Possible roles of Runx1 and Sox9 in incipient intramembranous ossification.
We evaluated the detailed expression patterns of Runx1 and Sox9 in various types of bone formation, and determined whether Runx1 expression was affected by Runx2 deficiency and Runx2 expression by Runx1 deficiency. Our results indicate that both Runx1 and Sox9 are intensely expressed in the future osteogenic cell compartment and in cartilage. The pattern of Runx1 and Sox9 expression suggests that both genes could potentially be involved in incipient intramembranous bone formation during craniofacial development. Runx1, a gene essential for hematopoiesis, contains RUNX binding sites in its promoter region, suggesting possible cross-regulation with Runx2 and potential regulatory roles in bone development. On the other hand, Sox9 is essential for chondrogenesis, and haploinsufficiency of Sox9 leads to premature ossification of the skeletal system. In this study, we studied the possible roles of Runx1 and Sox9 in bone development. Runx1, Runx2/Osf2, and Sox9 expression was evaluated by in situ hybridization in the growing craniofacial bones of embryonic day (E)12-16 mice and in the endochondral bone-forming regions of embryonic and postnatal long bones. In addition, we evaluated Runx2/Osf2 expression in the growing face of Runx1 knockout mice at E12.5 and Runx1 expression in Runx2 knockout mice at E14.5. Runx1 and Sox9 were expressed in cartilage, and the regions of expression expanded to the neighboring Runx2-expressing osteogenic regions. Expression of both Runx1 and Sox9 was markedly downregulated on ossification. Runx1 and Sox9 expression was absent in the regions of endochondral bone formation and in actively modeling or remodeling bone tissues in the long bones as well as in ossified craniofacial bones. Runx2 expression was not affected by gene disruption of Runx1, whereas the expression domains of Runx1 were extended in Runx2(-/-) mice compared with wildtype mice. Runx1 and Sox9 are specifically expressed in the osteogenic cell compartments in the craniofacial bones and the bone collar of long bones, and this expression is downregulated on terminal differentiation of osteoblasts. Our results suggest that Runx1 may play a role in incipient intramembranous bone formation.


Inhibition of insulin receptor phosphorylation by peptides derived from major histocompatibility complex class I antigens.
Peptides from the alpha 1 region (residues 61-85) of the D and K molecules of the major histocompatibility complex class I antigens inhibit insulin-induced tyrosine kinase activity of the purified human insulin receptors (IRs) as measured both by autophosphorylation and IR-mediated substrate [poly(Glu,Tyr)] phosphorylation. Half-maximal effect of the Dk-(61-85) peptide on IR autophosphorylation is obtained at 1.2 microM, and almost complete inhibition of IR kinase activity is obtained at 10 microM peptide. The corresponding K kappa-(61-85) peptide has a significantly weaker effect on autophosphorylation. No such effects are observed with nine peptides of similar length, but unrelated to major histocompatibility complex class I antigens. Neither of the major histocompatibility complex class I-derived peptides has any effect on the constitutively active kinase of a genetically engineered cytoplasmic IR domain. Further, insulin binding to IR is unaltered in the presence of the major histocompatibility complex class I-derived peptides. The inhibitory activity of the peptides on insulin-induced IR phosphorylation facilitated the observation that IRs require insulin to become substrate for an independent tyrosine kinase. In the presence of an inhibitory peptide, the constitutively active cytoplasmic IR kinase domain only phosphorylates the intact IR in the presence of insulin. We conclude that the tyrosine kinase activity of IRs may be altered by peptide interaction at an allosteric site and, moreover, IRs require insulin to assume a conformation permitting phosphorylation by an independent kinase.


Accelerating Research on Suicide Risk and Prevention in Women Veterans Through Research-Operations Partnerships.
Suicide rates for women veterans are increasing faster than for nonveterans. The 2017 suicide rate for women veterans was more than double that for women nonveterans. However, research to inform improved suicide prevention for women veterans is scant. To accelerate research on women veterans' unique risks and resiliencies for suicide, the Department of Veterans Affairs (VA) Women's Health Research Network launched a Women Veterans Suicide Prevention Research Work Group to target technical support for researchers, promote collaboration with national VA program offices, and ultimately increase dissemination and translation of research into clinical practice, public health strategies, and policies. The objective of this paper is to report on the process and outcomes of the Work Group's strategic planning efforts to identify and fill gaps in suicide prevention research among women veterans. An in-person meeting of 20 researchers and operational leaders was convened to summarize existing research evidence and identify research priorities and challenges. Research priorities included civilian reintegration, community connections, psychosocial stressors (eg, social determinants of health) and trauma, risk assessment, clinical interventions, upstream prevention, and health care access. The importance of increasing evidence on gender differences and for women veterans not using VA health care was emphasized. Research to inform suicide prevention tailored to meet women veterans' needs is essential; however, many priorities and challenges remain unaddressed. Although Work Group efforts have achieved funding gains, further work to formalize, promote and meet the demands of a suicide prevention research agenda for women veterans requires is ongoing focus.


An event-related neuroimaging study distinguishing form and content in sentence processing.
Two coordinated experiments using functional Magnetic Resonance Imaging (fMRI) investigated whether the brain represents language form (grammatical structure) separately from its meaning content (semantics). While in the scanner, 14 young, unimpaired adults listened to simple sentences that were either nonanomalous or contained a grammatical error (for example, *Trees can grew.), or a semantic anomaly (for example, *Trees can eat.). A same⁄different tone pitch judgment task provided a baseline that isolated brain activity associated with linguistic processing from background activity generated by attention to the task and analysis of the auditory input. Sites selectively activated by sentence processing were found in both hemispheres in inferior frontal, middle, and superior frontal, superior temporal, and temporo-parietal regions. Effects of syntactic and semantic anomalies were differentiated by some nonoverlapping areas of activation: Syntactic anomaly triggered significantly increased activity in and around Broca's area, whereas semantic anomaly activated several other sites anteriorly and posteriorly, among them Wernicke's area. These dissociations occurred when listeners were not required to attend to the anomaly. The results confirm that linguistic operations in sentence processing can be isolated from nonlinguistic operations and support the hypothesis of a specialization for syntactic processing.


Hip Arthroscopy in Patients Age 40 or Older: A Systematic Review.
To (1) report clinical outcomes, complication rates, and total hip arthroplasty (THA) conversion rates for patients age 40 or older who underwent hip arthroscopy, and (2) report any age-related predictors of outcome identified in the literature. MEDLINE, EMBASE, and PubMed were searched for relevant studies and pertinent data were abstracted from eligible studies. No meta-analysis was performed because of heterogeneity amongst studies. Seventeen studies were included in this review comprising 16,327 patients, including 9,954 patients age 40 or older. All studies reported statistically significant improvements in outcomes after hip arthroscopy for femoral osteochondroplasty, labral repair, or unspecified indications. In patients 40 or older who underwent labral debridement, these improvements were not clinically significant. Obesity and osteoarthritic changes predicted poorer outcomes. Only 1 of 3 studies directly comparing the 2 groups found that patients 40 or older had a significantly less improvement in a standardized hip outcome score than patients under 40 after hip arthroscopy, but all found that patients 40 or older had significantly higher rates of THA conversion. The rate of conversion to THA was 18.1% for patients 40 or older, 23.1% for patients over 50, and 25.2% for patients over 60 with a mean of 25.0 months to THA. Indications for hip arthroscopy including femoral osteochondroplasty and labral repair resulted in clinically significant improvements in patients 40 or older in most research studies examined in this review, whereas labral debridement did not produce clinically significant improvements postoperatively in the same studies. In these studies, the rate of conversion to THA is higher than in patients under 40 and increases with each decade of life, with many individual studies showing a significant increase in the rate of THA conversion. Hip arthroscopy may be suitable for some patients 40 or older, but patient selection is key and patients should be informed of the higher risk of conversion to THA. Level IV, systematic review of Level III and IV studies.


Fe3O4-CS-L: a magnetic core-shell nano adsorbent for highly efficient methyl orange adsorption.
A novel core-shell bio-adsorbent was fabricated by using biological materials for removing methyl orange (MO) from aqueous solution. The structure characteristics results of scanning electron microscopy (SEM), Fourier transform infrared spectrometry (FT-IR), thermo-gravimetric analysis (TGA), vibrating sample magnetometer (VSM), and Brunauer-Emmett-Teller (BET) shows that Fe3O4-CS-L has been successfully prepared. The effects of contact time, pH, temperature and initial concentration were explored. The results suggested pH was a negligible factor in adsorption progress. Kinetic studies showed that the experiment data followed pseudo-second-order model. Boyd mode suggested that external mass transfer showed a rather weak rate control for MO adsorption onto Fe3O4-CS-L. Equilibrium studies showed that isotherm data were the best described by Langmuir model. The maximum adsorption capacity of MO estimated to be 338.98 mg/g at 298 K. Moreover, the adsorption capacity of Fe3O4-CS-L can keep about 74% in the fifth adsorption-regeneration cycle. Thus, the Fe3O4-CS-L could be a kind of promising material for removing MO from wastewater.


Biliary Adenofibroma of Liver: Morphology, Tumor Genetics, and Outcomes in 6 Cases.
Biliary adenofibroma is a rare primary hepatic neoplasm, recognized in the World Health Organization classification, although only 14 cases have been reported to date. This series includes extended follow-up from 2 of the early case reports and 4 novel cases. Clinical history and histology were reviewed in all 6 cases. Tumor DNA was analyzed for point mutations by multiplex polymerase chain reaction and copy number alterations by array comparative genomic hybridization. The patients included 4 females and 2 males presenting between 46 and 83 years of age, with tumors ranging from 7 to 16 cm in diameter. The tumors had similar morphology, with tubules and cysts lined mainly by bland to mildly atypical cuboidal epithelium embedded in fibrous stroma. Multiplex polymerase chain reaction did not identify mutations in 4 tumors tested. Three tumors tested by array comparative genomic hybridization showed chromosomal copy number alterations, including 1 with amplifications of CCND1 and ERBB2. Three patients underwent resection with no recurrence at 21, 20, and 3 years of follow-up. One patient is alive after 14 months with no resection. Two patients with margin-positive resections had local recurrence at 1 and 6 years after surgery. No patient had distant metastasis. The distinct morphology and multiple clonal cytogenetic alterations in biliary adenofibromas indicate that the lesions are neoplastic. Amplifications of CCND1 and ERBB2 are not typical of benign neoplasms, and suggest that these tumors may have the ability to behave aggressively. However, the clinical outcomes in these patients suggest the neoplasms are only slowly progressive.


