Atrial Fibrillation with Rapid Ventricular Response following use of Dietary Supplement Containing 1,3 Dimethylamylamine and Caffeine.
Our nation?s servicemembers commonly use dietary supplements to enhance their performance. Despite this prolific use, many of these products have detrimental side-effects that compromise servicemembers? health and could, by proxy, compromise a mission. This paper presents the case of a 32-year old Navy Special Operations Forces (SOF) Sailor who, prior to physical training, used a supplement containing 1,3 Dimethylamylamine (DMAA), and then developed atrial fibrillation with rapid ventricular response. He required intravenous calcium channel blocker administration, followed by beta blockers, for rate control. As military providers, we routinely ask our patients about their use of supplements and while the regulation of these products is beyond the scope of practice for most of us, it is our duty to become better educated about the risks and benefits of these supplements. We must educate our patients and our commands on the potential harm that these supplements may pose.


Evaluation of cerebral blood flow using multi-phase pseudo continuous arterial spin labeling at 3-tesla.
Arterial spin labeling (ASL) methods have been widely used for evaluation of cerebral blood flow (CBF) by magnetic resonance imaging. However, ASL methods require setting of the post labeling delay (PLD) time for obtaining images. As the hemodynamic status cannot be estimated in each patient, the resultant quantitative values of blood flow may not be accurate. The multi-phase pseudo continuous arterial spin labeling (pCASL) method can be used to obtain images at various time-points. The purpose of this study was to create the transit-time maps for correcting the delayed blood flow and evaluate CBF using the transit-time maps obtained by the multi-phase pCASL method. Twelve patients who underwent both 3.0-tesla magnetic resonance imaging (MRI) and single photon emission computed tomography with iodine-123-N-isopropyl-p-iodoamphetamine (123I-IMP) were investigated. This study was approved by the institutional review board of our institution. MRI acquisitions included PLD time-fixed (1525ms) and multi-phase pCASL sequences. The transit-time maps were calculated from multi-phase pCASL images by software. The transit-time maps were applied to PLD-fixed pCASL images pixel by pixel, for calculating the CBF value corrected for peak blood transit time. Regions of interest were drawn on the brain. IMP-CBF, ASL-CBF (default and corrected) and transit time were measured for each segment. Twelve patients and 264 segments were investigated. The mean IMP-CBF, ASL-CBF (default, corrected) and transit time were 28.4, 23.0, 29.6, [ml/min/100g] and 1977.5 [ms], respectively. There were no significant differences between IMP-CBF and ASL-CBF (corrected). CBF values can be corrected by using the transit-time maps obtained using the multi-phase pCASL method.


Access of non-specialist sexual health services by men who have sex with men: do they differ from those attending specialist services?
Men who have sex with men (MSM) bear a disproportionate burden of STIs. While routine STI surveillance data suggest MSM regularly access specialist genitourinary medicine (GUM) clinics for their sexual healthcare, the extent to which MSM attend non-specialist sexual health services (SHSs) is unclear. We used data from the GUM Clinic Activity Data Set (GUMCADv2), the national STI surveillance system, to compare the characteristics, service usage and STI outcomes of MSM accessing specialist and non-specialist (non-GUM) SHSs in England in 2014. Pearson's χ2, Student's t-test and logistic regression analysis were used. Where sexual orientation was recorded (92%), 11% (4552/41 597) of non-GUM attendances were among MSM compared with 28% (280 466/999 331) of GUM attendances (p<0.001). Compared with those attending GUM services, MSM attending non-GUM services were younger (mean age: 30.2 years vs 37.7 years; p<0.001) and were more likely to be of mixed ethnicity (4.9% vs 3.5%; p<0.001), to have had a full sexual health screen (chlamydia, gonorrhoea, syphilis and HIV tests) (48.0% vs 37.0%; p<0.001) and to be diagnosed with chlamydia (7.4% vs 4.1%; p<0.001) and gonorrhoea (8.5% vs 6.5%: p<0.001). MSM attending non-GUM services had slightly lower HIV test uptake (87.0% vs 95.0%; p=0.157) and were less likely to be diagnosed with HIV (0.5% vs 0.8%; p=0.019), compared with those attending GUM clinics. Non-specialist SHSs play an important role in the care of MSM and should ensure services meet their needs.


Surface tension and the mechanics of liquid inclusions in compliant solids.
Eshelby's theory of inclusions has wide-reaching implications across the mechanics of materials and structures including the theories of composites, fracture, and plasticity. However, it does not include the effects of surface stress, which has recently been shown to control many processes in soft materials such as gels, elastomers and biological tissue. To extend Eshelby's theory of inclusions to soft materials, we consider liquid inclusions within an isotropic, compressible, linear-elastic solid. We solve for the displacement and stress fields around individual stretched inclusions, accounting for the bulk elasticity of the solid and the surface tension (i.e. isotropic strain-independent surface stress) of the solid-liquid interface. Surface tension significantly alters the inclusion's shape and stiffness as well as its near- and far-field stress fields. These phenomena depend strongly on the ratio of the inclusion radius, R, to an elastocapillary length, L. Surface tension is significant whenever inclusions are smaller than 100L. While Eshelby theory predicts that liquid inclusions generically reduce the stiffness of an elastic solid, our results show that liquid inclusions can actually stiffen a solid when R<3L/2. Intriguingly, surface tension cloaks the far-field signature of liquid inclusions when R=3L/2. These results are have far-reaching applications from measuring local stresses in biological tissue, to determining the failure strength of soft composites.


Survival analysis in systemic lupus erythematosus patients on maintenance dialysis: a nationwide population-based study in Taiwan.
This study aimed to identify the risk factors for mortality and the impact of dialysis modalities on the survival in SLE patients with end-stage renal disease (ESRD). This retrospective nationwide population-based study using the National Health Insurance Research Database in Taiwan collected data from 1073 SLE ESRD patients starting maintenance dialysis between March 1997 and December 2006. A multivariate Cox regression hazard model was applied to identify factors predicting mortality in cohorts using different dialysis modalities and the impact of dialysis modalities on the survival outcome of these patients of both genders. The major threat to SLE patients on maintenance dialysis was infections. For SLE patients undergoing regular haemodialysis (HD), age, male sex, and high or absence of daily steroid dosing were predictive of higher mortality. For those undergoing regular peritoneal dialysis (PD), age and high daily steroid dosing were the predictive factors. After adjusting confounding factors, male patients with HD had a significantly poorer outcome than the counterpart with PD or female patients with HD. There was no survival difference among female SLE patients with different dialysis modalities. No underlying comorbidities were identified to increase the mortality of patients receiving particular dialysis modalities after correcting for age and steroid factors. There was no impact of different dialysis modalities on survival of female SLE patients. However, male SLE patients seemed susceptible to fatal events complicated by HD, which led to an inferior survival rate.


JunD/AP1 regulatory network analysis during macrophage activation in a rat model of crescentic glomerulonephritis.
Function and efficiency of a transcription factor (TF) are often modulated by interactions with other proteins or TFs to achieve finely tuned regulation of target genes. However, complex TF interactions are often not taken into account to identify functionally active TF-targets and characterize their regulatory network. Here, we have developed a computational framework for integrated analysis of genome-wide ChIP-seq and gene expression data to identify the functional interacting partners of a TF and characterize the TF-driven regulatory network. We have applied this methodology in a rat model of macrophage dependent crescentic glomerulonephritis (Crgn) where we have previously identified JunD as a TF gene responsible for enhanced macrophage activation associated with susceptibility to Crgn in the Wistar-Kyoto (WKY) strain. To evaluate the regulatory effects of JunD on its target genes, we analysed data from two rat strains (WKY and WKY.LCrgn2) that show 20-fold difference in their JunD expression in macrophages. We identified 36 TFs interacting with JunD/Jun and JunD/ATF complexes (i.e., AP1 complex), which resulted in strain-dependent gene expression regulation of 1,274 target genes in macrophages. After lipopolysaccharide (LPS) stimulation we found that 2.4 fold more JunD/ATF-target genes were up-regulated as compared with JunD/Jun-target genes. The enriched 314 genes up-regulated by AP1 complex during LPS stimulation were most significantly enriched for immune response (P = 6.9 × 10⁻⁴) and antigen processing and presentation functions (P = 2.4 × 10⁻⁵), suggesting a role for these genes in macrophage LPS-stimulated activation driven by JunD interaction with Jun/ATF. In summary, our integrated analyses revealed a large network of TFs interacting with JunD and their regulated targets. Our data also suggest a previously unappreciated contribution of the ATF complex to JunD-mediated mechanisms of macrophage activation in a rat model of crescentic glomerulonephritis.


