. These have been selected because they readily simulate each other but have very different clinical therapies and, therefore, should be included routinely in differential diagnosis.


Developmental maturation of causal signaling hubs in voluntary control of saccades and their functional controllability.
The ability to adaptively respond to behaviorally relevant cues in the environment, including voluntary control of automatic but inappropriate responses and deployment of a goal-relevant alternative response, undergoes significant maturation from childhood to adulthood. Importantly, the maturation of voluntary control processes influences the developmental trajectories of several key cognitive domains, including executive function and emotion regulation. Understanding the maturation of voluntary control is therefore of fundamental importance, but little is known about the underlying causal functional circuit mechanisms. Here, we use state-space and control-theoretic modeling to investigate the maturation of causal signaling mechanisms underlying voluntary control over saccades. We demonstrate that directed causal interactions in a canonical saccade network undergo significant maturation between childhood and adulthood. Crucially, we show that the frontal eye field (FEF) is an immature causal signaling hub in children during control over saccades. Using control-theoretic analysis, we then demonstrate that the saccade network is less controllable in children and that greater energy is required to drive FEF dynamics in children compared to adults. Our findings provide novel evidence that strengthening of causal signaling hubs and controllability of FEF are key mechanisms underlying age-related improvements in the ability to plan and execute voluntary control over saccades.


Morphologic types of breast cancer: age, bilaterality, and family history.
Morphologic type is not generally included in the study of cancer risk factors. In breast cancer, attention is being given to age at diagnosis. In this study cases were analyzed by morphologic type as well as age at diagnosis for occurrence of bilateral disease and for family history of breast cancer. Of the morphologic types which were more frequent in younger patients--lobular in situ, medullary, and intraductal comedo--only lobular in situ had an increased frequency of bilaterality (fourfold increase). Of these, only patients with intraductal comedo reported familial breast cancer more frequently than the average. Lobular infiltrating carcinoma is diagnosed more frequently in elderly patients and is associated with 2.6 times more bilaterality and increased familial risk. Diagnosis at age 45 to 54 is also associated with increased bilaterality, but the diagnosis of lobular carcinoma has much stronger association with bilaterality than early age at diagnosis. Because of the high risk of bilaterality in lobular neoplasia and in those with a family history of cancer occurring before the menopause, bilateral biopsies and subsequent screening for malignancy should be done in these women.


Cross modulation between the androgen receptor axis and protocadherin-PC in mediating neuroendocrine transdifferentiation and therapeutic resistance of prostate cancer.
Castration-resistant prostate cancers (CRPCs) that relapse after androgen deprivation therapies (ADTs) are responsible for the majority of mortalities from prostate cancer (PCa). While mechanisms enabling recurrent activity of androgen receptor (AR) are certainly involved in the development of CRPC, there may be factors that contribute to the process including acquired neuroendocrine (NE) cell-like behaviors working through alternate (non-AR) cell signaling systems or AR-dependent mechanisms. In this study, we explore the potential relationship between the AR axis and a novel putative marker of NE differentiation, the human male protocadherin-PC (PCDH-PC), in vitro and in human situations. We found evidence for an NE transdifferentiation process and PCDH-PC expression as an early-onset adaptive mechanism following ADT and elucidate AR as a key regulator of PCDH-PC expression. PCDH-PC overexpression, in turn, attenuates the ligand-dependent activity of the AR, enabling certain prostate tumor clones to assume a more NE phenotype and promoting their survival under diverse stress conditions. Acquisition of an NE phenotype by PCa cells positively correlated with resistance to cytotoxic agents including docetaxel, a taxane chemotherapy approved for the treatment of patients with metastatic CRPC. Furthermore, knockdown of PCDH-PC in cells that have undergone an NE transdifferentiation partially sensitized cells to docetaxel. Together, these results reveal a reciprocal regulation between the AR axis and PCDH-PC signals, observed both in vitro and in vivo, with potential implications in coordinating NE transdifferentiation processes and progression of PCa toward hormonal and chemoresistance.