Push-Pull Receptive Field Organization and Synaptic Depression: Mechanisms for Reliably Encoding Naturalistic Stimuli in V1.
Neurons in the primary visual cortex are known for responding vigorously but with high variability to classical stimuli such as drifting bars or gratings. By contrast, natural scenes are encoded more efficiently by sparse and temporal precise spiking responses. We used a conductance-based model of the visual system in higher mammals to investigate how two specific features of the thalamo-cortical pathway, namely push-pull receptive field organization and fast synaptic depression, can contribute to this contextual reshaping of V1 responses. By comparing cortical dynamics evoked respectively by natural vs. artificial stimuli in a comprehensive parametric space analysis, we demonstrate that the reliability and sparseness of the spiking responses during natural vision is not a mere consequence of the increased bandwidth in the sensory input spectrum. Rather, it results from the combined impacts of fast synaptic depression and push-pull inhibition, the later acting for natural scenes as a form of "effective" feed-forward inhibition as demonstrated in other sensory systems. Thus, the combination of feedforward-like inhibition with fast thalamo-cortical synaptic depression by simple cells receiving a direct structured input from thalamus composes a generic computational mechanism for generating a sparse and reliable encoding of natural sensory events.


NGF is an essential survival factor for bronchial epithelial cells during respiratory syncytial virus infection.
Overall expression of neurotrophins in the respiratory tract is upregulated in infants infected by the respiratory syncytial virus (RSV), but it is unclear where (structural vs. inflammatory cells, upper vs. lower airways) and why, these changes occur. We analyzed systematically the expression of neurotrophic factors and receptors following RSV infection of human nasal, tracheal, and bronchial epithelial cells, and tested the hypothesis that neurotrophins work as innate survival factors for infected respiratory epithelia. Expression of neurotrophic factors (nerve growth factor, NGF; brain-derived neurotrophic factor, BDNF) and receptors (trkA, trkB, p75) was analyzed at the protein level by immunofluorescence and flow cytometry and at the mRNA level by real-time PCR. Targeted siRNA was utilized to blunt NGF expression, and its effect on virus-induced apoptosis/necrosis was evaluated by flow cytometry following annexin V/7-AAD staining. RSV infection was more efficient in cells from more distal (bronchial) vs. more proximal origin. In bronchial cells, RSV infection induced transcript and protein overexpression of NGF and its high-affinity receptor trkA, with concomitant downregulation of the low-affinity p75(NTR). In contrast, tracheal cells exhibited an increase in BDNF, trkA and trkB, and nasal cells increased only trkA. RSV-infected bronchial cells transfected with NGF-specific siRNA exhibited decreased trkA and increased p75(NTR) expression. Furthermore, the survival of bronchial epithelial cells was dramatically decreased when their endogenous NGF supply was depleted prior to RSV infection. RSV infection of the distal airway epithelium, but not of the more proximal sections, results in overexpression of NGF and its trkA receptor, while the other p75(NTR) receptor is markedly downregulated. This pattern of neurotrophin expression confers protection against virus-induced apoptosis, and its inhibition amplifies programmed cell death in the infected bronchial epithelium. Thus, pharmacologic modulation of NGF expression may offer a promising new approach for management of common respiratory infections.


Restricted antibody formation to sheep erythrocytes of allogeneic bone marrow chimeras histoincompatible at the K end of the H-2 complex.
Employing a new method for allogeneic bone marrow transplantation, irradiation chimeras constructed from various combinations of marrow cells from B10 H-2 recombinant mice and AKR recipients were prepared. Though these chimeras had well-developed populations of T and B cells, they showed strikingly different patterns of responses in the primary antibody formation to sheep erythrocytes (SRBC), a T dependent antigen. These are (a) AKR mice treated with C57BL/10 cells, [B10 leads to AKR] fully H-2 incompatible, and AKR mice treated with B10.A (5R) cells, [5R leads to AKR] I-J,E compatible chimeras that were almost completely unresponsive to SRBC; (b) AKR mice treated with B10.BR cells [BR leads to AKR] fully H-2 compatible, and AKR mice treated with B10 AKM cells, [AKM leads to AKR] chimeras where donor and recipient differed only at H-2D, showed the same number of plaque-forming cells (PFC) as B10 control mice; (c) AKR mice treated with B10.A cells, [B10 leads to AKR] chimeras, where donor and recipient were matched at H-2K-I-E region, showed about one-half the number of PFC as the control mice. From these results we conclude that in allogeneic bone marrow chimeras primary antibody response to T-dependent antigen, such as SRBC, is generated when at least the K end of the H-2 complex is compatible between donor and recipient.


Cognitive effects of short-term manipulation of serum sex steroids in healthy young men.
We examined the effects of sex steroids on cognitive functioning by exogenously manipulating circulating T levels in a group of healthy young men. Thirty-two men were randomized to receive 8 wk of treatment including: 1) im T enanthate 100 mg/wk plus daily oral placebo (T); 2) im placebo/wk plus 125 microg daily oral levonorgestrel (LNG); 3) im T enanthate 100 mg/wk plus 125 microg daily oral LNG (T + LNG); 4) im placebo/wk plus daily oral placebo. Cognitive functions were assessed at baseline and twice during treatment. Serum T and E2 levels were significantly increased in the T and T + LNG groups compared with baseline (P < 0.01) and T levels were significantly decreased in the LNG group (P < 0.05). Verbal memory significantly decreased in the LNG group (P < 0.01) and was maintained by coadministration of T in the T + LNG group. Divided attention was unaffected in the LNG group but improved significantly in the T + LNG group. In summary, decreased serum T levels induced by LNG or direct effects of the progestin, LNG, adversely affects verbal memory in normal young men. These results suggest that short-term changes in sex steroid levels have effects on cognitive function in healthy young men.


Histological subtypes of ovarian cancer associated with parity and breastfeeding in the prospective Million Women Study.
Ovarian cancer risk is known to be reduced amongst women who have had children, but reported associations with breastfeeding are varied. Few studies have had sufficient power to explore reliably these associations by tumour histotype. In a prospective study of 1.1 million UK women, 8719 developed ovarian cancer during follow-up. Cox regression yielded adjusted relative risks (RRs) overall and by tumour histotype amongst women with different childbearing patterns. Nulliparous women had a 24% greater ovarian cancer risk than women with one child, with significant heterogeneity by histotype (p = 0.01). There was no significant increase in serous tumours, a modest increase in mucinous tumours, but a substantial increase in endometrioid (RR = 1.49, 95% CI: 1.18-1.89) and clear-cell tumours (RR = 1.68, 1.29-2.20). Among parous women, each additional birth was associated with an overall 6% reduction in ovarian cancer risk; this association also varied by histotype (p = 0.0006), with the largest reduction in risk for clear-cell tumours (RR per birth = 0.75, 0.65-0.85, p < 0.001) and weak, if any, effect for endometrioid, high-grade serous, or mucinous tumours. We found little association with age at first or last birth. There was about a 10% risk reduction per 12-months breastfeeding (RR = 0.89, 0.84-0.94, p < 0.001), with no significant heterogeneity by histotype, but statistical power was limited. In this large prospective study, ovarian cancer risk associated with parity varied substantially by tumour histotype. Nulliparity was associated with a substantially greater overall risk than expected from the effect of a single birth, especially for clear cell and endometrioid tumours, perhaps suggesting that infertility is associated with these histotypes.


Random stack of resonant dielectric layers as a laser system.
We propose a random stack of resonant dielectric layers as a system for random-laser study. Owing to the Fabry-Perot resonance of the dielectric layers, the propagation of light in such systems is frequency dependent (a band structure). As a consequence, if the system is designed such that pump light is in passband while optical gain is in stop band, the laser threshold can be reduced dramatically compared with those of completely disordered systems.


Hematopoietic recovery following high-dose combined alkylating-agent chemotherapy and autologous bone marrow support in patients in phase-I clinical trials of colony-stimulating factors: G-CSF, GM-CSF, IL-1, IL-2, M-CSF.
Hematopoietic recovery in 115 patients with metastatic breast cancer or metastatic melanoma, enrolled in phase-I studies of recombinant growth factors while undergoing treatment with high-dose chemotherapy with autologous bone marrow support, was examined with assays of bone marrow progenitor cells and peripheral blood progenitor cells, and by evaluation of peripheral blood counts. Groups of patients receiving hematopoietic cytokine support [with interleukin-1 (IL-1), interleukin-2 (IL-2), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or monocyte CSF (M-CSF)] post marrow infusion were compared with contemporaneous control patients not receiving growth factor support. Patients receiving GM-CSF demonstrated statistically significant increases in the growth of granulocyte/macrophage colony-forming units (CFU-GM) in the bone marrow and peripheral blood compared with control patients. The effect of GM-CSF was dose dependent in the early period post marrow infusion (day +6) with bone marrow CFU-GM colonies at doses 8-16 micrograms/kg/day 34 times those measured in controls. Significant increases in bone marrow multipotential progenitor cells (CFU-GEMM) were seen in patients receiving GM-CSF day +21 post marrow infusion. Patients receiving IL-1 demonstrated significant increases in bone marrow CFU-GM at day +21, maximal at dosages of 24-32 ng/kg/day. There were no significant increases in burst forming unit-erythroid (BFU-E) among any study group. Patients receiving G-CSF had significantly increased absolute neutrophil counts (ANC) and total white blood cell counts (WBC) by day +11 post transplant compared with control patients. Patients receiving GM-CSF demonstrated significantly increased WBC (greater than 2000/mm3) at day +11 and ANC greater than 500/mm3 at day +16. Optimal dose of G-CSF and GM-CSF to stimulate neutrophil recovery post transplant was 4-8 micrograms/kg/day and 8-16 micrograms/kg/day, respectively. Platelet recovery did not differ among the six study groups. These data demonstrate accelerated myeloid recovery after high-dose chemotherapy and autologous bone marrow support in patients receiving either G-CSF or GM-CSF. Moreover, GM-CSF and IL-1 stimulate myelopoiesis at the level of bone marrow CFU-GM, while G-CSF causes earlier neutrophil recovery peripherally.