The grass isn't always greener: The effects of cannabis on embryological development.
With the increasing publicity of marijuana due to recent legislation, it is pertinent that the effects of fetal exposure to the drug are assessed. While in utero cannabis exposure has been associated with early pregnancy failure, birth defects and developmental delay, the mechanisms of such outcomes are largely unexplained. Furthermore, the use of cannabinoids in cancer treatment via growth inhibition and apoptosis may indicate how cannabis exposure likely harms a growing fetus. Cannabinoid signaling is required for proper pre-implantation development, embryo transport to the uterus, and uterine receptivity during implantation. In post-implantation development, cannabinoid signaling functions in a multitude of pathways, including, but not limited to, folic acid, VEGF, PCNA, MAPK/ERK, and BDNF. Disrupting the normal activity of these pathways can significantly alter many vital in utero processes, including angiogenesis, cellular replication, tissue differentiation, and neural cognitive development. This paper aims to demonstrate the effects of cannabis exposure on a developing embryo in order to provide a molecular explanation for the adverse outcomes associated with cannabis use during pregnancy.


Histopathological and clinical evaluation of serrated adenomas of the colon and rectum.
We evaluated the diagnostic utility of the histological characteristics ascribed in the literature to serrated adenomas and developed a practical working model to allow their reliable identification. We also documented the frequency and location of serrated adenomas identified in an unselected series of individuals undergoing colonoscopic evaluation, as well as the clinical characteristics of those individuals. One hundred forty consecutive individuals (prospective polyp data set; 97 male, 43 female; age mean: 63.3 y; age range: 29-98 y) with 255 polyps were identified from 919 individuals undergoing colonoscopy. Further polyps previously removed from these individuals were added for the purpose of histological assessment (extended polyp data set, n = 380). All polyps were assessed by two independent examiners for eight selected architectural and cytological features of serrated adenomas. In the prospective polyp data set, 56 patients had 72 hyperplastic polyps, 7 had 9 serrated adenomas, 3 had 4 admixed polyps, and 98 had 170 conventional adenomas. There was no difference in the age, sex, or cancer association of the seven patients with serrated adenomas when compared with the case of other individuals with polyps. The prevalence of serrated adenomas was 9/919 (1%) in our population, with an average size of 5.8 mm. When assessing serrated adenomas histologically, the combination of nuclear dysplasia and serration of >/=20% of crypts provided the most accurate model for detection of these lesions (sensitivity 100%, specificity 97%). Other criteria provided supportive evidence but did not increase the diagnostic yield. The optimum model for the histological identification of the serrated adenoma includes the presence of a serrated architecture in >/=20% of crypts in association with surface epithelial dysplasia.


Tumor cell resistance against targeted therapeutics: the density of cultured glioma tumor cells enhances Stat3 activity and offers protection against the tyrosine kinase inhibitor canertinib.
Tumor cell resistance to drug treatment severely limits the therapeutic success of treatment. Tumor cells, exposed to chemotherapeutic drugs, have developed intricate strategies to escape the cytotoxic effects and adapt to adverse conditions. The molecular mechanisms causing drug resistance can be based upon modifications of drug transport or metabolism, structural alterations of drug targets or adaptation of cellular signaling. An important component in the transformation of cells and the emergence of drug resistance is the activation of the transcription factor Stat3. The persistent, inappropriate activation of Stat3 causes the expression of target genes which promote tumor cell proliferation, survival, invasion and immune suppression, and it is instrumental in the process of the emergence of resistance to both conventional chemotherapeutic agents and novel targeted compounds. For these reasons, Stat3 inhibition is being pursued as a promising therapeutic strategy. We have investigated the effects of the tyrosine kinase inhibitor canertinib on the glioma cell line Tu-2449. In these cells Stat3 is persistently phosphorylated and activated downstream of the oncogenic driver v-Src and its effector, the cytoplasmic tyrosine kinase Bmx. Canertinib exposure of Tu-2449 cells rapidly caused the inhibition of the Bmx kinase and the deactivation of Stat3. Prolonged exposure of the cells to canertinib caused the death of the large majority of the cells. Only a few cells became resistant to canertinib and survived in tight clusters. These cells have become drug resistant. When the canertinib resistant cells were expanded and cultured at lower cell densities, they regained their sensitivity towards canertinib. We measured the extent of Stat3 activation as a function of cell density and found that higher cell densities are accompanied by increased Stat3 activation and a higher expression of Stat3 target genes. We suggest that Stat3 induction through tight cell-cell interactions, most likely through the engagement of cadherins, can counteract the inhibitory effects exerted by canertinib on Bmx. Cell-cell interactions induced Stat3 and compensated for the suppression of Stat3 by canertinib, thus transiently protecting the cells from the cytotoxic effects of the inhibitor.


Efficacy of injections of corticosteroids for subacromial impingement syndrome.
A prospective, randomized, controlled, double-blind clinical study was performed to determine the short-term efficacy of subacromial injection of corticosteroids for the treatment of subacromial impingement syndrome. Forty patients were randomized to receive either six milliliters of 1 per cent lidocaine without epinephrine (the control group) or two milliliters containing forty milligrams of triamcinolone acetonide per milliliter with four milliliters of 1 per cent lidocaine without epinephrine (the corticosteroid group). The patients were re-examined serially until completion of the study. Nineteen patients, whose mean age was fifty-six years (range, thirty-two to eighty years), were randomized to the corticosteroid group, and twenty-one patients, whose mean age was fifty-seven years (range, thirty-two to eighty-one years), were randomized to the control group. The mean duration of symptoms before the injection was eight months for both groups. Eighteen patients in the corticosteroid group and nineteen patients in the control group had moderate or severe pain before the injection. At the most recent follow-up evaluation, at a mean of thirty-three weeks for the corticosteroid group and twenty-eight weeks for the control group, three patients in the corticosteroid group had moderate or severe pain, compared with fifteen patients in the control group. The mean active range of forward elevation and external rotation improved by 24 and 11 degrees, respectively, for the corticosteroid group and by 10 and 5 degrees, respectively, for the control group. We concluded that subacromial injection of corticosteroids is an effective short-term therapy for the treatment of symptomatic subacromial impingement syndrome. The use of such injections can substantially decrease pain and increase the range of motion of the shoulder.


NO level and endothelial NO synthase gene polymorphism (Glu298Asp) in the patients with coronary artery disease from the Turkish population.
Nitric oxide is synthesized from L-arginine by endothelial nitric oxide synthase encoded by eNOS gene. This study was performed to investigate the relationship between the serum nitric oxide level and eNOS gene polymorphism in the Turkish population with angiographically diagnosed coronary artery disease (63.47 +/- 9.10 years old, n=250) and control subjects without any history and/or risk factors of coronary artery disease (60.71 +/- 9.14 years old, n=150). Griess assay and PCR-RFLP analysis were used to measure the serum nitric oxide metabolites and genotypes, respectively. It was found that Glu/Glu, Glu/Asp and Asp/Asp genotype frequencies of the eNOS were 49.3%, 41.3% and 9.3% respectively in the control group, and 45.6%, 41.2% and 13.2% in the patient group. Serum nitric oxide levels were (32.56 +/- 17.26) microM in controls and (29.84 +/- 11.88) microM in patients. Neither the frequencies of the Glu298Asp genotypes nor the serum nitricoxide levels showed a significant difference between the groups. There was also no correlation between serum nitric oxide levels and the frequencies of the eNOS genotypes. Result showed that the coronary artery disease of the Turkish population seemed to develop without any alterations in eNOS Glu298Asp genotype frequency and the serum nitric oxide level.


Initiation of Wnt signaling: control of Wnt coreceptor Lrp6 phosphorylation/activation via frizzled, dishevelled and axin functions.
Canonical Wnt/beta-catenin signaling has central roles in development and diseases, and is initiated by the action of the frizzled (Fz) receptor, its coreceptor LDL receptor-related protein 6 (Lrp6), and the cytoplasmic dishevelled (Dvl) protein. The functional relationships among Fz, Lrp6 and Dvl have long been enigmatic. We demonstrated previously that Wnt-induced Lrp6 phosphorylation via glycogen synthase kinase 3 (Gsk3) initiates Wnt/beta-catenin signaling. Here we show that both Fz and Dvl functions are critical for Wnt-induced Lrp6 phosphorylation through Fz-Lrp6 interaction. We also show that axin, a key scaffolding protein in the Wnt pathway, is required for Lrp6 phosphorylation via its ability to recruit Gsk3, and inhibition of Gsk3 at the plasma membrane blocks Wnt/beta-catenin signaling. Our results suggest a model that upon Wnt-induced Fz-Lrp6 complex formation, Fz recruitment of Dvl in turn recruits the axin-Gsk3 complex, thereby promoting Lrp6 phosphorylation to initiate beta-catenin signaling. We discuss the dual roles of the axin-Gsk3 complex and signal amplification by Lrp6-axin interaction during Wnt/beta-catenin signaling.