Azelastine nasal spray inhibiting parasympathetic function of tracheal smooth muscle.
Azelastine hydrochloride is a histamine receptor-1 (H(1)) antagonist with anti-inflammatory properties that is available in the United States as Astelin Nasal Spray for rhinitis patients who are suffering from sneezing and rhinorrhea. The effect of H(1) antagonists on nasal mucosa in vivo is well known; however, the effect of the drug on tracheal smooth muscle has rarely been explored. During administration via oral intake or inhalation of the H(1) antagonist for nasal symptoms, it might affect the trachea. We examined the effectiveness of azelastine on isolated rat tracheal smooth muscle by testing: 1) the effect on tracheal smooth muscle resting tension; 2) the effect on contraction caused by 10(-6) M methacholine as a parasympathetic mimetic; and 3) the effect on electrically induced tracheal smooth muscle contractions. The results indicated that addition of methacholine to the incubation medium caused the trachea to contract in a dose-dependent manner. Addition of azelastine at doses of 10(-5) M or above elicited a significant relaxation response to 10(-6) M methacholine-induced contraction. Azelastine could inhibit electrical field stimulation-induced spike contraction. It alone had a minimal effect on the basal tension of trachea as the concentration increased. This study indicated that high concentrations of azelastine might actually inhibit parasympathetic function of the trachea. Azelastine might reduce asthma attacks in rhinitis patients because it could inhibit parasympathetic function and reduce methacholine-induced contraction of tracheal smooth muscle.


Foxc2 regulates osteogenesis and angiogenesis of bone marrow mesenchymal stem cells.
The Forkhead/Fox transcription factor Foxc2 is a critical regulator of osteogenesis and angiogenesis of cells. Bone marrow mesenchymal stem cells (BMSCs) have the capacity to differentiate into osteoblasts, chondrocytes, adipocytes, myocytes and fibroblasts. The present study investigates the role of Foxc2 overexpression in osteogenesis and angiogenesis of BMSCs in vitro. BMSCs were isolated from SD rat femurs and tibias, and characterized by cell surface antigen identification and osteoblasts and adipocytes differentiation. The cells were transfected with lentiviral Foxc2 (Lv-Foxc2) or green fluorescent protein (Lv-GFP). Seventy hours later, Foxc2 expression was observed using real time-PCR and Western blot. The transfected cells were stained with Alizarin red S or alkaline phosphatase (ALP) after osteogenic induction. Meanwhile, the expression levels of osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), vascular endothelial growth factor (VEGF) and platelet-derived growth factor-β (PDGF-β) were measured by real time-PCR, Western blot and immunostaining. Results of cell characterization showed that the cells were positive to CD44 (99.56%) and negative to CD34 (0.44%), and could differentiate into osteoblasts and adipocytes. Foxc2 overexpression not only increased the numbers of mineralized nodes and ALP activity, but also enhanced the expressions of Runx2, OCN, VEGF and PDGF-β in transfected BMSCs after osteogenic induction. The effects of Foxc2 on osteogenesis and angiogenesis were significantly different between Lv-Foxc2 transfected BMSCs and Lv-GFP transfected BMSCs (P<0.05). In addition, the MAPK-specific inhibitors, PD98059 and LY294002, blocked the Foxc2-induced regulation of BMSC differentiation. Foxc2 gene is successfully transfected into BMSCs with stable and high expression. The overexpression of Foxc2 acts on BMSCs to stimulate osteogenesis and angiogenesis. The effect of Foxc2 on angiogenesis of the cells is mediated via activating PI3K and ERK.


Angiotensin II and renal tubular ion transport.
Angiotensin II, a potent vasoconstrictor, also participates in the regulation of renal sodium and water excretion, not only via a myriad of effects on renal hemodynamics, glomerular filtration rate, and regulation of aldosterone secretion, but also via direct effects on renal tubule transport. In addition, angiotensin II stimulates H+ secretion and HCO3- reabsorption in both proximal and distal tubules and regulates H+-ATPase activity in intercalated cells of the collecting tubule. Different results regarding the effect of angiotensin II on bicarbonate reabsorption and proton secretion have been reported at the functional level, depending on the angiotensin II concentration and tubule segment studied. It is likely that interstitial angiotensin II is more important in regulating hemodynamic and transport functions than circulating angiotensin II. In proximal tubules, stimulation of bicarbonate reabsorption, Na+/H+-exchange, and Na+/HCO3- cotransport has been found using low concentrations (<10(-9) M), while inhibition of bicarbonate reabsorption has been documented using concentrations higher than 10(-8) M. Evidence for the regulation of H+-ATPase activity in vivo and in vitro by trafficking/exocytosis has been provided. An additional level of H+-ATPase regulation via protein synthesis may be important as well. Recently, we have shown that both aldosterone and angiotensin II provide such a mechanism of regulation in vivo at the level of the medullary collecting tubule. Interestingly, in this part of the nephron, the effects of aldosterone and angiotensin II are not sodium dependent, whereas in the cortical collecting duct, both aldosterone and angiotensin II, by contrast, affect H+ secretion by sodium-dependent mechanisms.