Unusually severe heterozygous beta-thalassemia: evidence for an interacting gene affecting globin translation.
A common beta-thalassemia mutation in Asian populations is the C --> T substitution at position 654 of intron 2, which leads to the activation of two cryptic splicing sites and the incorporation of 73 extra nucleotides into the mutant mRNA. Like most beta-thalassemia mutations, it normally exhibits recessive inheritance. We investigated the unusually severe phenotype in two heterozygotes for this mutation, father and son, who had thalassemia intermedia and an apparent dominant mode of inheritance. An increased level of aberrantly spliced transcript in the reticulocytes of the probands compared with asymptomatic beta654 heterozygotes led us to investigate the production and processing of beta654 RNA. We showed that large amounts of the aberrant beta654 transcript were detectable in erythroblasts from one of the asymptomatic cases. The translation product of this mRNA was not detectable in vivo, and we were unable to demonstrate the translation of the mutant mRNA in a cell-free translation system. Although the reticulocyte alpha:beta mRNA ratios in the two probands were within the range observed in the asymptomatic heterozygotes, globin chain biosynthesis studies showed that the probands had considerably greater alpha:beta chain imbalance. These results imply that the more severe phenotype may be due to a second defect, possibly unlinked to the beta-globin cluster, that acts at the translational or posttranslational level.


Gender differences in survival among adult patients starting antiretroviral therapy in South Africa: a multicentre cohort study.
Increased mortality among men on antiretroviral therapy (ART) has been documented but remains poorly understood. We examined the magnitude of and risk factors for gender differences in mortality on ART. Analyses included 46,201 ART-naïve adults starting ART between January 2002 and December 2009 in eight ART programmes across South Africa (SA). Patients were followed from initiation of ART to outcome or analysis closure. The primary outcome was mortality; secondary outcomes were loss to follow-up (LTF), virologic suppression, and CD4+ cell count responses. Survival analyses were used to examine the hazard of death on ART by gender. Sensitivity analyses were limited to patients who were virologically suppressed and patients whose CD4+ cell count reached >200 cells/µl. We compared gender differences in mortality among HIV+ patients on ART with mortality in an age-standardised HIV-negative population. Among 46,201 adults (65% female, median age 35 years), during 77,578 person-years of follow-up, men had lower median CD4+ cell counts than women (85 versus 110 cells/µl, p<0.001), were more likely to be classified WHO stage III/IV (86 versus 77%, p<0.001), and had higher mortality in crude (8.5 versus 5.7 deaths/100 person-years, p<0.001) and adjusted analyses (adjusted hazard ratio [AHR] 1.31, 95% CI 1.22-1.41). After 36 months on ART, men were more likely than women to be truly LTF (AHR 1.20, 95% CI 1.12-1.28) but not to die after LTF (AHR 1.04, 95% CI 0.86-1.25). Findings were consistent across all eight programmes. Virologic suppression was similar by gender; women had slightly better immunologic responses than men. Notably, the observed gender differences in mortality on ART were smaller than gender differences in age-standardised death rates in the HIV-negative South African population. Over time, non-HIV mortality appeared to account for an increasing proportion of observed mortality. The analysis was limited by missing data on baseline HIV disease characteristics, and we did not observe directly mortality in HIV-negative populations where the participating cohorts were located. HIV-infected men have higher mortality on ART than women in South African programmes, but these differences are only partly explained by more advanced HIV disease at the time of ART initiation, differential LTF and subsequent mortality, and differences in responses to treatment. The observed differences in mortality on ART may be best explained by background differences in mortality between men and women in the South African population unrelated to the HIV/AIDS epidemic. Please see later in the article for the Editors' Summary.


Tumor necrosis factor-induced alopecia: alternative pathology and therapy.
Tumor necrosis factor (TNF) inhibitors are used to treat Crohn disease and psoriasis. Although they are typically well tolerated, adverse effects include the development of alopecia, and paradoxically, psoriatic lesions. We recently described a woman with Crohn disease who developed alopecia and scalp psoriasis during infliximab therapy. After discontinuing infliximab and beginning oral and topical therapies, her alopecia completely resolved. We compared our experience with that of the Craddock et al. who described a woman with Crohn disease and alopecia secondary to adalimumab therapy. Although the authors described typical histopathologic features of TNF inhibitor-induced alopecia, including decreased sebaceous glands, psoriasiform changes, superficial and deep perifollicular infiltrate of peribulbar lymphocytes, prominent plasma cells, and variable eosinophils, we observed atypical findings that included chronic folliculitis and perifolliculitis with dermal scarring and naked hair shafts in the dermis - reminiscent of folliculitis decalvans. Both patients experienced a complete recovery; however, Craddock et al. described continuing adalimumab therapy and using intralesional triamcinolone acetonide whereas our patient discontinued infliximab therapy, used a combination of topical scalp therapies including betamethasone lotion and mineral oil overnight under occlusion, and began oral minocycline. In conclusion, various histopathologies are observed with TNF-inhibitor induced alopecia and multiple, effective, therapeutic avenues exist for this affliction.


The interleukin-1 receptor antagonist and its delivery by gene transfer.
The interleukin-1 receptor antagonist (IL-1ra or IRAP) is a small, acidic glycoprotein that competitively inhibits the biological activities of interleukin-1 (IL-1). Alternative splicing gives rise to secreted and intracellular forms of IL-1ra. Both forms block cellular responses to IL-1 by occupying IL-1 receptors without triggering an agonist response. The affinity of IL-1ra for the type I IL-1 receptor is approximately that of IL-1. However, because of IL-1's pronounced "spare receptor" effect, IL-1ra is a weak inhibitor of biological responses to IL-1. The value for the affinity constant of IL-1ra's binding to the type II IL-1 receptor has been the subject of disagreement. However, recent data suggest that human IL-1ra has only weak affinity for the human type II receptor. This is consistent with the likelihood that the type II receptor plays no role in signal transduction, instead being a "decoy" that can be shed as a soluble receptor with the ability bind, and thus inhibit, IL-1. Under the name Antril, IL-1ra is being tested in clinical trials of a number of human diseases where IL-1 plays a major pathophysiologic role. These diseases include sepsis, rheumatoid arthritis, chronic myelogenous leukemia, and asthma, among others. Although IL-1ra has clear pharmacologic potential in such conditions, its application in chronic diseases is limited by difficulties associated with delivering proteins as drugs. As an alternative, we have suggested transfer of the gene coding for IL-1ra; strategies for both local and systemic gene delivery are being developed.(ABSTRACT TRUNCATED AT 250 WORDS)


Clinical characteristics of patients with variant angina complicated by myocardial infarction or death within 1 month.
Of 132 consecutive patients hospitalized during a 5 year period because of active variant angina, 18 died or had a myocardial infarction within 1 month. In 4 patients an episode of pain and S-T elevation unrelieved by calcium antagonist drugs and intravenous nitroglycerin persisted for more than 1 hour, inducing cardiogenic shock and death before the appearance of Q waves and elevated serum enzyme levels. In the other 14 patients myocardial infarction developed in the electrocardiographic leads in which S-T elevation had occurred during attacks of variant angina. Clinical features were not helpful in distinguishing the 18 patients with complications from the other 114. Angina at rest had been present for less than 1 month in 7 of the 18 patients with infarction compared with 31 of 114 in the other group (probability [p] not significant [NS]). Before infarction the artery presumed to be perfusing the involved territory contained a fixed stenosis of 70 percent or more of luminal diameter in 8 of the 14 patients with complications who had coronary arteriograms compared with 50 of 112 in the other group (p = NS). In 13 of the 18 patients, complications occurred in spite of large doses of calcium antagonist drugs. In 11 of these 13, attacks of variant angina were monitored for 3 to 17 days both before and during treatment. All 11 had fewer attacks with treatment and 5 had no attacks. Daily attacks per patient decreased from 4.6 +/- 4.3 to 0.5 +/- 0.7 (mean +/- standard deviation) (p less than 0.01). It is concluded that in variant angina of recent onset myocardial infarction occurs frequently and unpredictably. Myocardial infarction may occur in the absence of severe fixed lesions and in spite of apparent clinical improvement with administration of calcium antagonist drugs.


A phylogenomic study of DNA repair genes, proteins, and processes.
The ability to recognize and repair abnormal DNA structures is common to all forms of life. Studies in a variety of species have identified an incredible diversity of DNA repair pathways. Documenting and characterizing the similarities and differences in repair between species has important value for understanding the origin and evolution of repair pathways as well as for improving our understanding of phenotypes affected by repair (e.g., mutation rates, lifespan, tumorigenesis, survival in extreme environments). Unfortunately, while repair processes have been studied in quite a few species, the ecological and evolutionary diversity of such studies has been limited. Complete genome sequences can provide potential sources of new information about repair in different species. In this paper, we present a global comparative analysis of DNA repair proteins and processes based upon the analysis of available complete genome sequences. We use a new form of analysis that combines genome sequence information and phylogenetic studies into a composite analysis we refer to as phylogenomics. We use this phylogenomic analysis to study the evolution of repair proteins and processes and to predict the repair phenotypes of those species for which we now know the complete genome sequence.