Population genetic structure of Guizhou snub-nosed monkeys (Rhinopithecus brelichi) as inferred from mitochondrial control region sequences, and comparison with R. roxellana and R. bieti.
The Guizhou snub-nosed monkey (Rhinopithecus brelichi) is a primate species endemic to the Wuling Mountains in southern China. With a maximum of 800 wild animals, the species is endangered and one of the rarest Chinese primates. To assess the genetic diversity within R. brelichi and to analyze its genetic population structure, we collected fecal samples from the wild R. brelichi population and sequenced the hypervariable region I of the mitochondrial control region from 141 individuals. We compared our data with those from the two other Chinese snub-nosed species (R. roxellana, R. bieti) and reconstructed their phylogenetic relationships and divergence times. With only five haplotypes and a maximum of 25 polymorphic sites, R. brelichi shows the lowest genetic diversity in terms of haplotype diversity (h), nucleotide diversity (π), and average number of pairwise nucleotide differences (Π). The most recent common ancestor of R. brelichi lived ∼0.36 million years ago (Ma), thus more recently than those of R. roxellana (∼0.91 Ma) and R. bieti (∼1.33 Ma). Phylogenetic analysis and analysis of molecular variance revealed a clear and significant differentiation among the three Chinese snub-nosed monkey species. Population genetic analyses (Tajima's D, Fu's F(s) , and mismatch distribution) suggest a stable population size for R. brelichi. For the other two species, results point in the same direction, but population substructure possibly introduces some ambiguity. Because of the lower genetic variation, the smaller population size and the more restricted distribution, R. brelichi might be more vulnerable to environmental changes or climate oscillations than the other two Chinese snub-nosed monkey species. Am J Phys Anthropol, 2012. © 2011 Wiley Periodicals, Inc.


Relationship continuity: when and why do primary care patients think it is safer?
Doctor-patient continuity is popular with patients and practitioners, and is associated with better outcomes; however, changes in policy and practice organisation have diminished its scope. Although there has been some discussion of safety implications from professionals' perspective, patients' views remain largely unexplored. To explore patients' understanding of safety in primary care. An interview-based study with patients from general practices in the northwest of England. Patients were recruited from five general practices through patient participation groups and posters in waiting rooms, with further participants recruited through snowballing techniques until no new themes emerged. In-depth interviews were digitally recorded and transcribed. Anonymised transcripts were coded and analysed inductively. Emergent themes were discussed by the team. For patients, relationship continuity was not simply a matter of service quality but an important safety concern that offered greater psychosocial security than consultations with unfamiliar GPs. Relationship continuity enabled the GP to become a repository of information; acquire specialist knowledge of a patient's condition; become familiar with the patient's consulting behaviour; provide holistic care; and foster the development of trust. Patients were also aware of the risks: a false sense of security and lack of a fresh perspective. Their desire for continuity varied with the nature of their concerns, psychological vulnerability, and perception of GPs' qualities and skills. No one supported a return to imposed continuity. Relationship continuity and choice of GP were important safety strategies, neither of which is adequately supported by recent policy changes.


Three-dimensional power Doppler vascular sonographic sampling for predicting ovarian cancer in cystic-solid and solid vascularized masses.
The purpose of this study was to explore the role of 3-dimensional (3D) power Doppler (PD) sonography to discriminate between benign and malignant cystic-solid and solid vascularized adnexal masses and to define cutoff values for 3D PD indices to be used in a clinical setting. A total of 143 consecutive women (mean age, 50.4 years; range, 17-82 years) with diagnoses of cystic-solid or solid vascularized adnexal masses on B-mode and 2-dimensional PD sonography were evaluated by 3D PD sonography before surgery. Three-dimensional PD sonography was used to assess vascularization within papillary projections and solid areas with a virtual organ computer-aided analysis program. Three-dimensional PD vascular indices (vascularization index [VI], flow index [FI], and vascularization-flow index [VFI]) were automatically calculated. A definitive histologic diagnosis was obtained in each case. A total of 113 masses (74%) were malignant, and 39 (26%) were benign. Morphologic evaluation revealed 30 unilocular solid masses (19.7%), 43 multilocular solid masses (28.3%), and 79 mostly solid masses (52%). The mean VI (9.365% versus 3.3%; P< .001), FI (34.318 versus 28.794; P< .001), and VFI (3.233 versus 1.15; P<0.01) were significantly higher in malignant tumors. No differences were found in the resistive index, pulsatility index, and peak systolic velocity. Receiver operating characteristic analysis revealed an area under the curve of 0.77 (95% confidence interval, 0.69-0.85), 0.71 (0.60-0.81), and 0.75 (0.66-0.83) for the VI, FI and VFI, respectively. For reducing the false-positive rate by almost one-third, sensitivity values for the VI (cutoff, 1.556%), FI (25.212), and VFI (0.323) were 92%, 95%, and 93%, respectively. Three-dimensional PD vascular indices could be helpful for reducing the false-positive rate in cystic-solid and solid vascularized adnexal masses.


Prevalence of Hyponatremia in Hypothyroid Patients during Radioactive ¹³¹I Ablation for Differentiated Thyroid Cancer: Single Institution Experience.
Hyponatremia developing in hypothyroid patients has been encountered in clinical practice; however, its prevalence has not been well established. Thirty patients diagnosed with differentiated thyroid cancer, rendered hypothyroid after surgery and levothyroxine withdrawal, and who are for radioactive iodine (RAI) ablation were included. Serum sodium concentrations were measured twice, at the time of admission for RAI ablation, and before discharge after increased oral fluid intake. The outcome measures were to determine the prevalence of hyponatremia among hypothyroid patients prior to RAI ablation and after oral hydration post-RAI, and to correlate the serum sodium levels pre-RAI and post-RAI with thyroid-stimulating hormone (TSH) concentration and age. Thirty patients were included, with ages from 23 to 65 years old (median, 40). Two patients (6.7%) were hyponatremic prior to RAI ablation, and eight patients (26.7%) had mild hyponatremia (130 to 134 mEq/L) after RAI and hydration. There was no significant correlation between TSH levels and serum sodium levels prior to or after RAI. There was also no significant correlation between pre- and post-RAI sodium concentration and age. The prevalence of hyponatremia pre-RAI was 6.7%, and 26.7% post-RAI. No significant correlation was noted between TSH concentration and age on pre- or post-RAI sodium concentrations. Routine measurement of serum sodium post-RAI/isolation is still not advised. Measurement of sodium post-RAI may be considered in patients who are elderly, with comorbid conditions or on medications.


Inactivation of Bap1 Cooperates with Losses of Nf2 and Cdkn2a to Drive the Development of Pleural Malignant Mesothelioma in Conditional Mouse Models.
Pleural malignant mesothelioma is a therapy-resistant cancer affecting the serosal lining of the thoracic cavity. Mutations/deletions of BAP1, CDKN2A, and NF2 are the most frequent genetic lesions in human malignant mesothelioma. We introduced various combinations of these deletions in the pleura of conditional knockout (CKO) mice, focusing on the contribution of Bap1 loss. While homozygous CKO of Bap1, Cdkn2a, or Nf2 alone gave rise to few or no malignant mesotheliomas, inactivation of Bap1 cooperated with loss of either Nf2 or Cdkn2a to drive development of malignant mesothelioma in approximately 20% of double-CKO mice, and a high incidence (22/26, 85%) of malignant mesotheliomas was observed in Bap1;Nf2;Cdkn2a (triple)-CKO mice. Malignant mesothelioma onset was rapid in triple-CKO mice, with a median survival of only 12 weeks, and malignant mesotheliomas from these mice were consistently high-grade and invasive. Adenoviral-Cre treatment of normal mesothelial cells from Bap1;Nf2;Cdkn2a CKO mice, but not from mice with knockout of one or any two of these genes, resulted in robust spheroid formation in vitro, suggesting that mesothelial cells from Bap1;Nf2;Cdkn2a mice have stem cell-like potential. RNA-seq analysis of malignant mesotheliomas from triple-CKO mice revealed enrichment of genes transcriptionally regulated by the polycomb repressive complex 2 (PRC2) and others previously implicated in known Bap1-related cellular processes. These data demonstrate that somatic inactivation of Bap1, Nf2, and Cdkn2a results in rapid, aggressive malignant mesotheliomas, and that deletion of Bap1 contributes to tumor development, in part, by loss of PRC2-mediated repression of tumorigenic target genes and by acquisition of stem cell potential, suggesting a potential avenue for therapeutic intervention. SIGNIFICANCE: Combinatorial deletions of Bap1, Nf2, and Cdkn2a result in aggressive mesotheliomas, with Bap1 loss contributing to tumorigenesis by circumventing PRC2-mediated repression of oncogenic target genes.


Discharge Patterns for Ischemic and Hemorrhagic Stroke Patients Going From Acute Care Hospitals to Inpatient and Skilled Nursing Rehabilitation.
The aim of the study was to explore variation in acute care use of inpatient rehabilitation facilities and skilled nursing facilities rehabilitation after ischemic and hemorrhagic stroke. A secondary analysis of Medicare claims data linked to inpatient rehabilitation facilities and skilled nursing facilities assessment files (2013-2014) was performed. The sample included 122,084 stroke patients discharged to inpatient or skilled nursing facilities from 3677 acute hospitals. Of the acute hospitals, 3649 discharged patients with an ischemic stroke (range = 1-402 patients/hospital, median = 15) compared with 1832 acute hospitals that discharged patients with hemorrhagic events (range = 1-73 patients/hospital, median = 4). The intraclass correlation coefficient examined variation in discharge settings attributed to acute hospitals (ischemic intraclass correlation coefficient = 0.318, hemorrhagic intraclass correlation coefficient = 0.176). Patients older than 85 yrs and those with greater numbers of co-morbid conditions were more likely to discharge to skilled nursing facilities. Comparison of self-care and mobility across stroke type suggests that patients with ischemic stroke have higher functional abilities at admission. This study suggests demographic and clinical differences among stroke patients admitted for postacute rehabilitation at inpatient rehabilitation facilities and skilled nursing facilities settings. Furthermore, examination of variation in ischemic and hemorrhagic stroke discharges suggests acute facility-level differences and indicates a need for careful consideration of patient and facility factors when comparing the effectiveness of inpatient rehabilitation facilities and skilled nursing facilities rehabilitation.