Retinal vessel diameters and their associations with age and blood pressure.
To describe the cross-sectional relationship between retinal arteriolar and venular diameters with age and blood pressure. A population-based study was conducted in Beaver Dam, Wisconsin (n=4926, age range, 43-84 years). Retinal photographs of right eyes taken at the baseline examination (1988-90) were digitized. All arterioles and venules located in the area between one-half and one disc diameter from the optic disc margin were measured with a computer-based program. These measurements were combined to provide the average diameters of retinal arterioles and venules of each eye, and the association with age and blood pressure (BP) was analyzed. After controlling for gender, hypertension, diabetes, serum glucose and lipids, cigarette smoking, and body mass index, retinal arteriolar diameters were found to be decreased by 2.1 microm (95% confidence interval [CI], 1.5-2.7) for each decade increase in age, and by 4.4 microm (95% CI, 3.8-5.0) for each 10-mm Hg increase in mean arterial BP. The association of narrowed retinal arterioles and higher BP was stronger in younger persons. For each 10-mm Hg increase in mean arterial BP, arteriolar diameters decreased by 7.0 microm in persons aged 43 to 54 years but by only 2.5 microm in persons aged 75 to 84 years. In contrast, retinal venular diameters narrowed with increasing age but not with increasing BP. Retinal arteriolar diameters are narrower in older persons and in persons with higher BP, independent of other factors. The weaker association of retinal arteriolar diameters and BP in older people may reflect greater sclerosis of the retinal arterioles, preventing a degree of narrowing with higher BP similar to that seen in younger persons.


Implementing total quality management in the health care industry.
Health care organizations across the nation have begun instituting quality improvement programs in order to meet the demands of improving service and clinical quality in health care. The implementation process requires time, effort, and money in order for the health care organizations to learn who their customers are and what they want. The results, which sometimes are not recognized until after a two- to three-year period, include reduced costs by cutting waste and complexity and by doing things right the first time. Still, there are many challenges in adapting total quality management (TQM) to public organizations such as the health care industry. This article discusses the founding principles of TQM and how they are applied in implementing TQM to enhance quality in health care organizations. This article also forecasts the future of TQM implementation in public health care.


Importance of the C2, N7, and C8 positions to the mutagenic potential of 8-Oxo-2'-deoxyguanosine with two A family polymerases.
8-Oxo-2'-deoxyguanosine (OdG) is a prominent DNA lesion produced from the reaction of 2'-deoxyguanosine (dG) with reactive oxygen species. While dG directs the insertion of only dCTP during replication, OdG can direct the insertion of either dCTP or dATP, allowing for the production of dG → dT transversions. When replicated by Klenow fragment-exo (KF-exo), OdG preferentially directs the incorporation of dCTP over dATP, thus decreasing its mutagenic potential. However, when replicated by a highly related polymerase, the large fragment of polymerase I from Bacillus stearothermophilus (BF), dATP incorporation is preferred, and a higher mutagenic potential results. To gain insight into the reasons for this opposite preference and the effects of the C2, N7, and C8 positions on OdG mutagenicity, single-nucleotide insertions of dCTP and/or dATP opposite dG, OdG, and seven of their analogues were examined by steady state kinetics with both KF-exo and BF. Results from these studies suggest that the two enzymes behave similarly and are both sensitive not only to steric and electronic changes within the imidazole ring during both dCTP and dATP incorporation but also to the presence of the C2-exocyclic amine during dATP incorporation. The difference in incorporation preference opposite OdG appears to be due to a somewhat increased sensitivity to structural perturbations during dCTP incorporation with BF. Single-nucleotide extensions past the resulting base pairs were also studied and were not only similar between the two enzymes but also consistent with published ternary crystallographic studies with BF. These results are analyzed in the context of previous biochemical and structural studies, as well as stability studies with the resulting base pairs.