Patterning of the follicle cell epithelium along the anterior-posterior axis during Drosophila oogenesis.
Gurken signals from the oocyte to the adjacent follicle cells twice during Drosophila oogenesis; first to induce posterior fate, thereby polarising the anterior-posterior axis of the future embryo and then to induce dorsal fate and polarise the dorsal-ventral axis. Here we show that Gurken induces two different follicle cell fates because the follicle cells at the termini of the egg chamber differ in their competence to respond to Gurken from the main-body follicle cells in between. By removing the putative Gurken receptor, Egfr, in clones of cells, we show that Gurken signals directly to induce posterior fate in about 200 cells, defining a terminal competence domain that extends 10-11 cell diameters from the pole. Furthermore, small clones of Egfr mutant cells at the posterior interpret their position with respect to the pole and differentiate as the appropriate anterior cell type. Thus, the two terminal follicle cell populations contain a symmetric prepattern that is independent of Gurken signalling. These results suggest a three-step model for the anterior-posterior patterning of the follicular epithelium that subdivides this axis into at least five distinct cell types. Finally, we show that Notch plays a role in both the specification and patterning of the terminal follicle cells, providing a possible explanation for the defect in anterior-posterior axis formation caused by Notch and Delta mutants.


Laser Doppler particle measuring system using nonsinusoidal forced vibration and bispectral analysis.
A new laser Doppler particle measuring method which resists additive Gaussian noises is proposed. Particles are forced-vibrated by nonsinusoidal waves with fixed bispectral characteristics, and the responses are measured by using a velocity measuring system which consists of the optics of a laser Doppler velocimeter, FM discriminator, and a bispectral analyzer. Application of bispectral analysis is very effective in eliminating additive Gaussian noise even when the power of noise is fairly large. The principle, practical construction, and some experimental results are shown. The results show clearly the effectiveness of the method.


Development of a multilocus sequence typing method for analysis of Lactobacillus plantarum strains.
Lactobacillus plantarum is a species of considerable industrial and medical interest. To date, the lack of reliable molecular methods for definite identification at strain level has hindered studies of the population biology of this organism. Here, a multilocus sequence typing (MLST) system for this organism is described, which exploits the genetic variation present in six housekeeping loci to determine the genetic relationship among isolates. The MLST system was established using 16 L. plantarum strains that were also characterized by ribotyping and restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified 16S-23S rDNA intergenic spacer region (ISR). Ribotyping grouped the strains into four groups; however, RFLP analysis of the ISRs showed no differences in the strains analysed. In contrast, MLST had a good discriminatory ability. The sequence analysis of the six genes showed 14 different allelic combinations, with 12 of them represented by only one strain. By using this MLST approach we were able to confirm the identity of two strains deposited in the Spanish Type Culture Collection as different strains. Phylogenetic analysis indicated a panmictic population structure of L. plantarum and split decomposition analysis indicated that recombination plays a role in creating genetic heterogeneity in L. plantarum. As MLST allows precise identification, and easy comparison and exchange of results obtained in different laboratories, the future application of this new molecular method could be useful for the identification of valuable L. plantarum strains.


Redetermination of the low-temperature polymorph of Li(2)MnSiO(4) from single-crystal X-ray data.
Crystals of dilithium manganese(II) silicate were grown under high-temperature hydro-thermal conditions in the system LiOH-MnO(2)-SiO(2). The title compound crystallizes in the β(II)-Li(3)PO(4) structure type. The coordination polyhedra of all cations are slightly distorted tetra-hedra (m symmetry for MnO(4) and SiO(4)), which are linked by corner-sharing to each other. The vertices of the tetra-hedra point to the same direction perpendicular to the distorted hexa-gonal close-packed (hcp) array of O atoms within which half of the tetra-hedral voids are occupied by cations. In comparison with the previous refinement from powder X-ray data [Dominko et al. (2006 ▶). Electrochem. Commun.8, 217-222], the present reinvestigation from single-crystal X-ray data allows a more precise determination of the distribution of the Li(+) and Mn(2+) cations, giving a perfectly site-ordered structure model for both Li(+) and Mn(2+).


Effect of oral nimodipine on platelet function.
Nimodipine, a calcium antagonist, has been reported to have beneficial effects in acute ischemic infarction. Some calcium channel antagonists have antiplatelet effects. We investigated the effect of oral nimodipine on platelet function in healthy volunteers. Twelve healthy volunteers (6 men and 6 women, mean age 32.9 +/- 5.6 years) took 30 mg nimodipine every 6 hours for 24 hours, followed by a week with no medication, followed by 60 mg every 6 hours for 24 hours. Ex vivo platelet function was measured at baseline, 1 hour after the first dose at each dosage strength, and 1 hour after the last dose at each dosage. Platelet studies included aggregation and adenosine triphosphate release in response to collagen, epinephrine, and adenosine diphosphate; maximal rate of primary aggregation; threshold adenosine diphosphate concentration for second-phase aggregation; and thromboxane B2 release at threshold aggregation. The bleeding time was measured at baseline and after the last 60-mg dose of nimodipine. No change in any platelet function study was seen with 30 mg nimodipine every 6 hours. Platelet function studies were also unchanged after 60 mg every 6 hours, except for a slight decrease in aggregation and adenosine triphosphate release in response to suprathreshold (10 microM) adenosine diphosphate (p = 0.001, Student's paired t test). There was no significant change in bleeding times. Oral nimodipine has minimal antiplatelet activity in young, healthy subjects.


Global and Arctic climate engineering: numerical model studies.
We perform numerical simulations of the atmosphere, sea ice and upper ocean to examine possible effects of diminishing incoming solar radiation, insolation, on the climate system. We simulate both global and Arctic climate engineering in idealized scenarios in which insolation is diminished above the top of the atmosphere. We consider the Arctic scenarios because climate change is manifesting most strongly there. Our results indicate that, while such simple insolation modulation is unlikely to perfectly reverse the effects of greenhouse gas warming, over a broad range of measures considering both temperature and water, an engineered high CO2 climate can be made much more similar to the low CO2 climate than would be a high CO2 climate in the absence of such engineering. At high latitudes, there is less sunlight deflected per unit albedo change but climate system feedbacks operate more powerfully there. These two effects largely cancel each other, making the global mean temperature response per unit top-of-atmosphere albedo change relatively insensitive to latitude. Implementing insolation modulation appears to be feasible.


The clinical symptom profile of early radiographic knee arthritis: a pain and function comparison with advanced disease.
Early knee OA is a significant problem that can be disabling. The purpose of this study was to understand the symptomatic profile of patients with early knee OA when compared to those with end-stage knee OA. A cross-sectional case control study design was used to compare those with early structural change to those with advanced structural change. In total, 100 consecutive patients with early radiographic knee OA presenting to the knee service outpatient clinic from December 2010 to August 2011 were prospectively identified on the basis of their radiographic changes. All met the symptomatic and radiological diagnostic criteria of early knee OA as defined by Luyten et al. They were compared with 200 knees with full thickness anteromedial knee OA and 200 knees with full thickness tricompartmental knee OA for their demographic, pain and functional profile. Patients with early knee OA were younger than those with full thickness disease. However, 78% of individual patients with early radiographic OA had pain and function scores equal to individual patients presenting for UKA, whilst 74% of individual patients with early radiographic OA had pain and function scores that are equal to or worse than individual patients presenting for TKA. Patients with early radiographic knee OA demonstrate considerable overlap in the severity of their symptoms with those demonstrating end-stage structural changes within the knee. Patients with early structural changes of arthritis should not be assumed by clinicians to have mild disease. In many cases, their symptoms are as bad as those with end-stage structural changes. This work will help clinicians to identify and categorise those with early arthritis and thereby assist in guiding appropriate treatments.


Ethnic differences in alcohol and drug use and related sexual risks for HIV among vulnerable women in Cape Town, South Africa: implications for interventions.
Alcohol and other drug (AOD) use among poor Black African and Coloured women in South Africa compounds their sexual risk for HIV. Given South Africa's history of ethnic disparities, ethnic differences in sex risk profiles may exist that should be taken into account when planning HIV risk reduction interventions. This paper aims to describe ethnic differences in AOD use and AOD-related sexual risks for HIV among vulnerable women from Cape Town, South Africa. Cross-sectional data on 720 AOD-using women (324 Black African; 396 Coloured) recruited from poor communities in Cape Town were examined for ethnic differences in AOD use and AOD-related sexual risk behavior. Ethnic differences in patterns of AOD use were found; with self-reported drug problems, heavy episodic drinking and methamphetamine use being most prevalent among Coloured women and cannabis use being most likely among Black African women. However, more than half of Black African women reported drug-related problems and more than a third tested positive for recent methamphetamine use. More than a third of women reported being AOD-impaired and having unprotected sex during their last sexual encounter. Coloured women had four-fold greater odds of reporting that their last sexual episode was AOD-impaired and unprotected than Black African women. In addition, close to one in two women reported that their sexual partner was AOD-impaired at last sex, with Coloured women having three-fold greater odds of reporting that their partner was AOD-impaired at last sex than Black African women. Findings support the need to develop and test AOD risk reduction interventions for women from both ethnic groups. In addition, findings point to the need for tailored interventions that target the distinct profiles of AOD use and AOD-related sex risks for HIV among Black African and Coloured women.


Pif1 helicase lengthens some Okazaki fragment flaps necessitating Dna2 nuclease/helicase action in the two-nuclease processing pathway.
We have developed a system to reconstitute all of the proposed steps of Okazaki fragment processing using purified yeast proteins and model substrates. DNA polymerase delta was shown to extend an upstream fragment to displace a downstream fragment into a flap. In most cases, the flap was removed by flap endonuclease 1 (FEN1), in a reaction required to remove initiator RNA in vivo. The nick left after flap removal could be sealed by DNA ligase I to complete fragment joining. An alternative pathway involving FEN1 and the nuclease/helicase Dna2 has been proposed for flaps that become long enough to bind replication protein A (RPA). RPA binding can inhibit FEN1, but Dna2 can shorten RPA-bound flaps so that RPA dissociates. Recent reconstitution results indicated that Pif1 helicase, a known component of fragment processing, accelerated flap displacement, allowing the inhibitory action of RPA. In results presented here, Pif1 promoted DNA polymerase delta to displace strands that achieve a length to bind RPA, but also to be Dna2 substrates. Significantly, RPA binding to long flaps inhibited the formation of the final ligation products in the reconstituted system without Dna2. However, Dna2 reversed that inhibition to restore efficient ligation. These results suggest that the two-nuclease pathway is employed in cells to process long flap intermediates promoted by Pif1.