Homophilic complex formation of MT1-MMP facilitates proMMP-2 activation on the cell surface and promotes tumor cell invasion.
Activation of proMMP-2 by MT1-MMP is considered to be a critical event in cancer cell invasion. In the activation step, TIMP-2 bound to MT1-MMP on the cell surface acts as a receptor for proMMP-2. Subsequently, adjacent TIMP-2-free MT1-MMP activates the proMMP-2 in the ternary complex. In this study, we demonstrate that MT1-MMP forms a homophilic complex through the hemopexin-like (PEX) domain that acts as a mechanism to keep MT1-MMP molecules close together to facilitate proMMP-2 activation. Deletion of the PEX domain in MT1-MMP, or swapping the domain with the one derived from MT4-MMP, abolished the ability to activate proMMP-2 on the cell surface without affecting the proteolytic activities. In addition, expression of the mutant MT1-MMP lacking the catalytic domain (MT1PEX-F) efficiently inhibited complex formation of the full-length enzymes and activation of pro MMP-2. Furthermore, expression of MT1PEX-F inhibited proMMP-2 activation and Matrigel invasion activity of invasive human fibrosarcoma HT1080 cells. These findings elucidate a new function of the PEX domain: regulating MT1-MMP activity on the cell surface, which accelerates cellular invasiveness in the tissue.


Predictors of intensive care unit and hospital length of stay in diabetic ketoacidosis.
To determine the predictive value for prolonged intensive care unit (ICU) and hospital length of stay (LOS) in patients with diabetic ketoacidosis (DKA) of the Acute Physiology and Chronic Health Evaluation II (APACHE II) score and Logistic Organ Dysfunction System (LODS), and to identify associated characteristics. Prospective cohort, 18-month observation. All admissions to a 12-bed, inner-city, university-affiliated hospital, medical ICU from July 1999 to December 2000. Data for APACHE II and LODS scoring systems were collected within 24 hours of admission. Lengths of ICU and hospital stay were the primary outcomes. Prolonged ICU and hospital LOS were defined as 3 or more and 6 or more days. A total of 584 patients, mean age 49, 56% men, 82% African American were admitted to the ICU. At admission they had (mean +/-SD) APACHE II (18 +/- 10), LODS (5 +/- 4), and predicted mortality of 32% +/- 29%. DKA was the admitting diagnosis in 42 (7.6%) patients; they had lower APACHE II (12 +/- 6), LODS (2 +/- 1), and predicted mortality 5% +/- 5% than the general ICU population (all, P <.001). Hospital mortality in non-DKA patients was 18%; there were no deaths in patients with DKA. Among DKA patients, those with insulin noncompliance had a shorter hospital stay (2.8 +/- 1 d) than those with an underlying illness as the DKA trigger (4.8 +/- 3, P =.02). Between patients with DKA, regardless of the LOS, there were no significant differences in APACHE II, LODS, or predicted mortality. ICU-admitted patients with DKA are less ill, and have lower disease severity scores, mortality, and shorter length of ICU and hospital stay than non-DKA patients. Disease severity scores are not, but precipitating cause is, predictor associated with prolonged hospital LOS in patients with DKA.


Mature ovarian cystic teratoma containing well-differentiated cerebellar tissue.
A 38-year-old female patient experienced groin pain; ultrasound imaging revealed a dermoid cystic mass in the right ovary and a cystectomy was then performed. Unusually, a mature cerebellum is found in the cyst wall. The pathological diagnosis was 'mature cystic teratoma with well-differentiated cerebral and cerebellar tissue'. Glial tissue is a common neural component of teratomas, but a cerebellum is extremely rare in mature ovarian cystic teratomas. The authors report the case because of its rare component; they acknowledge that a cystic teratoma is the most common neoplasm of ovarian germ cells.


Donor derived hepatitis B virus infection: Analysis of the Organ Procurement & Transplantation Network/United Network for Organ Sharing Ad Hoc Disease Transmission Advisory Committee.
Hepatitis B virus (HBV) can be transmitted from organ donor to recipient, but details of transmission events are not widely published. The Disease Transmission Advisory Committee (DTAC) evaluated 105 cases of potential donor derived transmission events of HBV between 2009-2017. Proven, probable or possible transmission of HBV occurred in 25 (23.8%) cases. Recipients of liver grafts were most commonly infected (20 of 21 exposed recipients) compared to 9 of 21 exposed non-hepatic recipients. Eleven of 25 donors were HBV core antibody (HBcAb) positive/HBV surface antigen (HBsAg) negative and infected 8/20 recipients. Of the 10 liver recipients and 1 liver-kidney recipient who received organs from these donors: six were not given antiviral prophylaxis, two developed infection after antiviral prophylaxis was discontinued, two developed HBV while on lamivudine prophylaxis, one was on antiviral prophylaxis and did not develop HBV viremia or antigenemia. One recipient of a HBcAb positive/HBsAg negative kidney developed active HBV infection. Unexpected donor-derived transmission of HBV was a rare event in reports to DTAC, but was often detected in the recipient late post-transplant. Six of 11 recipients (54.5%) of a liver from a HBcAb positive donor did not receive prophylaxis; all of these were potentially preventable with the use of anti-viral prophylaxis.


Extrapulmonary transport of MWCNT following inhalation exposure.
Inhalation exposure studies of mice were conducted to determine if multi-walled carbon nanotubes (MWCNT) distribute to the tracheobronchial lymphatics, parietal pleura, respiratory musculature and/or extrapulmonary organs. Male C57BL/6 J mice were exposed in a whole-body inhalation system to a 5 mg/m3 MWCNT aerosol for 5 hours/day for 12 days (4 times/week for 3 weeks, lung burden 28.1 ug/lung). At 1 day and 336 days after the 12 day exposure period, mice were anesthetized and lungs, lymph nodes and extrapulmonary tissues were preserved by whole body vascular perfusion of paraformaldehyde while the lungs were inflated with air. Separate, clean-air control groups were studied at 1 day and 336 days post-exposure. Sirius Red stained sections from lung, tracheobronchial lymph nodes, diaphragm, chest wall, heart, brain, kidney and liver were analyzed. Enhanced darkfield microscopy and morphometric methods were used to detect and count MWCNT in tissue sections. Counts in tissue sections were expressed as number of MWCNT per g of tissue and as a percentage of total lung burden (Mean ± S.E., N = 8 mice per group). MWCNT burden in tracheobronchial lymph nodes was determined separately based on the volume density in the lymph nodes relative to the volume density in the lungs. Field emission scanning electron microscopy (FESEM) was used to examine MWCNT structure in the various tissues. Tracheobronchial lymph nodes were found to contain 1.08 and 7.34 percent of the lung burden at 1 day and 336 days post-exposure, respectively. Although agglomerates account for approximately 54% of lung burden, only singlet MWCNT were observed in the diaphragm, chest wall, liver, kidney, heart and brain. At one day post exposure, the average length of singlet MWCNT in liver and kidney, was comparable to that of singlet MWCNT in the lungs 8.2 ± 0.3 versus 7.5 ± 0.4 um, respectively. On average, there were 15,371 and 109,885 fibers per gram in liver, kidney, heart and brain at 1 day and 336 days post-exposure, respectively. The burden of singlet MWCNT in the lymph nodes, diaphragm, chest wall and extrapulmonary organs at 336 days post-exposure was significantly higher than at 1 day post-exposure. Inhaled MWCNT, which deposit in the lungs, are transported to the parietal pleura, the respiratory musculature, liver, kidney, heart and brain in a singlet form and accumulate with time following exposure. The tracheobronchial lymph nodes contain high levels of MWCNT following exposure and further accumulate over nearly a year to levels that are a significant fraction of the lung burden 1 day post-exposure.


A decade of progress in critical care echocardiography: a narrative review.
This narrative review focusing on critical care echocardiography (CCE) has been written by a group of experts in the field, with the aim of outlining the state of the art in CCE in the 10 years after its official recognition and definition. In the last 10 years, CCE has become an essential branch of critical care ultrasonography and has gained general acceptance. Its use, both as a diagnostic tool and for hemodynamic monitoring, has increased markedly, influencing contemporary cardiorespiratory management. Recent studies suggest that the use of CCE may have a positive impact on outcomes. CCE may be used in critically ill patients in many different clinical situations, both in their early evaluation of in the emergency department and during intensive care unit (ICU) admission and stay. CCE has also proven its utility in perioperative settings, as well as in the management of mechanical circulatory support. CCE may be performed with very simple diagnostic objectives. This application, referred to as basic CCE, does not require a high level of training. Advanced CCE, on the other hand, uses ultrasonography for full evaluation of cardiac function and hemodynamics, and requires extensive training, with formal certification now available. Indeed, recent years have seen the creation of worldwide certification in advanced CCE. While transthoracic CCE remains the most commonly used method, the transesophageal route has gained importance, particularly for intubated and ventilated patients. CCE is now widely accepted by the critical care community as a valuable tool in the ICU and emergency department, and in perioperative settings.