Postpartum sexual function of women and the effects of early pelvic floor muscle exercises.
To evaluate the effects of early pelvic floor muscle training after vaginal delivery on sexual function. Prospective randomized study. Urogynecology clinic of a tertiary medical center in Istanbul, Turkey. Total of 75 primiparous women. Pelvic floor-muscle strength was assessed during rest and straining in primiparous women in their 4th postpartum month, after which the women were randomized into training (n = 37) and control (n = 38) groups. Patients were re-evaluated in the 7th postpartum month. Female sexual function and pelvic muscle strength scores. Desire, pain and total female sexual index scores were significantly higher in the 7th month compared to 4th month in both groups (p < 0.05). However, sexual arousal, lubrication, orgasm, and satisfaction scores were improved in the 7th month in the training group (paired t-test, p < 0.001), but not significantly in the control group (p > 0.05). All domains except satisfaction were significantly higher in the training group compared with the controls. Pelvic floor-muscle strength was found to be increased in the 7th month in the training group (Wilcoxon rank test, Z = 4.123, p < 0.001), whereas there was no significant difference between the 4th and 7th month measurements in the controls (p > 0.05). Pelvic floor-muscle training improves pelvic floor-muscle function, and starting after the puerperal period, exercise appears to have positive effects on female sexual function.


Loss of keratins 8 and 18 leads to alterations in α6β4-integrin-mediated signalling and decreased neoplastic progression in an oral-tumour-derived cell line.
Keratins 8 and 18 (K8 and K18) are predominantly expressed in simple epithelial tissues and perform both mechanical and regulatory functions. Aberrant expression of K8 and K18 is associated with neoplastic progression and invasion in squamous cell carcinomas (SCCs). To understand the molecular basis by which K8 promotes neoplastic progression in oral SCC (OSCC), K8 expression was inhibited in AW13516 cells. The K8-knockdown clones showed a significant reduction in tumorigenic potential, which was accompanied by a reduction in cell motility, cell invasion, decreased fascin levels, alterations in the organization of the actin cytoskeleton and changes in cell shape. Furthermore, K8 knockdown led to a decrease in α6β4 integrin levels and α6β4-integrin-dependent signalling events, which have been reported to play an important role in neoplastic progression in epithelial tissues. Therefore, modulation of α6β4 integrin signalling might be one of the mechanisms by which K8 and K18 promote malignant transformation and/or progression in OSCCs.


Influences on visit retention in clinical trials: insights from qualitative research during the VOICE trial in Johannesburg, South Africa.
Although significant progress has been made in clinical trials of women-controlled methods of HIV prevention such as microbicides and Pre-exposure Prophylaxis (PrEP), low adherence to experimental study products remains a major obstacle to being able to establish their efficacy in preventing HIV infection. One factor that influences adherence is the ability of trial participants to attend regular clinic visits at which trial products are dispensed, adherence counseling is administered, and participant safety is monitored. We conducted a qualitative study of the social contextual factors that influenced adherence in the VOICE (MTN-003) trial in Johannesburg, South Africa, focusing on study participation in general, and study visits in particular. The research used qualitative methodologies, including in-depth interviews (IDI), serial ethnographic interviews (EI), and focus group discussions (FGD) among a random sub-sample of 102 female trial participants, 18 to 40 years of age. A socio-ecological framework that explored those factors that shaped trial participation and adherence to study products, guided the analysis. Key codes were developed to standardize subsequent coding and a node search was used to identify texts relating to obstacles to visit adherence. Our analysis includes coded transcripts from seven FGD (N = 40), 41 IDI, and 64 serial EI (N = 21 women). Women's kinship, social, and economic roles shaped their ability to participate in the clinical trial. Although participants expressed strong commitments to attend study visits, clinic visit schedules and lengthy waiting times interfered with their multiple obligations as care givers, wage earners, housekeepers, and students. The research findings highlight the importance of the social context in shaping participation in HIV prevention trials, beyond focusing solely on individual characteristics. This points to the need to focus interventions to improve visit attendance by promoting a culture of active and engaged participation.


Determination of total protein in human milk: comparison of methods.
We evaluated four spectrophotometric methods for suitability in determining total protein in human milk samples. Results were compared with those by an established method for the determination of total nitrogen (micro-Kjeldahl). Values for total protein by all four methods significantly correlated with micro-Kjeldahl. For the biuret assay, Lowry-Peterson assay, Bio-Rad Coomassie Blue assay, and Pierce BCA assay, the correlation coefficients were 0.96, 0.97, 0.89, 0.99, respectively. We also assessed the sensitivity of each assay to several purified human milk proteins. The Pierce BCA assay showed the least difference in values among different types of protein. For this reason, and because it showed the greatest precision (with acceptable constant and proportional error), we recommend the BCA method.