Constrained choices? Linking employees' and spouses' work time to health behaviors.
There are extensive literatures on work conditions and health and on family contexts and health, but less research asking how a spouse or partners' work conditions may affect health behaviors. Drawing on the constrained choices framework, we theorized health behaviors as a product of one's own time and spouses' work time as well as gender expectations. We examined fast food consumption and exercise behaviors using survey data from 429 employees in an Information Technology (IT) division of a U.S. Fortune 500 firm and from their spouses. We found fast food consumption is affected by men's work hours-both male employees' own work hours and the hours worked by husbands of women respondents-in a nonlinear way. The groups most likely to eat fast food are men working 50 h/week and women whose husbands work 45-50 h/week. Second, exercise is better explained if work time is conceptualized at the couple, rather than individual, level. In particular, neo-traditional arrangements (where husbands work longer than their wives) constrain women's ability to engage in exercise but increase odds of men exercising. Women in couples where both partners are working long hours have the highest odds of exercise. In addition, women working long hours with high schedule control are more apt to exercise and men working long hours whose wives have high schedule flexibility are as well. Our findings suggest different health behaviors may have distinct antecedents but gendered work-family expectations shape time allocations in ways that promote men's and constrain women's health behaviors. They also suggest the need to expand the constrained choices framework to recognize that long hours may encourage exercise if both partners are looking to sustain long work hours and that work resources, specifically schedule control, of one partner may expand the choices of the other.


Phasing in the presence of severe site-specific radiation damage through dose-dependent modelling of heavy atoms.
The case of a brominated RNA crystal structure determination in which standard three-wavelength MAD phasing was unsuccessful because of fast X-ray-induced debromination was reinvestigated [Ennifar et al. (2002), Acta Cryst. D58, 1262-1268]. It was found that if the data are kept unmerged and if a dose-stamp is associated with each reflection measurement, dose-dependent occupancies can be refined for the Br atoms. Such a parametrization has been implemented in the macromolecular phasing program SHARP. Refining such dose-dependent occupancies on an unmerged data set gave a dramatic improvement, even for SAD phases from only the first wavelength (peak), and resulted in a good electron-density map after solvent flattening. The adverse effect of radiation damage has been turned into a beneficial one. The crucial difference is made by the use of unmerged data: phasing power is generated through the intensity differences of symmetry-related reflections recorded at different doses, i.e. corresponding to different states of the X-ray-induced debromination. This approach should prove useful in all situations of experimental phasing where site-specific radiation damage occurs unavoidably and undesirably and not only in cases in which radiation damage is purposely being created in order to demonstrate its potential usefulness.


Occurrence of cystacanths of Polyacanthorhynchus kenyensis larvae (Acanthocephala) in four teleostean fishes from a tropical lake, Lake Naivasha, Kenya.
From January 1992 to December 1993, a total of 2158 fish, namely Oreochromis leucostictus (Trewavas, 1983), Micropterus salmoides (Lacépède, 1802), Tilapia zillii (Gervais, 1848) and Barbus amphigrama (Boulenger, 1902) were sampled from thirteen stations on Lake Naivasha, Kenya, using a fleet of gill nets and examined for helminth parasites. The prevalence of infection due to cystacanths of an acanthocephalan, Polyacanthorhynchus kenyensis Schmidt et Canaris, 1967 among parasitized O. leucostictus ranged from 30.4 to 86.9%; among T. zillii from 4.1 to 77.7%; in M. salmoides from 20 to 50%; and in B. amphigrama from 5.8 to 100%. In 735 hosts belonging to the above four species, a total of 4198 immature specimens of P. kenyensis were recovered. All cystacanths were found in extraintestinal sites, either free within the fish body cavity or encysted within the host visceral organs. There was no significant variation in the prevalence of the parasite within months (P > 0.001). Host sex ratio was significant (P < 0.001) in favour of male T. zillii, and also highly significant (P < 0.001) in favour of male O. leucostictus. Moreover, in this fish, prevalence of infection was observed to increase with the increase in the size of the fish. Among infected M. salmoides, there was no significant departure from a 1:1 sex ratio.


Derivation of a simple clinical model to categorize patients probability of pulmonary embolism: increasing the models utility with the SimpliRED D-dimer.
We have previously demonstrated that a clinical model can be safely used in a management strategy in patients with suspected pulmonary embolism (PE). We sought to simplify the clinical model and determine a scoring system, that when combined with D-dimer results, would safely exclude PE without the need for other tests, in a large proportion of patients. We used a randomly selected sample of 80% of the patients that participated in a prospective cohort study of patients with suspected PE to perform a logistic regression analysis on 40 clinical variables to create a simple clinical prediction rule. Cut points on the new rule were determined to create two scoring systems. In the first scoring system patients were classified as having low, moderate and high probability of PE with the proportions being similar to those determined in our original study. The second system was designed to create two categories, PE likely and unlikely. The goal in the latter was that PE unlikely patients with a negative D-dimer result would have PE in less than 2% of cases. The proportion of patients with PE in each category was determined overall and according to a positive or negative SimpliRED D-dimer result. After these determinations we applied the models to the remaining 20% of patients as a validation of the results. The following seven variables and assigned scores (in brackets) were included in the clinical prediction rule: Clinical symptoms of DVT (3.0), no alternative diagnosis (3.0), heart rate >100 (1.5), immobilization or surgery in the previous four weeks (1.5), previous DVT/PE (1.5), hemoptysis (1.0) and malignancy (1.0). Patients were considered low probability if the score was <2.0, moderate of the score was 2.0 to 6.0 and high if the score was over 6.0. Pulmonary embolism unlikely was assigned to patients with scores < or =4.0 and PE likely if the score was >4.0. 7.8% of patients with scores of less than or equal to 4 had PE but if the D-dimer was negative in these patients the rate of PE was only 2.2% (95% CI = 1.0% to 4.0%) in the derivation set and 1.7% in the validation set. Importantly this combination occurred in 46% of our study patients. A score of <2.0 and a negative D-dimer results in a PE rate of 1.5% (95% CI = 0.4% to 3.7%) in the derivation set and 2.7% (95% CI = 0.3% to 9.0%) in the validation set and only occurred in 29% of patients. The combination of a score < or =4.0 by our simple clinical prediction rule and a negative SimpliRED D-Dimer result may safely exclude PE in a large proportion of patients with suspected PE.


Outbreak of melioidosis and leptospirosis co-infection following a rescue operation.
We analyzed the epidemiological data of all people who were involved in the search and rescue operation in Lubuk Yu, a natural recreational forest with waterfall and stream. The hospital admission records of the cases who fulfilled the case definition and the environmental samples result taken at Lubuk Yu recreational area were studied. 153 people were exposed to this outbreak, 85 (55.5%) were professional rescuers from various government agencies and 68 (44.5%) were villagers. 21 fulfilled the case definition. Ten cases were confirmed melioidosis, six melioidosis alone and four coinfected with leptospirosis. There were eight deaths in this outbreak, seven were villagers and one professional rescuer. Overall case fatality was 70%. All confirmed melioidosis cases and seven who died had diabetes mellitus. The morbidity rate were higher among the villagers, 23.5% compared to professional rescuers, 5.9%. The case fatality rate were also higher in this group which was 100% compared to 33.3% in professional rescuers. The soil and water samples in Lubuk Yu recreational area were positive for leptospira and Burkholderia pseudomallei. The presence of co-infection and co-morbidities especially diabetes mellitus among the exposed led to the high mortality in this outbreak hence a high index of suspicion is important among the healthcare professionals in the management of melioidosis cases. To avoid similar incident in future, search and rescue operation should be only conducted by professional rescuers with appropriate personal protective equipment. A register of rescuers should be maintained for surveillance and follow up if necessary.


Diet and Alzheimer's disease risk factors or prevention: the current evidence.
Preventing or postponing the onset of Alzheimer's disease (AD) and delaying or slowing its progression would lead to a consequent improvement of health status and quality of life in older age. Elevated saturated fatty acids could have negative effects on age-related cognitive decline and mild cognitive impairment (MCI). Furthermore, at present, epidemiological evidence suggests a possible association between fish consumption, monounsaturated fatty acids and polyunsaturated fatty acids (PUFA; in particular, n-3 PUFA) and a reduced risk of cognitive decline and dementia. Poorer cognitive function and an increased risk of vascular dementia (VaD) were found to be associated with a lower consumption of milk or dairy products. However, the consumption of whole-fat dairy products may be associated with cognitive decline in the elderly. Light-to-moderate alcohol use may be associated with a reduced risk of incident dementia and AD, while for VaD, cognitive decline and predementia syndromes, the current evidence is only suggestive of a protective effect. The limited epidemiological evidence available on fruit and vegetable consumption and cognition generally supports a protective role of these macronutrients against cognitive decline, dementia and AD. Only recently, higher adherence to a Mediterranean-type diet was associated with decreased cognitive decline, although the Mediterranean diet (MeDi) combines several foods, micro- and macro-nutrients already separately proposed as potential protective factors against dementia and predementia syndromes. In fact, recent prospective studies provided evidence that higher adherence to a Mediterranean-type diet could be associated with slower cognitive decline, reduced risk of progression from MCI to AD, reduced risk of AD and a decreased all-cause mortality in AD patients. These findings suggested that adherence to the MeDi may affect not only the risk of AD, but also of predementia syndromes and their progression to overt dementia. Based on the current evidence concerning these factors, no definitive dietary recommendations are possible. However, following dietary advice for lowering the risk of cardiovascular and metabolic disorders, high levels of consumption of fats from fish, vegetable oils, nonstarchy vegetables, low glycemic index fruits and a diet low in foods with added sugars and with moderate wine intake should be encouraged. Hopefully this will open new opportunities for the prevention and management of dementia and AD.