[Malnutrition: a secular challenge to child nutrition]
OBJECTIVE: To review current knowledge about child malnutrition, including the historical aspects of the problem, its dimension as a childhood public health problem, its natural history, physiopathology, clinical features, diagnosis and treatment, and strategies used by the health sector to control this disease. METHODS: Information was collected by researching the Medline system, the Bireme library, internet sites of interest, catalogues of publications produced by Brazilian governmental organizations and international institutions dealing with child nutrition. RESULTS: The review pointed out that despite recent world prevalence reduction, child malnutrition is a major public health problem in developing countries. Malnutrition, in any of its forms, contributes for more than 50% of deaths among children under 5 years in those countries. Mortality rates of severely malnourished children treated as in patients have been unchanged for the last five decades. Guidelines for improving the treatment and reducing mortality rates of severely malnourished children treated in hospitals were recently defined by the World Health Organization. Even though some positive results have been achieved by the health sector in reducing child malnutrition prevalence, the effectivity of the interventions is often low. Lack of food might limit the success in treating and preventing malnutrition. Factors that may contribute to the effectiveness of interventions against malnutrition include approaches which reassure the confidence of health professionals about achieving positive results with the proper treatment of malnourished children, establishment of an effective relationship between health professionals and mothers, as well as practical support to mothers in recognizing them as valuable active agents for their children nutrition rehabilitation at the household level. CONCLUSIONS: Throughout the centuries, malnutrition has been the biggest challenge faced by developing countries in order to guarantee to children under five years of age their right of being well nourished and healthy. The current challenge is the proper use of the available scientific knowledge on child nutrition to further reduce the figures for all the types of child malnutrition.


A meta-analytic examination of maternal reminiscing style: Elaboration, gender, and children's cognitive development.
Sociocultural theories of development privilege the role of parent-child conversation as a critical interpersonal context for cognitive and socioemotional development. Research on maternal reminiscing suggests that mothers differ on the elaborative nature of their reminiscing style. Individual differences in maternal elaborative style are thought to contribute to children's cognitive development in at least 3 critical areas: (a) memory; (b) language; and (c) theory of mind (ToM). Further, mothers are thought to be more elaborative with daughters than sons. After more than 30 years of research on maternal reminiscing, there has yet to be a quantitative summary of the literature. As such, we conducted a series of meta-analyses to summarize the effect sizes present in the literature, focusing on the 3 domains listed above as well as the potential impact of child gender on maternal elaborative style. The mean age range for children was set to include 30-60 months; roughly the developmental onset of autobiographical memory. Given these criteria, k = 38 studies (51 independent samples) with N = 2,492 mother-child dyads were included in this meta-analysis. Results indicated that maternal elaborative style did not differ by child gender. However, elaboration was positively associated with child memory, child language ability, and ToM. Ethnicity significantly moderated maternal elaborations by child gender, such that samples with majority non-Caucasian mothers elaborated more with daughters than sons. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Concentrations of diazepam and nordiazepam in 1,000 blood samples from apprehended drivers--therapeutic use or abuse of anxiolytics?
Using an in-house forensic toxicology database, we selected 1000 cases of driving under the influence of drugs (DUIDs) over a 12-month period if diazepam (D) and nordiazepam (ND) were both present in the blood samples. Quantitative analysis of D and ND in blood was done by solvent extraction (butyl acetate) and capillary column gas chromatography (GC) with a nitrogen-phosphorous (N-P) detector. The limits of quantitation of this analytical method for D and ND in blood were 0.05 mg/L. The correlation between D and ND concentrations in blood was statistically significant (r = .58, P < .001), as expected for a parent drug and its primary metabolite. However, the frequency distributions were markedly skewed to the right with mean (median) and highest concentrations of 0.37 (0.20) and 6.1 mg/L for D and 0.39 (0.20) and 5.6 mg/L for ND. The mean (median) total concentration (D + ND) was 0.76 mg/L (0.50 mg/L), and the concentration ratios D/ND and ND/D were 1.29 (median 0.95) and 1.41 (median 1.06), respectively. In 90 cases (9%), the concentration of D in blood exceeded 0.83 mg/L, which corresponds to an upper therapeutic limit in plasma (∼1.5 mg/L), assuming a plasma/blood distribution ratio of 1.8:1.


Roles of human hepatic and pulmonary cytochrome P450 enzymes in the metabolism of the environmental carcinogen 6-nitrochrysene.
6-Nitrochrysene is remarkably tumorigenic in the lung and liver of newborn mice and approximates the activities of certain ultimate carcinogenic metabolites of polycyclic aromatic hydrocarbons. Previous studies have indicated that the major metabolic activation pathway of 6-nitrochrysene in newborn mice is initially through the formation of the proximate tumorigen trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene with subsequent formation of 1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-aminochrysene. In order to provide information on the possible risk associated with human exposure to 6-nitrochrysene, the ability of human hepatic and pulmonary microsomes to metabolize 6-nitrochrysene was investigated. The major metabolites identified in 11 hepatic microsomes were trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene, trans-9,10-dihydro-9,10-dihydroxy-6-nitrochrysene, trans-1,2-dihydro-1,2-dihydroxy-6-aminochrysene, 6-aminochrysene, and chrysene-5,6-quinone. Following the incubations of 6-nitrochrysene with 11 different human pulmonary microsomes, qualitatively similar metabolic patterns were obtained, although quantitative differences were evident. These results demonstrated that human liver and lung are capable of metabolizing 6-nitrochrysene to known potent carcinogenic metabolites via ring oxidation and nitroreduction. In an attempt to define the roles of individual human hepatic P450 involved in the metabolism of 6-nitrochrysene, the catalytic activities known to be associated with a specific P450 were analyzed and compared with the levels of each metabolite of 6-nitrochrysene formed with the same microsomes. Rates of phenacetin O-deethylation (P450 1A2) and nifedipine oxidation (P450 3A4) were well correlated with the rates of formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively. Inhibition studies with specific P450 inhibitors and antibodies further support the view that P450 1A2 and P450 3A4 are the major forms responsible for the formation of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene and 6-aminochrysene, respectively, in human liver. Further metabolism of trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene appears to require P450 3A4. In the human lung, P450 1A1 appears to play a major role in the metabolism of 6-nitrochrysene to trans-1,2-dihydro-1,2-dihydroxy-6-nitrochrysene. These results provide some requisite knowledge for evaluating human susceptibility to 6-nitrochrysene.


Salmonella enterica Serotype Javiana Infections Linked to a Seafood Restaurant in Maricopa County, Arizona, 2016.
On 10 August 2016, the Maricopa County Department of Public Health identified culture-confirmed Salmonella enterica serotype Javiana isolates from two persons who reported eating at a seafood restaurant; seven additional cases were reported by 15 August. We investigated to identify a source and prevent further illness. We interviewed persons with laboratory-reported Salmonella Javiana infection. Pulsed-field gel electrophoresis (PFGE) and whole genome sequencing of isolates were performed. A case was defined as diarrheal illness in a person during July to September 2016; confirmed cases had Salmonella Javiana isolate yielding outbreak-related PFGE patterns; probable cases had diarrheal illness and an epidemiologic link to a confirmed case. Case finding was performed (passive surveillance and identification of ill meal companions). A case-control study assessed risk factors for Salmonella Javiana infection among restaurant diners; control subjects were chosen among meal companions. No restaurant workers reported illness. Foods were reportedly cooked according to the Food Code. Food and environmental samples were collected and cultured; Salmonella Javiana with an indistinguishable PFGE pattern was isolated from portioned repackaged raw shrimp, halibut, and a freezer door handle. We identified 50 Salmonella Javiana cases (40 confirmed and 10 probable); illness onset range was from 22 July to 17 September 2016. Isolates from 40 patients had highly related PFGE patterns. Thirty-three (73%) of 45 patients interviewed reported eating at the restaurant. Among 21 case patients and 31 control subjects, unfried cooked shrimp was associated with illness (odds ratio, 6.7; 95% confidence interval, 1.8 to 24.9; P = 0.004). Among restaurant diners, laboratory and case-control evidence indicated shrimp as the possible outbreak source; poor thermal inactivation of Salmonella on shrimp is theorized as a possible cause. Cross-contamination might have prolonged this outbreak; however, the source was not identified and highlights limitations that can arise during these types of investigations.


Humanitarian Aid Workers: The Forgotten First Responders.
Humanitarian aid workers are an overlooked population within the structure of posttraumatic stress disorder (PTSD) research and assistance. This negligence is an industry-wide failure to address aid workers' psychological health issues. The suspected numbers of death by suicide, diagnosed PTSD, depression, anxiety disorders, hazardous alcohol and drug consumption, emotional exhaustion, and other stress-related problems are impossible to quantify but are considered endemic. Tools for establishing organizational frameworks for mental health and psychosocial support are readily available. However, the capacity to implement this assistance requires the creation and practice of an open and non-judgmental culture, based on the realistic acceptance that aid work has become inherently dangerous. The possibility of developing a psychological problem because of aid work has increased along with the rise in levels of disease, injury, kidnapping, and assault. As a result, expressions of traumatic stress have become the norm rather than an exception. This commentary outlines the essential steps and components necessary to meet these requirements.