Inhibition of lysyl hydroxylase by malathion and malaoxon.
The inhibition of lysyl hydroxylation in newly synthesized collagen by malathion and its oxidation product malaoxon were studied with cultured rat fetal lung fibroblasts. Exposure of these cells to 125 microM malathion or malaoxon for 96 h resulted in a 25 and a 30% decrease in the ratio of hydroxylated lysine/lysine residues, respectively, in acid hydrolyzed cell lysates compared to control values. This relative decrease in hydroxylysine was not caused by cytotoxicity or changes in total collagen content, which were found to remain constant as measured by Alamar Blue metabolism and Sircol dye binding assays. Direct inhibition of lysyl hydroxylase by malathion and malaoxon was observed using an in vitro enzyme assay with recombinant lysyl hydroxylase with a baculoviral system. The IC50 values for malathion and malaoxon were estimated to be approximately 60 and 45 microM, respectively. These observed IC50 values are consistent with calculated values for the intracellular concentration of malathion in the cell culture experiments. These results support a significant role for inhibition of lysyl hydroxylase activity as causing, or contributing to, the teratogenic effects of malathion and malaoxon.


Electroacupuncture ameliorates cognitive impairment in APP/PS1 mouse by modulating TFEB levels to relieve ALP dysfunction.
Recently, the underlying mechanisms of acupuncture on the effects of Alzheimer's disease (AD) treatment have not been fully elucidated. Defects in ALP (autophagy-lysosomal pathway) and TFEB (transcription factor EB) play critical roles in AD. Our previous studies have demonstrated that electroacupuncture (EA) can ameliorate both β-amyloid (Aβ) pathology and cognitive function in APP/PS1 mice. However, the effects of EA on the expression of ALP and TFEB and their potential mechanisms require further investigation. Twenty-eight male APP/PS1 mice were randomly divided into Tg and Tg + EA groups, and 14 C57BL/6 mice served as the wild-type (WT) group. After 1 week of adaptation to the living environment, mice in the Tg + EA group were restrained in mouse bags and received manual acupuncture at Baihui (GV20) acupoint and EA stimulation at bilateral Yongquan (KI1) acupoints, using the same restraint method for WT and Tg groups. The intervention was applied for 15 min each time, every other day, lasting for six weeks. After intervention, the spatial learning and memory of the mice was assessed using the Morris water maze test. Hippocampal Aβ expression was detected by immunohistochemistry and ELISA. Transmission electron microscopy (TEM) was used to observe autophagic vacuoles and autolysosomes in the hippocampus. Immunofluorescence method was applied to examine the expression of TFEB in CA1 region of the hippocampus and the co-localization of CTSD or LAMP1 with Aβ. Western blot analysis was performed to evaluate the changes of LC3, p62, CTSD, LAMP1, TFEB and n-TFEB (nuclear TFEB) in the hippocampus. The findings of behavioral assessment indicated that EA alleviated the cognitive impairment of APP/PS1 mice. Compared with the WT group, the Tg group showed significant cognitive decline and abnormalities in ALP and TFEB function (P < 0.01 or P < 0.05). However, these abnormal changes were alleviated in the Tg + EA group (P < 0.01 or P < 0.05). The Tg group also showed more senile plaques and ALP dysfunction features, compared with the WT group, and these changes were alleviated by EA. In conclusion, this study highlights that EA ameliorated Aβ pathology-related cognitive impairments in the APP/PS1 model associated with ALP and TFEB dysfunction.


[Celiac disease and myelodysplastic syndrome. A case report].
Celiac disease is an immune-mediated disorder induced by the intake of gluten proteins involving primarily the gastrointestinal tract. Myelodysplastic syndromes are clonal hematologic disorders, expanded from myeloid stem cells of uncertain pathogenesis. Anaemia is a common finding in patients with celiac disease. Frequently it is secondary to malabsorption of iron, folic acid or vitamin B12 and usually disappears completely with a strict adherence to a gluten-free diet and supplement of deficient factors. To the best of our knowledge, in medical literature only two cases of myelodysplastic syndrome associated with celiac disease have been described. Here we describe the case of a patient affected by adult celiac disease who went into remission following a gluten free diet. Later a macrocytic anaemia without vitamin B12 or folate deficiency appeared. Hematologic tests showed findings consistent with refractory anemia with ring sideroblasts. The association of celiac disease with myelodysplastic syndromes seems not to be casual. It raises the hypothesis of a primitive immunological disorder in both diseases.