Impaired cardiac muscarinic receptor function in dogs with heart failure.
Prior physiological studies have suggested that parasympathetic control is altered in heart failure. The goal of our studies was to investigate the influence of heart failure on the muscarinic receptor, and its coupling to adenylate cyclase. Ligand binding studies using [3H]quinuclidinyl benzilate and enriched left ventricular (LV) sarcolemma, demonstrated that muscarinic receptor density in heart failure declined 36% from a control of 5.6 +/- 0.6 pmol/mg, with no change in antagonist affinity. However, agonist competition studies with both carbachol and oxotremorine showed that it was a loss of high affinity agonist binding sites in the sarcolemma from failing LV that accounted for this difference. The functional efficacy of the muscarinic receptor was also examined. When 1 microM methacholine was added to 0.1 mM GTP and 0.1 mM isoproterenol, adenylate cyclase stimulated activity was inhibited by 15% in normal LV but only 5% in LV sarcolemma from animals with heart failure even when the reduced adenylate cyclase in these heart failure animals was taken into account. Even at 100-fold greater concentrations of methacholine, significantly less inhibition of adenylate cyclase activity was observed in LV failure as compared with normal LV sarcolemma. Levels of the GTP-inhibitory protein known to couple the muscarinic receptor to adenylate cyclase, as measured with pertussis toxin labeling, were not depressed in LV failure. Thus, the inhibitory pathway regulating LV adenylate cyclase activity is defective in heart failure. The decrease in muscarinic receptor density, and in particular the specific loss of the high affinity agonist binding component of this receptor population, appears to be the major factor underlying this abnormality.


The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women.
BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD. Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score). CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts. The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.


Drosophila nervous system muscarinic acetylcholine receptor: transient functional expression and localization by immunocytochemistry.
The pharmacological properties of a cloned Drosophila muscarinic acetylcholine receptor (mAChR) were investigated using two independent transient expression systems. The binding characteristics of the expressed receptor were determined using transfected COS-7 cells, whereas the mAChR functional properties were analyzed using nuclearly injected Xenopus oocytes. Competition displacement studies with transfected COS-7 cell membranes showed that N-[3H]methylscopolamine binding was displaced most effectively by atropine, followed by 4-diphenylacetoxy-N-methylpiperidine methiodide, pirenzepine, and AFDX-116. This same order of effectiveness (4-diphenylacetoxy-N-methylpiperidine methiodide > pirenzepine > AFDX-116) was observed in oocytes expressing Dm1 when carbamylcholine-induced currents were inhibited by the same antagonists. Thus, the expressed Drosophila mAChR (Dm1) exhibits a pharmacology that broadly resembles that of the vertebrate M1 and M3 mAChR subtypes. To determine the anatomical localization of the Drosophila mAChR, polyclonal antiserum was raised against a peptide corresponding to the predicted carboxyl-terminal domain of the receptor. Immunocytochemistry on fly sections demonstrated that the mAChR gene product was found in the nervous system and was not seen in skeletal muscle. The most intense staining was localized to the glomeruli of the antennal lobes, an area of the insect brain where first-order synaptic processing of olfactory information occurs.


Left Upper-Quadrant Appendicitis in a Patient with Congenital Intestinal Malrotation and Polysplenia.
BACKGROUND Appendicitis is the most common cause of abdominal pain requiring emergent surgical intervention. Although typically presenting as right lower-quadrant pain, in rare cases it may present as left upper-quadrant pain secondary to abnormal position due to intestinal malrotation. Since atypical presentations may result in diagnostic and management delay, increasing morbidity and mortality, accurate and prompt diagnosis is important. Therefore, acute appendicitis should be considered in the differential diagnosis of left upper-quadrant abdominal pain. In this setting, medical imaging plays a key role in diagnosis. We report a case of a 13-year-old female with undiagnosed intestinal malrotation presenting with left-sided acute appendicitis. CASE REPORT A 13-year-old Hispanic female presented at the emergency room with anorexia and left upper-quadrant abdominal pain with involuntary guarding. The laboratory work-up was remarkable for elevated white blood cell count and elevated erythrocyte sedimentation rate. A nasogastric tube was placed and abdominal x-rays performed to rule-out bowel obstruction, showing distended bowel loops throughout all abdominal quadrants, with sigmoid and proximal rectal gas, raising concern for ileus rather than an obstructive pattern. Lack of symptomatic improvement prompted an IV contrast-enhanced abdominopelvic CT, revealing intestinal malrotation and with an inflamed left upper-quadrant appendix. Surgical management proceeded with a laparoscopic Ladd's procedure. CONCLUSIONS Acute appendicitis may present with atypical symptoms due to unusual appendix locations, such as in malrotation. Most cases are asymptomatic until development of acute complications, requiring imaging for diagnosis. Clinicians and radiologists should have a high index of suspicion and knowledge of its clinical presentations to achieve early diagnosis and intervention.


A cognitive behavioural based assessment of women with chronic pelvic pain.
From population-based surveys, chronic pelvic pain (CPP) in women is a common condition with a spectrum of associated disability and distress. Those seen by gynaecologists in a referral setting often have substantial impairment of function and mood disturbance. Because in most cases, the aetiology of CPP cannot be explained and the range of effective interventions remains limited, treatment of CPP might easily result in a sense of frustration not only for the patient but also for the gynaecologist. To avoid this situation in clinical practice, a structured assessment of women suffering from CPP using a cognitive behavioural model, is suggested. This type of assessment provides information about the impact of CPP on a particular patient's daily life. It also facilitates referral for pain management. Future studies are needed to show further evidence of benefit of this approach for women with CPP.


Identification of lifestyle patterns associated with obesity and fat mass in children: the Healthy Growth Study.
To investigate possible associations of lifestyle patterns with obesity and fat mass in children. Cross-sectional epidemiological study. Principal component analysis was used to identify lifestyle patterns. Primary schools from four regions in Greece. A total of 2073 schoolchildren (aged 9-13 years). Children in the fourth quartile of the lifestyle pattern combining higher dairy foods with more adequate breakfast consumption were 39·4%, 45·2% and 32·2% less likely to be overweight/obese and in the highest quartile of sum of skinfold thicknesses and fat mass, respectively, than children in the first quartile of this pattern. Similarly, children in the fourth quartile of a lifestyle pattern comprising consumption of high-fibre foods, such as fruits, vegetables and wholegrain products, were 27·4% less likely to be in the highest quartile of sum of skinfold thicknesses than children in the first lifestyle pattern quartile. Finally, children in the fourth quartile of a lifestyle pattern characterized by more time spent on moderate-to-vigorous physical activity and more frequent meals were 38·0%, 26·3% and 29·5% less likely to be overweight, centrally obese and in the highest quartile of fat mass, respectively, than their peers in the first quartile of this lifestyle pattern (all P < 0·05). The current study identified three lifestyle patterns (i.e. one pattern comprising higher dairy consumption with a more adequate breakfast; a second pattern characterized by increased consumption of high-fibre foods; and a third pattern combining higher physical activity levels with more frequent meals), which were all related with lower odds of obesity and/or increased fat mass levels. From a public health perspective, promotion of these patterns among children and their families should be considered as one of the components of any childhood obesity preventive initiative.


Elite athletes' experiences of musculoskeletal pain management using neuroanatomical dry needling: A qualitative study in Swedish track and field.
To investigate how elite track and field athletes with a history of musculoskeletal pain (MSKP) describe their perceptions of clinical treatments based on dry needling guided by a neurological map (neuroanatomical dry needling (naDN)). Qualitative study. In-depth interviews were conducted with eight elite Swedish track and field athletes (6 males, 2 females, median age 28.5) treated at a clinic specialised in MSKP management. All interviews were audio recorded and transcribed verbatim. The data were structured and analysed using a thematic method. The athletes approached clinical MSKP treatment from a performance-orientated perspective. They explained that they inevitably suffered MSKP episodes due to the intense physical demands of their sport. The use of naDN was considered an integral part of their sports practice and the study clinic's services were readily utilised when MSKP caused minor reductions in physical capacity. The athletes appreciated an unambiguous anatomical diagnosis, preferably supported by imaging scans, as this increased their confidence in clinical services. They valued the naDN treatment as it was perceived to provide fast-acting analgesia that enabled rapid return-to-play. These factors combined to reduce performance-related stress. Elite track and field athletes with a history of MSKP sought and appreciated clinical treatment with naDN largely because it provided fast-acting analgesia that enabled rapid return-to-play at a high-performance level. These athletes' expectations of MSKP diagnosis and management appear incongruent with current research indicating that MSKP sensitivity within the nervous system does not accurately reflect musculoskeletal tissue state or recovery following tissue damage.


Oligosaccharide and peptidoglycan of Ganoderma lucidum activate the immune response in human mononuclear cells.
The acid-hydrolyzed fragments of Ganoderma lucidum polysaccharides (GLPS) obtained by Smith degradation were separated by size-exclusion chromatography into two major water-soluble fractions: peptidoglycans (GLPS-SF1) and oligosaccharides (GLPS-SF2). Both fractions induced CD69 in human peripheral blood mononuclear cells (hPB-MNCs), and they displayed distinct immunomodulating properties. GLPS-SF1, with a molecular weight of around 20 kDa, were heterogeneous peptidoglycans composed of glucose/mannose (4:1) that exhibited biological activities with Th1 cytokines IL-12, IL-2, TNF-α, and IFN-γ in hPB-MNCs and stimulated macrophage cytokine expression via Toll-like receptor 4 (TLR4) signaling. For GLPS-SF2, with a molecular weight of around several kilodaltons, its sugar sequence was elucidated by mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy as [-α-1,4-Glc-(β-1,4-GlcA)(3)-](n). This oligosaccharide displayed specific immune property with low monocyte induction, greatly stimulated cell activation and proliferation of NK and T cells. This oligosaccharide isolated from G. lucidum polysaccharides with internal glucuronic acids/glucose repeat unit in a 3:1 ratio may be responsible for the active stimulation of NK and T cells.