Differential effects of earthquakes on patients with bipolar disorder versus schizophrenia: Findings from Crete, Greece, 2008-2010.
Electromagnetic radiation influences in many ways humans and animals, while earthquakes are known to be related with electromagnetic phenomena. We recently showed that large earthquakes reduced admissions of psychiatric patients, whereas small earthquakes were associated with increased number of admissions. Our aim was to examine the effect of seismic-related electromagnetic activity on two chronic and severe psychiatric disorders varying in terms of etiology and treatment, i.e. bipolar disorder and schizophrenia. Retrospective data concerning monthly admission rates of patients diagnosed with schizophrenia or bipolar disorder in the Psychiatric Unit of the University Hospital of Heraklion, Crete, Greece between 2008 and 2010 were analyzed in relation to the number of earthquakes with small (≥2) or larger magnitude in the Crete region in Greece. Results showed a marked reduction of acute admissions during a storm of large earthquakes, which was greater in patients with bipolar disorder (91.2%) than schizophrenia patients (52.4%). In addition there was a significant increase of admissions during a period of frequent small earthquakes, primarily among patients with bipolar disorder. The results suggest that electrostatic fields that accompany large earthquakes may have a protective effect on psychiatric disorders, particularly on bipolar disorder. These findings are consistent with the ameliorating effect of electromagnetic fields used in Electroconvulsive therapy (ECT) and Transcranial Magnetic Stimulation (TMS) in patients with bipolar disorder. Future studies focusing on the underlying mechanisms may lead to more specific treatments of psychiatric disorders.


Culture-Negative Early-Onset Neonatal Sepsis - At the Crossroad Between Efficient Sepsis Care and Antimicrobial Stewardship.
Sepsis is a leading cause of mortality and morbidity in neonates. Presenting clinical symptoms are unspecific. Sensitivity and positive predictive value of biomarkers at onset of symptoms are suboptimal. Clinical suspicion therefore frequently leads to empirical antibiotic therapy in uninfected infants. The incidence of culture confirmed early-onset sepsis is rather low, around 0.4-0.8/1000 term infants in high-income countries. Six to 16 times more infants receive therapy for culture-negative sepsis in the absence of a positive blood culture. Thus, culture-negative sepsis contributes to high antibiotic consumption in neonatal units. Antibiotics may be life-saving for the few infants who are truly infected. However, overuse of broad-spectrum antibiotics increases colonization with antibiotic resistant bacteria. Antibiotic therapy also induces perturbations of the non-resilient early life microbiota with potentially long lasting negative impact on the individual's own health. Currently there is no uniform consensus definition for neonatal sepsis. This leads to variations in management. Two factors may reduce the number of culture-negative sepsis cases. First, obtaining adequate blood cultures (0.5-1 mL) at symptom onset is mandatory. Unless there is a strong clinical or biochemical indication to prolong antibiotics physician need to trust the culture results and to stop antibiotics for suspected sepsis within 36-48 h. Secondly, an international robust and pragmatic neonatal sepsis definition is urgently needed. Neonatal sepsis is a dynamic condition. Rigorous evaluation of clinical symptoms ("organ dysfunction") over 36-48 h in combination with appropriately selected biomarkers ("dysregulated host response") may be used to support or refute a sepsis diagnosis.


Protective effect of high protein and calcium intake on the risk of hip fracture in the Framingham offspring cohort.
The effect of protein on bone is controversial, and calcium intake may modify protein's effect on bone. We evaluated associations of energy-adjusted tertiles of protein intake (ie, total, animal, plant, animal/plant ratio) with incident hip fracture and whether total calcium intake modified these associations in the Framingham Offspring Study. A total of 1752 men and 1972 women completed a baseline food frequency questionnaire (1991-1995 or 1995-1998) and were followed for hip fracture until 2005. Hazard ratios (HRs) were estimated using Cox proportional hazards regression adjusting for confounders. Baseline mean age was 55 years (SD 9.9 years, range 26 to 86 years). Forty-four hip fractures occurred over 12 years of follow-up. Owing to significant interaction between protein (total, animal, animal/plant ratio) and calcium intake (p interaction range = .03 to .04), stratified results are presented. Among those with calcium intakes less than 800 mg/day, the highest tertile (T3) of animal protein intake had 2.8 times the risk of hip fracture [HR = 2.84, 95% confidence interval (CI) 1.20-6.74, p = .02] versus the lowest tertile (T1, p trend = .02). In the 800 mg/day or more group, T3 of animal protein had an 85% reduced hip fracture risk (HR = 0.15, 95% CI 0.02-0.92, p = .04) versus T1 (p trend = .04). Total protein intake and the animal/plant ratio were not significantly associated with hip fracture (p range = .12 to .65). Our results from middle-aged men and women show that higher animal protein intake coupled with calcium intake of 800 mg/day or more may protect against hip fracture, whereas the effect appears reversed for those with lower calcium intake. Calcium intake modifies the association of protein intake and the risk of hip fracture in this cohort and may explain the lack of concordance seen in previous studies.


Liver receptor homolog 1 controls the expression of carboxyl ester lipase.
The orphan nuclear receptor liver receptor homolog 1 (LRH-1) plays a central role in cholesterol homeostasis by regulating a number of hepatic and intestinal genes critical for reverse cholesterol transport and bile acid homeostasis. Herein, we describe the identification of carboxyl ester lipase (CEL) as a novel target of LRH-1 in pancreas, a tissue in which LRH-1 is abundantly expressed. In situ hybridization and gene expression studies demonstrate that both LRH-1 and CEL are co-expressed and confined to the exocrine pancreas. LRH-1 interacts with a consensus LRH-1 response element in the human CEL promoter, which is perfectly conserved in the rat gene, and induces CEL promoter activity in cotransfection assays. As reported for other LRH-1 target genes, the nuclear receptor short heterodimer partner represses LRH-1-induced CEL promoter activity. Chromatin immunoprecipitation demonstrates that binding of LRH-1 to the CEL promoter increases histone H4 acetylation corresponding with the activation of endogenous CEL gene transcription. Our data, identifying CEL as the first pancreatic LRH-1 target gene, indicate that LRH-1 is an important player in enterohepatic cholesterol homeostasis.


Mechanism of nucleic acid unwinding by SARS-CoV helicase.
The non-structural protein 13 (nsp13) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) is a helicase that separates double-stranded RNA (dsRNA) or DNA (dsDNA) with a 5' → 3' polarity, using the energy of nucleotide hydrolysis. We determined the minimal mechanism of helicase function by nsp13. We showed a clear unwinding lag with increasing length of the double-stranded region of the nucleic acid, suggesting the presence of intermediates in the unwinding process. To elucidate the nature of the intermediates we carried out transient kinetic analysis of the nsp13 helicase activity. We demonstrated that the enzyme unwinds nucleic acid in discrete steps of 9.3 base-pairs (bp) each, with a catalytic rate of 30 steps per second. Therefore the net unwinding rate is ~280 base-pairs per second. We also showed that nsp12, the SARS-CoV RNA-dependent RNA polymerase (RdRp), enhances (2-fold) the catalytic efficiency of nsp13 by increasing the step size of nucleic acid (RNA/RNA or DNA/DNA) unwinding. This effect is specific for SARS-CoV nsp12, as no change in nsp13 activity was observed when foot-and-mouth-disease virus RdRp was used in place of nsp12. Our data provide experimental evidence that nsp13 and nsp12 can function in a concerted manner to improve the efficiency of viral replication and enhance our understanding of nsp13 function during SARS-CoV RNA synthesis.


Effects of adrenergic agonists and insulin on porcine adipose tissue lipid metabolism in vitro.
Because this laboratory has been able to demonstrate only a small and somewhat inconsistent stimulation of glucose metabolism by insulin in porcine adipose tissue in vitro, the tissue was preincubated with insulin to attempt to enhance the hormone effect. Preincubation with or without insulin did not increase insulin stimulation. Furthermore, insulin did not stimulate triacylglycerol biosynthesis. Adrenergic hormones stimulated lipolysis in porcine adipose tissue in vitro. Several analogs of norepinephrine incubated with porcine adipose tissue in vitro did not inhibit glucose incorporation into CO2 or total lipids, in contrast to inhibition observed in adipose tissue from other species. Isoproterenol inhibited glycerol-3-phosphate incorporation into lipids; the maximal inhibition was 50% for the initial stages of the pathway. Palmitate incorporation into lipids also was inhibited 50% by isoproterenol but this may have been an artifact. Preincubation of adipose tissue, with no exogenous hormone, might decrease the concentration of endogenous adrenergic hormones and thus make the tissue more responsive to exogenous adrenergic hormones. Preincubation of porcine adipose tissue did not consistently lower the basal lipolytic rate but enhanced the stimulated lipolytic rate; the mechanism is not known. These experiments provide no evidence that preincubation is beneficial to measurement of lipolysis or glucose metabolism in porcine adipose tissue in vitro.