Photochemical Organocatalytic Benzylation of Allylic C-H Bonds.
We report a radical-based organocatalytic method for the direct benzylation of allylic C-H bonds. The process uses nonfunctionalized allylic substrates and readily available benzyl radical precursors and is driven by visible light. Crucial was the identification of a dithiophosphoric acid that performs two distinct catalytic roles, sequentially acting as a catalytic donor for the formation of photoactive electron donor-acceptor (EDA) complexes and then as a hydrogen atom abstractor. By mastering these orthogonal radical generation paths, the organic catalyst enables the formation of benzylic and allylic radicals, respectively, to then govern their selective coupling. The protocol was also used to design a three-component radical process, which increased the synthetic potential of the chemistry.


Magnitude of HIV infection among older people in Mufindi and Babati districts of the Tanzania mainland.
According to the 2011-2012 HIV and Malaria Indicator Survey, the prevalence of HIV infection in Tanzania is 5.1%, with limited information on its magnitude among older people, as the community believes that the elderly are not at risk. Consequently, little attention is given to the fight against HIV and AIDS in this group. The present study investigated the magnitude of HIV and AIDS infection among older people in rural and urban areas of the Tanzania mainland. The study was conducted in Mufindi and Babati districts of Iringa and Manyara regions, respectively, through multistage sampling procedures. Dried blood spot cards were used to collect blood samples for HIV testing among consenting participants. HIV testing was done and retested using different enzyme-linked immunosorbent assay kits. A total of 720 individuals, 340 (47.2%) males and 380 (52.8%) females, were randomly selected, of whom 714 (99.2%) consented to HIV testing while six (0.8%) refused to donate blood. The age ranged from 50 to 98 years, with a mean age of 64.2 years. Overall, a total of 56 (7.8%) participants were HIV-positive. Females had a higher prevalence (8.3%) than males (7.4%), with Mufindi district recording the higher rate (11.3%) compared to the 3.7% of Babati district. The prevalence was higher in the rural population (9.4%) compared to 6.4% of their urban counterparts. Although HIV/AIDS is considered a disease of individuals aged 15-49 years, the overall prevalence among the older people aged 50 years and above for Mufindi and Babati districts was higher than the national prevalence in the general population. These findings point to the need to consider strengthening interventions targeting older populations against HIV/AIDS in these districts while establishing evidence countrywide to inform policy decisions.


[The conditioned-reflex reaction of the sympathoadrenal system to an aversive taste stimulus].
A non-reinforced taste stimulus with aversive properties was found to increase the level of excretion of adrenaline, noradrenaline and dopamine, thus reflecting occurring anxiety. The dopamine increase seems to be due to unspecific reasons of the experimental procedure. Catecholamines increase more in males rather than in females. The conditioned taste aversion seems to be preserved for a longer period of time in activating of the sympathetic-adrenal system.


Binary Logistic Regression Modeling of Voice Impairment and Voice Assessment in Iranian Patients with Nonlaryngeal Head-and-Neck Cancers after Chemoradiation Therapy: Objective and Subjective Voice Evaluation.
Laryngeal damages after chemoradiation therapy (RT) in nonlaryngeal head-and-neck cancers (HNCs) can cause voice disorders and finally reduce the patient's quality of life (QOL). The aim of this study was to evaluate voice and predict laryngeal damages using statistical binary logistic regression (BLR) models in patients with nonlaryngeal HNCs. This cross-section experimental study was performed on seventy patients (46 males, 24 females) with an average age of 50.43 ± 16.54 years, with nonlaryngeal HNCs and eighty individuals with assumed normal voices. Subjective and objective voice assessment was carried out in three stages including before, at the end, and 6 months after treatment. Eventually, the Enter method of the BLR was used to measure the odds ratio of independent variables. In objective evaluation, the acoustic parameters except for F0 increased significantly (P < 0.001) at the end treatment stage and decreased 6 months after treatment. The same trend can be seen in the subjective evaluations, whereas none of the values returned to pretreatment levels. Statistical models of BLR showed that chemotherapy (P < 0.05), mean laryngeal dose (P < 0.05), V50 Gy (P = 0.002), and gender (P = 0.008) had the greatest effect on incidence laryngeal damages. The model based on acoustic analysis had the highest percentage accuracy of 84.3%, sensitivity of 87.2%, and the area under the curve of 0.927. Voice evaluation and the use of BLR models to determine important factors were the optimum methods to reduce laryngeal damages and maintain the patient's QOL.