Minnesota multiphasic personality inventory-2 restructured form (MMPI-2-RF) scale score differences in bariatric surgery candidates diagnosed with binge eating disorder versus BMI-matched controls.
Binge Eating Disorder (BED) is among the most common psychiatric disorders in bariatric surgery candidates. The Minnesota Multiphasic Personality Inventory-2 Restructured Form (MMPI-2-RF) is a broadband, psychological test that includes measures of emotional and behavioral dysfunction, which have been associated with BED behaviors in bariatric surgery candidates; however these studies have lacked appropriate controls. In the current study, we compared MMPI-2-RF scale scores of bariatric surgery patients diagnosed with BED (BED+) with BMI-matched controls without BED (BED-). Three-hundred and seven BED+ participants (72.64% female and 67.87% Caucasian; mean BMI of 51.36 kg/m(2) [SD = 11.94]) were drawn from a large, database (N = 1304). Three-hundred and seven BED- participants were matched on BMI and demographics (72.64% female, 68.63% Caucasian, and mean BMI of 51.30 kg/m(2) [SD = 11.70]). The BED+ group scored significantly higher on measures of Demoralization, Low Positive Emotions, and Dysfunctional Negative Emotions and scored lower on measures of Antisocial Behaviors, reflecting behavioral constraint. Optimal T-Score cutoffs were below the traditional 65 T score for several MMPI-2-RF scales. MMPI-2-RF externalizing measures also added incrementally to differentiating between the groups beyond the Binge Eating Scale (BES). BED+ individuals produced greater elevations on a number of MMPI-2-RF internalizing scales and externalizing scales. Use of the test in conjunction with a clinical interview and other self-report data can further aid the clinician in guiding patients to appropriate treatment to optimize outcome.


Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study.
Little is known about the natural course of nonalcoholic fatty liver disease (NAFLD) with advanced fibrosis. We describe long-term outcomes and evaluate the effects of clinical and histologic parameters on disease progression in patients with advanced NAFLD. We conducted a multi-national study of 458 patients with biopsy-confirmed NAFLD with bridging fibrosis (F3, n = 159) or compensated cirrhosis (222 patients with Child-Turcotte-Pugh scores of A5 and 77 patients with scores of A6), evaluated from April 1995 through November 2013 and followed until December 2016, death, or liver transplantation at hepatology centers in Spain, Australia, Hong Kong, and Cuba. Biopsies were re-evaluated and scored; demographic, clinical, laboratory, and pathology data for each patient were collected from the time of liver biopsy collection. Cox proportional and competing risk models were used to estimate rates of transplantation-free survival and major clinical events and to identify factors associated with outcomes. During a mean follow-up time of 5.5 years (range, 2.7-8.2 years), 37 patients died, 37 received liver transplants, 88 had initial hepatic decompensation events, 41 developed hepatocellular carcinoma, 14 had vascular events, and 30 developed nonhepatic cancers. A higher proportion of patients with F3 fibrosis survived transplantation-free for 10 years (94%; 95% confidence interval [CI], 86%-99%) than of patients with cirrhosis and Child-Turcotte-Pugh A5 (74%; 95% CI, 61%-89%) or Child-Turcotte-Pugh A6 (17%; 95% CI, 6%-29%). Patients with cirrhosis were more likely than patients with F3 fibrosis to have hepatic decompensation (44%; 95% CI, 32%-60% vs 6%, 95% CI, 2%-13%) or hepatocellular carcinoma (17%; 95% CI, 8%-31% vs 2.3%, 95% CI, 1%-12%). The cumulative incidence of vascular events was higher in patients with F3 fibrosis (7%; 95% CI, 3%-18%) than cirrhosis (2%; 95% CI, 0%-6%). The cumulative incidence of nonhepatic malignancies was higher in patients with F3 fibrosis (14%; 95% CI, 7%-23%) than cirrhosis (6%; 95% CI, 2%-15%). Death or transplantation, decompensation, and hepatocellular carcinoma were independently associated with baseline cirrhosis and mild (<33%) steatosis, whereas moderate alcohol consumption was associated with these outcomes only in patients with cirrhosis. Patients with NAFLD cirrhosis have predominantly liver-related events, whereas those with bridging fibrosis have predominantly nonhepatic cancers and vascular events.


A novel real-time PCR to detect Chlamydia trachomatis in first-void urine or genital swabs.
Screening for Chlamydia trachomatis infections can be performed on urine samples and genital swabs using molecular techniques. A novel approach was developed that combined an automated extraction procedure, an automated liquid-handling system and real-time PCR to detect C. trachomatis from urine or swabs. This novel real-time PCR approach was compared to the commercial Cobas Amplicor system on 628 specimens. In a retrospective analysis, 51 samples that tested positive using the Cobas assay were also positive with the real-time PCR, whereas the 49 samples negative with Cobas were also negative with the real-time PCR, for an overall agreement of 100 %. Among 528 prospective samples consecutively received at the authors' laboratory with a request for C. trachomatis PCR, five PCR reactions were inhibited when tested with Cobas. These five inhibited samples were found negative with the real-time PCR. Among the remaining 523 samples, 45 (8.6 %) were positive with both methods, 476 (91 %) were negative with both methods, and 2 (0.4 %) were positive with Cobas but negative with the real-time PCR. Thus, when considering Cobas as the gold standard, the overall agreement was 99.6 %, the sensitivity of the real-time PCR was 95.7 % and the specificity was 100 %. The two discrepant samples were retested in parallel and were found negative with both methods. When testing a batch of 25 samples, both reagent costs and laboratory technician time were reduced with the new technique (7.30 euros per sample and 134 min) compared to Cobas (11.20 euros per sample and 232 min). Moreover, due to reduced organizational constraints, the median time from sample reception to result was only 24 h using the automated platform. Overall, this novel real-time PCR approach exhibited an excellent specificity and a sensitivity similar to that of Cobas Amplicor PCR for the detection of C. trachomatis. Given its high throughput potential and low costs/laboratory technician time requirement, it may be useful for future use in large C. trachomatis screening programs.


Vitamin K2 Induces Mitochondria-Related Apoptosis in Human Bladder Cancer Cells via ROS and JNK/p38 MAPK Signal Pathways.
The effects of vitamin K2 on apoptosis in a variety of cancer cells have been well established in previous studies. However, the apoptotic effect of vitamin K2 on bladder cancer cells has not been evaluated. The aim of this study is to examine the apoptotic activity of Vitamin K2 in bladder cancer cells and investigate the underlying mechanism. In this study, Vitamin K2 induced apoptosis in bladder cancer cells through mitochondria pathway including loss of mitochondria membrane potential, cytochrome C release and caspase-3 cascade. Furthermore, the phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAPK was detected in Vitamin K2-treated cells and both SP600125 (an inhibitor of JNK) and SB203580 (an inhibitor of p38 MAPK) completely abolished the Vitamin K2-induced apoptosis and loss of mitochondria membrane potential. Moreover, the generation of reactive oxygen species (ROS) was detected in bladder cancer cells, upon treatment of vitamin K2 and the anti-oxidant N-acetyl cysteine (NAC) almost blocked the Vitamin K2-triggered apoptosis, loss of mitochondria membrane potential and activation of JNK and p38 MAPK. Taken together, these findings revealed that Vitamin K2 induces apoptosis in bladder cancer cells via ROS-mediated JNK/p38 MAPK and Mitochondrial pathways.


SCADA-Based Message Generator for Multi-Vendor Smart Grids: Distributed Integration and Verification of TASE.2.
Recent developments in massive machine-type communication (mMTC) scenarios have given rise to never-seen requirements, which triggered the Industry 4.0 revolution. The new scenarios bring even more pressure to comply with the reliability and communication security and enable flawless functionality of the critical infrastructure, e.g., smart grid infrastructure. We discuss typical network grid architecture, communication strategies, and methods for building scalable and high-speed data processing and storage platform. This paper focuses on the data transmissions using the sets of standards IEC 60870-6 (ICCP/TASE.2). The main goal is to introduce the TASE.2 traffic generator and the data collection back-end with the implemented load balancing functionality to understand the limits of current protocols used in the smart grids. To this end, the assessment framework enabling generating and collecting TASE.2 communication with long-term data storage providing high availability and load balancing capabilities was developed. The designed proof-of-concept supports complete cryptographic security and allows users to perform the complex testing and verification of the TASE.2 network nodes configuration. Implemented components were tested in a cloud-based Microsoft Azure environment in four geographically separated locations. The findings from the testing indicate the high performance and scalability of the proposed platform, allowing the proposed generator to be also used for high-speed load testing purposes. The load-balancing performance shows the CPU usage of the load-balancer below 15% while processing 5000 messages per second. This makes it possible to achieve up to a 7-fold improvement of performance resulting in processing up to 35,000 messages per second.


Face recognition in age-related maculopathy.
Patients with age-related maculopathy (ARM) complain frequently of difficulty with face recognition. The authors attempted to quantify the level of impairment by comparing face recognition with clinical tests of visual function, namely contrast sensitivity, grating acuity, letter-chart acuity, and word-reading acuity. For face recognition, we used 32 black-and-white photographs that had been cropped to remove the outline of hair so that identification was predominantly dependent on the facial features. The observer's distance from the screen on which the photographs were projected was varied. The angular size of the faces was indicated by the equivalent viewing distance (EVD). Four male and four female models were used, and for each model, there were four photographs with different facial expressions--happy, sad, angry, and afraid. For each photograph, the subject's task was to name the model and identify the facial expression. Threshold EVD (50%) was determined for correct identity recognition and expression recognition. For eight subjects all experimental procedures were repeated at a lower luminance level. For ARM subjects, increasing task complexity (grating/letters/words) substantially decreased resolution. Face-recognition abilities were most closely related to word-reading acuity when comparisons were made either across subjects or across luminances within subjects. Contrast sensitivity was associated poorly with face-recognition thresholds. In some subjects with more advanced ARM, identity recognition was substantially poorer than expression recognition.