Neanderthal ancestry drives evolution of lipid catabolism in contemporary Europeans.
Although Neanderthals are extinct, fragments of their genomes persist in contemporary humans. Here we show that while the genome-wide frequency of Neanderthal-like sites is approximately constant across all contemporary out-of-Africa populations, genes involved in lipid catabolism contain more than threefold excess of such sites in contemporary humans of European descent. Evolutionally, these genes show significant association with signatures of recent positive selection in the contemporary European, but not Asian or African populations. Functionally, the excess of Neanderthal-like sites in lipid catabolism genes can be linked with a greater divergence of lipid concentrations and enzyme expression levels within this pathway, seen in contemporary Europeans, but not in the other populations. We conclude that sequence variants that evolved in Neanderthals may have given a selective advantage to anatomically modern humans that settled in the same geographical areas.


Update on Treatment Guideline in Fibromyalgia Syndrome with Focus on Pharmacology.
Fibromyalgia syndrome (FMS) is a chronic condition with unknown aetiology. The pathophysiology of the disease is incompletely understood; despite advances in our knowledge with regards to abnormal central and peripheral pain processing, and hypothalamo-pituitary-adrenal dysfunction, there is no clear specific pathophysiological therapeutic target. The management of this complex condition has thus perplexed the medical community for many years, and several national and international guidelines have aimed to address this complexity. The most recent guidelines from European League Against Rheumatism (EULAR) (2016), Canadian Pain Society (2012), and The Association of the Scientific Medical Societies in Germany (AWMF) (2012) highlight the change in attitudes regarding the overall approach to FMS, but offer varying advice with regards to the use of pharmacological agents. Amitriptyline, Pregabalin and Duloxetine are used most commonly in FMS and though modestly effective, are useful adjunctive treatment to non-pharmaceutical measures.


Effects of combined extract of cocoa, coffee, green tea and garcinia on lipid profiles, glycaemic markers and inflammatory responses in hamsters.
Dyslipidaemia is highly associated with cardiovascular and cerebrovascular diseases, which have been ranked second and third place of leading causes of death in Taiwan. Some plant extracts have been proved effective against dyslipidaemia. However, the combination of plant extracts was rarely studied. The purpose of the present study is to understand the beneficial effects of a combined extract (comprising cocoa, coffee, green tea and garcinia; CCGG) on lipid profiles in serum, liver, and faeces as well as glycaemic markers and related proinflammatory cytokines by using an appropriate animal model, the golden Syrian hamster. A total of 40 male hamsters were randomly assigned to five groups: (1) vehicle control, (2) high-cholesterol diet control, (3) high-cholesterol diet of 311 mg/kg/d of CCGG, (4) high-cholesterol diet of 622 mg/kg/d of CCGG and (5) high-cholesterol diet of 1555 mg/kg/d of CCGG. At the end of the experiment, blood, tissue and faecal samples were collected for further analysis. After 6 weeks of treatment, CCGG supplementation significantly reduced serum lipid content (triglycerides, total cholesterol and LDL-C) and hepatic lipid content (triglycerides and cholesterol) with dose-dependent effects. In addition, an increase in excretion of faecal lipids (bile acids) was observed after supplementation. Furthermore, the homeostasis model assessment of insulin resistance (HOMA-IR) index and serum proinflammatory cytokine levels (TNF-α and IL-6) involved in dyslipidaemia was markedly improved. In addition, by monitoring biochemical parameters as well as histopathology of major tissues, no toxicity was observed after the consumption of CCGG. Dietary CCGG supplementation may exert potential effects on ameliorating hyperlipidaemia, insulin resistance, liver steatosis and related inflammation.


Cross-talk analysis in a telecentric adaptive free-space optical relay based on a spatial light modulator.
We present an analysis of the performance limit of an adaptive multichannel free-space optical interconnect based on a spatial light modulator (SLM). The SLM function is to provide an active alignment of the signal beam in the detector plane. A thorough cross-talk analysis based on the diffractive properties of an ideal SLM in an isoplanatic optical system is shown. We analyze the performance in terms of the bit-error rate (BER) due to cross talk between different channels in the optical interconnect for different alignment states and for different phase-modulation schemes.


The association between lifetime smoking exposure and breast cancer mortality--results from a Norwegian cohort.
Several recent cohort studies have found an association between smoking and breast cancer, but the association between lifetime smoking exposure and breast cancer mortality is less well described. We examined whether smoking before breast cancer diagnosis is a predictor of breast cancer mortality in a large cohort with more than 4.1 million years of follow-up, with a special focus on women who initiated smoking before first childbirth. Information on smoking status was collected before breast cancer diagnosis and used to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) of breast cancer mortality in a cohort of 302,865 Norwegian women with 1106 breast cancer deaths. Women were enrolled between 1974 and 2003 and followed up through linkages to national registries until 31 December 2007. We found that breast cancer mortality was slightly but significantly increased for current (HR = 1.15, 95% CI 1.01-1.32) and ever (HR = 1.15, 95% CI 1.02-1.30) smokers as compared to never smokers. No statistically significantly increased mortality was found for women who initiated smoking before first childbirth, and no dose-response association was revealed for any of the different measures of smoking exposure. A large proportion of heavy smokers may have died from other causes than breast cancer during follow-up, possibly diluting our results. This study found that lifetime smoking exposure had a significantly increased risk of breast cancer mortality compared with never smokers.


Supporting preterm cardiovascular function.
Preterm infants are at higher risk of adverse neurodevelopmental outcomes. Inadequate cerebral oxygen delivery resulting from poor cardiovascular function is likely to be a significant contributor to preterm brain injury. In this context, improved support of cardiovascular function is integral to improving preterm outcomes. Many of the treatments used to support preterm cardiovascular function are based on adult physiology and may not be appropriate for the unique physiology of the preterm infant. The preterm heart is structurally immature with reduced contractility and low cardiac output. However, there is limited evidence that inotropic support with dopamine and/or dobutamine is effective in preterm babies. Hypovolemia may also contribute to poor preterm cardiovascular function; there is evidence that capillary leakage results in considerable loss of plasma from the circulation of newborn preterm babies. In addition, the vasoconstrictor response to acute stimuli does not develop until quite late in gestation and is limited in the preterm infant. This may lead to inappropriate vasodilatation adding to functional hypovolemia. The first line treatment for hypotension in preterm infants is volume expansion with crystalloid solutions, but this has limited efficacy in the preterm infant. More effective methods of volume expansion are required. Effective support of preterm cardiovascular function requires better understanding of preterm cardiovascular physiology so that treatments can target mechanisms that are sufficiently mature to respond.


Do we need to adjust for interim analyses in a Bayesian adaptive trial design?
Bayesian adaptive methods are increasingly being used to design clinical trials and offer several advantages over traditional approaches. Decisions at analysis points are usually based on the posterior distribution of the treatment effect. However, there is some confusion as to whether control of type I error is required for Bayesian designs as this is a frequentist concept. We discuss the arguments for and against adjusting for multiplicities in Bayesian trials with interim analyses. With two case studies we illustrate the effect of including interim analyses on type I/II error rates in Bayesian clinical trials where no adjustments for multiplicities are made. We propose several approaches to control type I error, and also alternative methods for decision-making in Bayesian clinical trials. In both case studies we demonstrated that the type I error was inflated in the Bayesian adaptive designs through incorporation of interim analyses that allowed early stopping for efficacy and without adjustments to account for multiplicity. Incorporation of early stopping for efficacy also increased the power in some instances. An increase in the number of interim analyses that only allowed early stopping for futility decreased the type I error, but also decreased power. An increase in the number of interim analyses that allowed for either early stopping for efficacy or futility generally increased type I error and decreased power. Currently, regulators require demonstration of control of type I error for both frequentist and Bayesian adaptive designs, particularly for late-phase trials. To demonstrate control of type I error in Bayesian adaptive designs, adjustments to the stopping boundaries are usually required for designs that allow for early stopping for efficacy as the number of analyses increase. If the designs only allow for early stopping for futility then adjustments to the stopping boundaries are not needed to control type I error. If one instead uses a strict Bayesian approach, which is currently more accepted in the design and analysis of exploratory trials, then type I errors could be ignored and the designs could instead focus on the posterior probabilities of treatment effects of clinically-relevant values.


Beneficial effects of vitamin E treatment in acute myocardial infarction.
Vitamin E (Vit E), an antioxidant, is considered to prolong survival in patients and animals after myocardial infarction. Because myocardial infarction is associated with arrhythmia and heart dysfunction, this study tested the hypothesis that early treatment with Vit E reduces mortality because of its protective effects against arrhythmia and cardiac dysfunction induced by acute myocardial infarction. Rats were randomly divided into 4 groups: sham control, myocardial infarcted, Vit E-treated sham control, and Vit E-treated infarcted animals. Myocardial infarction was induced by ligation of the left anterior descending coronary artery. Treated animals received Vit E (25 mg/kg/d) through a gastric tube beginning 1 hour after the coronary occlusion, whereas control rats received tap water. Electrocardiograms (lead II) at 1, 3, 7, and 21 days after coronary occlusion in the untreated animals showed ST-segment elevation, abnormal Q waves, premature ventricular complex (PVC), and QTc prolongation. Conversely, Vit E-treated rats showed attenuated ST-segment changes, fewer abnormal Q waves, and decreased incidence of PVC after coronary occlusion. Total mortality was reduced from 38% to 16%, whereas the infarct size was decreased from 44.2% to 22.3% in infarcted rats treated with Vit E. The depression in left ventricular function as well as elevation of malondialdehyde content and conjugated diene formation in the 21-day infarcted rat hearts were prevented by Vit E treatment. These results indicate that Vit E may exert beneficial effects on the heart by reducing oxidative stress in acute myocardial infarction.