Evidence for common binding sites for ferrichrome compounds and bacteriophage phi 80 in the cell envelope of Escherichia coli.
Mutants ton A and ton B of Escherichia coli K12, known to be resistant to bacteriophage phi80, were found to be insensitive as well to albomycin, an analogue of the specific siderochrome ferrichrome. Ferrichrome at micromolar concentrations strongly inhibited plaque production by phi80. Preincubation with ferrichrome did not inactivate the phage. At a concentration at which ferrichrome allowed 90% inhibition of plaque formation, the chromium analogue of ferrichrome showed no detectable activity. Similarly, ethylenediaminetetraacetic acid, ferrichrome A, and certain siderochromes structurally distinct from ferrichrome, such as ferrioxamine B, schizokinen, citrate, and enterobactin, did not show detectable inhibitory activity. However, rhodotorulic acid showed moderate activity. A host range mutant of phi80, phi80h, was also inhibited by ferrichrome, as was a hybrid of phage lambda possessing the host range of phi80. However, phage lambdacI- and a hybrid of phi80 possessing the host range of lambda were not affected by ferrichrome. Finally, ferrichrome and chromic deferriferrichrome were shown to inhibit adsorption of phi80 to sensitive cells, ferrichrome giving 50% inhibition of adsorption at a minimal concentration of 8 nM. It is suggested that a component of the ferrichrome uptake system may reside in the outer membrane of E. coli K12 and may also function as a component of the receptor site for bacteriophage phi80, and that ferrichrome inhibition of the phage represents a competition for this common site.


Ewe and lamb contact at lambing is influenced by both shelter type and birth number.
A significant number of lambs born each year in Australia die within 72 h of birth. Periods of high wind, combined with rain and low temperatures can lead to marked increases in the mortality level. Under these climatic conditions mortality levels may be reduced with the provision of shelter. This study used contact loggers to compare interactions between ewes with twin lambs across two shelter types (Hessian and shrubs), while also comparing ewes with single and twin lambs in a single shelter type (Hessian). The contact loggers record the time of the initial contact (within approximately 4 to 5 m) between collared animals and the duration of each contact. Contact levels between ewes immediately after lambing were only 10% of the initial levels (1 h/day). For single-born lambs, lambs averaged 11 h contact per day with their mother, while for twinborn lambs, each lamb averaged 9.25 h/day with its mother and 14.7 h/day with its sibling. The level of contact between ewes and each of their offspring in the Hessian was 24% lower (P < 0.05) for ewes with twin lambs than with singles. For ewes with twin lambs the level of contact was 17% lower (P < 0.05) in the Hessian shelter compared with shrub shelter. We conclude that shelter type and birth number can affect the level of contact between ewes and their offspring.


Nucleo-cytoplasmic interactions that control nuclear envelope breakdown and entry into mitosis in the sea urchin zygote.
In sea urchin zygotes and mammalian cells nuclear envelope breakdown (NEB) is not driven simply by a rise in cytoplasmic cyclin dependent kinase 1-cyclin B (Cdk1-B) activity; the checkpoint monitoring DNA synthesis can prevent NEB in the face of mitotic levels of Cdk1-B. Using sea urchin zygotes we investigated whether this checkpoint prevents NEB by restricting import of regulatory proteins into the nucleus. We find that cyclin B1-GFP accumulates in nuclei that cannot complete DNA synthesis and do not break down. Thus, this checkpoint limits NEB downstream of both the cytoplasmic activation and nuclear accumulation of Cdk1-B1. In separate experiments we fertilize sea urchin eggs with sperm whose DNA has been covalently cross-linked to inhibit replication. When the pronuclei fuse, the resulting zygote nucleus does not break down for >180 minutes (equivalent to three cell cycles), even though Cdk1-B activity rises to greater than mitotic levels. If pronuclear fusion is prevented, then the female pronucleus breaks down at the normal time (average 68 minutes) and the male pronucleus with cross-linked DNA breaks down 16 minutes later. This male pronucleus has a functional checkpoint because it does not break down for >120 minutes if the female pronucleus is removed just prior to NEB. These results reveal the existence of an activity released by the female pronucleus upon its breakdown, that overrides the checkpoint in the male pronucleus and induces NEB. Microinjecting wheat germ agglutinin into binucleate zygotes reveals that this activity involves molecules that must be actively translocated into the male pronucleus.