Activation of Raf kinase by phorbol ester does not correlate with enhanced phosphorylation or transactivation activity of tumor suppressor protein p53.
The tumor suppressor protein p53 appears to be regulated by various means including phosphorylation. We investigated a possible influence of the raf kinase on phosphorylation and transactivation of p53. The phosphorylation pattern of p53 was analysed in normal or v-raf-transformed rat cells or in insect cells which were co-infected with recombinant baculoviruses encoding p53, protein kinase C and c-Raf. The presence of activated v-raf kinase or treatment of cells with PMA, which resulted in activation of both v-raf and c-Raf kinases, did not reveal any additional phosphorylation sites in p53 nor did any of the known sites show enhanced phosphorylation, neither in rat nor in baculovirus-infected insect cells. Instead, PMA treatment led to reduced phosphorylation of p53. This latter effect was similar in normal and v-raf-transformed cells suggesting that it is mediated by a PKC-dependent but raf-independent mechanism. Okadaic acid treatment compensated this reduced phosphorylation of p53 suggesting that it was due to activation of phosphatase(s). The transactivation activity of p53 was assayed under the same conditions, using an mdm2-promoter luciferase reporter gene construct. In this case, we obtained conflicting results: in normal rat cells both PMA and okadaic acid had a stimulatory effect which was additive. In the v-raf transformed cells, on the other hand, PMA alone reduced, whereas okadaic acid alone enhanced transcriptional activation and application of both drugs resulted in a slight net increase in transactivation. Thus, PMA seemed to have separable effects on phosphorylation and transactivation activity of p53. Our data suggest i) that neither Raf-l kinase nor PKC phosphorylate p53 directly in vivo, ii) that the reduced phosphorylation observed upon PMA treatment is independent of Raf, and perhaps mediated by indirect activation of phosphatases, iii) that the effects of PMA on p53-dependent transcription are not mediated by changes in the phosphorylation state of p53 itself.


Stroke-like migraine attacks after radiation therapy (SMART) syndrome-a case series and review.
Cranial irradiation is used both prophylactically and for the treatment of brain tumors. There are various complications associated with it. The rare complication of stroke-like migraine attacks after radiation therapy (SMART) syndrome usually occurs several years after radiation therapy but is a reversible phenomenon. It usually presents with headaches, seizures, or other focal neurological deficits concerning stroke or recurrence of the underlying disease. We aim to present two cases of SMART syndrome highlighting the typical presentation, imaging findings, and differential diagnosis. We also conducted the literature review since the early recognition of this rare delayed onset complication is crucial, given its self-limited course and to avoid misinterpretations of the cases. Our extensive review favors MRI, CT, and prolonged EEG monitoring to rule out other differentials and showed that initiation of corticosteroid therapy and antiepileptic treatment were helpful in the resolution of symptoms and prevent recurrences. Therefore, future studies should be focused on early identification and management guidelines for SMART syndrome.


Experience of radiotherapy in lethal midline granuloma with special emphasis on centrofacial T-cell lymphoma: a retrospective analysis covering a 34-year period.
Lethal midline granuloma (LMG) is characterized by progressive ulceration and destruction of the midfacial tissue. It occurs more frequently in Oriental than in Western populations. Because of the progress in clinical pathology and immunohistochemistry, most cases have been proven to be malignant lymphomas, especially of T-cell lineage. We describe 92 cases of lethal midline granuloma or centrofacial malignant lymphoma in the period 1959-1993. All received complete courses of radiotherapy. Twenty of them also received combination chemotherapy. Thirty-six cases had specimens available for immunohistochemical study; 25 (69%) of these had a T-cell phenotype, and 6 (17%) were of B-cell lineage. The dose to the nasal region was in the range of 3000-7500 cGy in 11-58 days, and to the neck 3000-6400 cGy in 11-48 days. The overall survival rate for the LMGs was 59.5% at 5 years and 56.2% at 10 years (Kaplan-Meier). Combined chemotherapy seemed not to improve the overall survival in this study (p = 0.63), but the patient number was too small to make a firm conclusion. Based on the results of this study, we recommend a dose of 4500-5000 cGy to the midfacial region, since a higher dosage did not improve the treatment results (p = 0.88). Irradiation has a definite role in good locoregional control of this disease. The recent clarification of the disease nature and the recognition of the background clinicopathological features should provide valuable information for future patient management and prospective studies.


Using the Internet as source of information during pregnancy - a descriptive cross-sectional study among fathers-to-be in Sweden.
The aim of this study was to identify how fathers-to-be used the Internet as a source of information during their partners' pregnancy and how it affected them. A descriptive cross-sectional study was conducted. Data were collected through a questionnaire and distributed at a maternity clinic in south of Sweden. The data were analysed descriptively. Ninety-two Swedish fathers participated in the study, and the response rate was 98.9%. Of all the fathers-to-be, 76% sought pregnancy-related information on the Internet. One sought information on a daily basis, 40.6% every week and 58% every month or more rarely. The fathers-to-be who participated at all/most visits at antenatal care searched for information on the Internet more often than those who only attended few/no visits (p = 0.012). A total of 33.4% of fathers-to-be had been recommended a web page by the midwife at the antenatal care. The main reason for using the Internet was to find information about pregnancy related subjects and read about people in similar situations. More than half of the fathers-to-be (61.8%) had at some point been worried by something they read online. These concerns were commonly addressed by asking the midwife at their next appointment (33.9%). Almost 26% of the fathers-to-be chose not to take any action at all to address their concerns. The majority of all fathers-to-be searched for information on the Internet, and more than half of the fathers were, at some point, worried about the information they read on the Internet. One way to address questions and concerns could be for the fathers-to-be to ask and discuss with the midwives what they read online so that midwives can recommend appropriate and credible websites. To achieve this, there must be opportunities for midwives to gain knowledge on how best to use the Internet as a tool.


The epidemiology of cold injury in Antarctica.
A retrospective study was performed of 10 yr of medical records to determine the type, severity, etiological factors and treatment of cold injury experienced by members of the British Antarctic Survey between 1986-95. There were 61 new consultations for cold injury. These comprised 2.5% of all new consultations with an incidence of 65.6 per 1000 per year. Cold injuries seen were frostbite (95%), hypothermia (3%) and trench foot (2%). Superficial frostbite was the most common injury (74% of cases) with the face the most frequently affected area (47% of injuries). No cases of frostbite severe enough to cause permanent tissue loss were seen. The prevalence of cold injury increased with falling temperature to a maximum between -25 and -35 degrees C, despite these temperatures occurring infrequently. The relationship with windchill is not as clear cut with frequency of injury tending to follow the frequency of windchill values except at higher windchill values. Neither temperature nor windchill were found to significantly influence the severity of frostbite. Prior cold injury was shown to be significantly (chi2 p < 0.001) associated with further cold injury. Most injuries (78%) occurred during recreation; skiing and snowmobile driving were often implicated. Cold injury is uncommon in Antarctica. Despite this, it warrants a continued high profile as under most circumstances it may be regarded as an entirely preventable occurrence.


Marine soundscape shaped by fishing activity.
Marine communities face anthropogenic pressures that degrade ecosystems. Because underwater soundscapes carry information about habitat quality, we explored whether destructive impacts of fishing could be evaluated via the soundscape. Maerl beds are recognized as biodiversity hotspots and they experience major worldwide degradation owing to fishing. We collected field acoustic recordings in maerl beds exposed to different fishing practices. We found that unfished maerl beds were threefold louder and exhibited sound frequencies more diversified than those recorded in fished maerl beds. Analyses of associated fauna samples indicated that snapping shrimps provided a major contribution to the maerl bed soundscape. Moreover, sea urchins and squat lobsters most likely contributed to differences between the soundscapes of unfished and fished maerl beds. Our results supported the idea that the soundscape can provide valuable information on maerl bed ecosystem health related to fishing activity.


Functional variant in the autophagy-related 5 gene promotor is associated with childhood asthma.
Autophagy is a cellular process directed at eliminating or recycling cellular proteins. Recently, the autophagy pathway has been implicated in immune dysfunction, the pathogenesis of inflammatory disorders, and response to viral infection. Associations between two genes in the autophagy pathway, ATG5 and ATG7, with childhood asthma were investigated. Using genetic and experimental approaches, we examined the association of 13 HapMap-derived tagging SNPs in ATG5 and ATG7 with childhood asthma in 312 asthmatic and 246 non-allergic control children. We confirmed our findings by using independent cohorts and imputation analysis. Finally, we evaluated the functional relevance of a disease associated SNP. We demonstrated that ATG5 single nucleotide polymorphisms rs12201458 and rs510432 were associated with asthma (p = 0.00085 and 0.0025, respectively). In three independent cohorts, additional variants in ATG5 in the same LD block were associated with asthma (p<0.05). We found that rs510432 was functionally relevant and conferred significantly increased promotor activity. Furthermore, Atg5 expression was increased in nasal epithelium of acute asthmatics compared to stable asthmatics and non-asthmatic controls. Genetic variants in ATG5, including a functional promotor variant, are associated with childhood asthma. These results provide novel evidence for a role for ATG5 in childhood asthma.


Endoscopic management of pediatric brain tumors.
Primary endoscopic procedures for children with intraventricular brain tumors include endoscopic tumor biopsy and endoscopic tumor removal. The simultaneous treatment of hydrocephalus with endoscopic third ventriculostomy (ETV) or endoscopic septostomy increases the appeal of a minimally invasive endoscopic approach. Eighty-five patients who underwent endoscopic management of an intraventricular brain tumor were identified from a prospective database. Of these patients, 26 were younger than 21 years of age at the time of diagnosis. The surgical technique, its success rate, and patient outcome were assessed. Illustrative cases are used in this study to detail the procedure of endoscopic tumor biopsy and resection. Endoscopic tumor procedures were successful in 96% of cases (23 of 24 endoscopic tumor biopsy samples and both endoscopic tumor removals). Fourteen simultaneous procedures were performed to treat hydrocephalus successfully. There was no recognized morbidity from the surgical procedures. Endoscopic surgery in children with intraventricular brain tumors is an effective and safe method for sampling of the lesion and, in select cases, its resection. This minimally invasive technique should be considered in situations in which the patient might thereby avoid a more conventional procedure, given the high rate of success and low morbidity associated with endoscopic management.