Lymphoblastic response to autologous colon epithelial cells in ulcerative colitis in vitro.
The blastic transformation in vitro of peripheral blood lymphocytes was measured by the 72-hour uptake of tritiated thymidine ((3)H-6-thymidine) in 23 patients with mucosal ulcerative colitis, three patients with acute Crohn's colitis with rectal involvement, and seven normal subjects. The 23 patients with ulcerative colitis were subdivided into three groups, graded according to severity into seven with acute, severe, nine with active, chronic, and seven with quiescent disease. In the control cultures of lymphocytes without any added potential stimulant the uptake of (3)H-6-thymidine in the clinical subgroup of seven patients with acute, severe ulcerative colitis was significantly greater than in seven normal subjects (p<0.01). This contrasted with a reduced uptake of (3)H-6-thymidine by lymphocytes from seven patients with acute severe colitis when compared with seven normal subjects after stimulation with phytohaemagglutinin-P (PHA-P) (p<0.01). In further duplicate cultures of lymphocytes specifically stimulated by an equal number of viable autologous rectal epithelial cells, the uptake of (3)H-6-thymidine was significantly greater in seven patients with acute severe colitis when compared with seven normal subjects (p<0.01). The results in three patients with acute Crohn's colitis with rectal involvement showed no such evidence of lymphocyte sensitivity to autologous rectal epithelial cells and their uptake of (3)H-6-thymidine lay within the normal range.Evidence that the degree of lymphoblastic transformation was related to the clinical severity of ulcerative colitis was provided by the results obtained in the unstimulated and epithelial cell stimulant cultures. The uptake of (3)H-6-thymidine was directly related to the clinical severity of ulcerative colitis in the three subgroups studied. In addition, four of the seven patients with acute severe colitis were studied later in clinical remission. They were then found to have a significantly reduced uptake of (3)H-6-thymidine in response to autologous rectal epithelial cells (p < 0.01).


Attomole detection of mesophilic DNA polymerase products by nanoparticle-enhanced surface plasmon resonance imaging on glassified gold surfaces.
DNA microarrays are invaluable tools for biosensing applications such as diagnostic detection of DNA and analysis of gene expression. Surface plasmon resonance imaging can detect unlabeled oligonucleotide targets adsorbed to the array elements. The variety of biosensing applications can be expanded by enzymatic manipulation of DNA microarray elements, and the sensitivity of detection can be enhanced with the use of oligonucleotide immobilized onto a gold nanoparticle surface. We describe a novel method that couples a template-directed polymerase extension of a surface array element with nanoparticle-enhanced detection of the reaction product. Using this technique, it is possible to see as little as 10-100 amol of polymerase product, representing as little as 0.25% of a monolayer. This sensitivity would allow for the detection of a specific DNA target that is present in low amounts in a sample and with partially unknown sequence. One application of this method would be to identify the presence of the aberrantly recombined DNA sequences, such as those found in the fragile sites of chromosomes.


Effect of Photofunctionalization on Early Implant Failure.
This study retrospectively evaluated the effects of bone density, staging strategy, implant stability, healing process, implant length, surface type, and photofunctionalization on early implant failure. Consecutive study samples at Yokohama City University Hospital were analyzed for their early implant failure potentially influenced by patient-, surgical protocol-, and implant-related factors. Through the screening process using univariate analysis for those factors, candidate influential factors such as bone density, staging strategy, the level of initial implant stability, postoperative wound breakdown, the length of implants, the surface type of implants, and use or nonuse of photofunctionalization were selected as independent variables in forward multivariate logistic regression analysis. The odds ratio (OR) for candidate factors was calculated. A total of 563 implants placed in 219 patients from 2005 to 2017 were analyzed for their early implant failure. Stepwise logistic regression analysis finally identified postoperative wound breakdown (OR = 0.21) and the use of photofunctionalization (OR = 0.30) that significantly reduced the risk of early implant failure (P < .01 and P < .05, respectively). The implant failure rate was 10.0% with postoperative wound breakdown and 1.0% without it, whereas it was 4.3% without photofunctionalization and 1.3% with it. Among various patient-, surgical protocol-, and implant-related factors, the absence of postoperative wound breakdown and use of photofunctionalization significantly reduced the risk of early implant failure. It was notable that photofunctionalization, a unique, chairside measure to improve implant surfaces, was effective exclusively among implant-related factors.