Neurootological differential therapy for vertigo patients.
Major neurootological complaints, which mostly need drug treatment, are: giddiness, dizziness, hearing loss and tinnitus. The neurootological differential diagnosis is the basis for planning the mostly supportive treatment of vertigo patients. In planning the therapy, we are utilizing a computerbased expert system Clamedex for establishing the neurootological diagnosis through history, ORL inspection, ENG, calorics, rotatory chair test, cranio-corpo-graphy (CCG), optokinetics, psychophysical audiometry, acoustic brainstem and late evoked potentials, visually evoked potentials etc. On this knowledge base we are designing an individually adapted case oriented drug therapy.Nausea and vomitus are the important subjective complications of dysequilibrium states. Therefore antivertiginous and antiemetic therapies have to be applied if necessary. Usually the duration is of limited time.Other drugs being chosen for a supportive pharmaco therapy according to the functional topodiagnostics of the lesions usually possess one or more of the following actions upon the equilibrium regulating network:increase of cerebral blood flow,enhanced penetration through the blood brain barrier,increase of neuronal metabolism andstabilization of specific neurotransmitters.The neurootological patients are treated and monitored by regular neurootometric follow up investigations.


MALDI-TOF mass spectral analysis of siRNA degradation in serum confirms an RNAse A-like activity.
Synthetic siRNA duplexes are used widely as reagents for silencing of mRNA targets in cells and are being developed for in vivo use. Serum stability is a major concern if siRNA is to be used for therapeutic delivery within blood circulation. We have developed the use of MALDI-TOF mass spectrometry as a rapid and convenient analytical tool to identify the most vulnerable sites within siRNA to serum degradation. Using this approach, we found that one siRNA duplex (Dh3) with UpA sequences close to one end was particularly vulnerable to rapid cleavage. This produced a fragment of mass consistent with the presence of a 2',3'-cyclic phosphate that was slowly hydrolysed to a 2'-(3'-)phosphate on extended incubation. Substitution of these sites with 2'-O-methyl U residues prevented cleavage and confirmed that the major pathway for initial degradation is via cleavage by an RNAse A-like activity. Mass spectral analysis was used to follow the serum degradation of siRNA over more prolonged periods to show the accumulation of many fragments, almost all showing cleavage following pyrimidine nucleoside residues. Overall, the MALDI-TOF mass spectral analysis technique should prove useful for preliminary screening of the serum stability of siRNA duplexes and for identification of the most vulnerable cleavage sites.


The effect of suprarenal cross-clamping on abdominal aortic aneurysm repair.
Two hundred five patients who underwent elective abdominal aortic aneurysm repair were divided into two groups: those who underwent infrarenal cross-clamping alone (n = 166) and those who underwent suprarenal cross-clamping alone or combined with infrarenal cross-clamping (n = 39). Mortality was comparable between groups (1.2% for infrarenal cross-clamping vs 2.6% for suprarenal cross-clamping). Transient renal insufficiency was more frequent in the suprarenal group than in the infrarenal group (28% vs 10%), but dialysis rates (3% for suprarenal vs 2% for infrarenal) were similar. Cardiac morbidity was comparable between groups as well. Operating room data reflected the technical challenge of complex aneurysm repairs. The retroperitoneal approach was the preferred exposure in the suprarenal group since better access to the suprarenal aorta may be achieved with this technique. While abdominal aortic aneurysm repairs requiring suprarenal cross-clamping remain a technical challenge, the risks are not formidable and suprarenal cross-clamping should be considered when confronted with difficult periaortic dissection.


Chemo protective activity of carotenoid meso-zeaxanthin against doxorubicin-induced cardio toxicity.
Carotenoid meso-zeaxanthin (MZ) was evaluated for its protective effect against doxorubicin (DOX) induced cardio toxicity in Wistar rats. Oral administration of MZ was started 15 days prior to doxorubicin (30mg/kg b.wt, i.p, single dose) injection. Animals in all groups were sacrificed 24 hours after doxorubicin administration. Serum markers of cardiac injury-LDH, CPK, SGOT and SGPT levels, which were increased drastically by doxorubicin treatment, were decreased to normal level by MZ pre-treatment. MZ significantly mitigated DOX-provoked reductions of cardiac activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), as well as depletion of glutathione (GSH).Pretreatment of MZ significantly guarded against DOX-induced rise of oxidative stress markers like lipid peroxidation (LPO), tissue hydroperoxides (HP) and conjugated dienes (CD) in cardiac tissue. Moreover, DOX-induced myocardial injury, which was manifested by arrhythmias and conduction abnormalities in ECG (increased ST, QT interval and ST elevation), was reversed significantly by MZ pre-treatment. Histopathological analysis further confirmed cardio-protective potential of this carotenoid.


Association of birth order with cardiovascular disease risk factors in young adulthood: a study of one million Swedish men.
Birth order has been suggested to be linked to several cardiovascular disease (CVD) risk factors, but the evidence is still inconsistent. We aim to determine the associations of birth order with body mass index (BMI), muscle strength and blood pressure. Further we will analyse whether these relationships are affected by family characteristics. BMI, elbow flexion, hand grip and knee extension strength and systolic and diastolic blood pressure were measured at conscription examination in 1,065,710 Swedish young men born between 1951 and 1975. The data were analysed using linear multivariate and fixed effects regression models; the latter compare siblings and account for genetic and social factors shared by brothers. Fixed effect regression analysis showed that birth order was inversely associated with BMI: second and third born had 0.8% and 1.1% (p<0.001) lower BMI than first-born, respectively. The association pattern differed among muscle strengths. After adjustment for BMI, first-born presented lower elbow flexion and hand grip strength than second-born (-5.9 N and -3.8 N, respectively, p<0.001). Knee extension strength was inversely related to birth order though not always significantly. The association between birth order and blood pressure was not significant. Birth order is negatively associated with BMI and knee extension strength, positively with elbow flexion and hand grip strength, and is not associated with blood pressure among young men. Although the effects are small, the link between birth order and some CVD risk factors is already detectable in young adulthood.


Evaluation of a communication course for new hearing aid users.
A communication course for new hearing aid users, covering explanations of hearing loss and hearing aids, hearing tactics, lipreading and relaxation techniques in three 2 h sessions, was developed. The course was tested on groups of adults fitted with NHS post-aural hearing aids at the Audiology Clinic at the Royal South Hants Hospital. The course content, presentation, length and pace were evaluated by means of a questionnaire given at the end of the last session, and the effects on aid usage, satisfaction and benefit ratings were assessed by pre- and post-fitting questionnaires given to those who attended and to a matched group of control subjects. The course was offered to 41 men and 46 women. The acceptance rate was rather higher for women than for men, but attendance rates were similar for both sexes, men attending 33% and women 36% of the sessions offered. No relationship was observed between age or degree of hearing loss and rates of acceptance and attendance. All those who completed the evaluation questionnaire were satisfied with the content, length, pace and presentation of the course, and considered that it had helped them to understand and cope with their hearing loss. Most (28 out of 31) felt that they would use their aids more as a result of the course. However, their aid usage and ratings of benefit derived from the aids did not differ significantly from those of a matched group of controls who were not offered the course.


Alteration of rat hepatic insulin metabolism by glyburide and glipizide.
The sulfonylurea class of compounds has demonstrated its effectiveness in treating non-insulin-dependent diabetes mellitus, although the exact mechanisms of action are still not fully defined. Clinical studies have suggested the action may be at least in part due to alterations of insulin's effect on liver. We have examined the effects of glyburide and glipizide on insulin metabolism in isolated hepatocytes and perfused livers. Our studies show that both drugs increase insulin binding to hepatocyte, but only glyburide-treated animals exhibit a concomitant increase in degradation. Studies with recycling perfused liver agreed with these results, with glyburide treatment causing a significantly more rapid clearance than control or glipizide treatment. Single-pass perfusion studies showed significantly less insulin retained by glipizide-treated animals as compared to control- and glyburide-treated animals. Further, hepatocytes from glipizide-treated animals required higher concentrations of insulin to achieve the same stimulation of amino acid transport (as measured by aminoisobutyric acid uptake) as in control- and glyburide-treated animals, suggesting that the altered processing affects insulin's action. Taken together, these studies demonstrate alterations in liver insulin metabolism that may explain clinical differences identified in these two drugs.


The developmental genetics of human hemoglobin.
Clearly, it is impossible to combine the diverse information briefly outlined in this review to provide a coherent model of the regulation of globin gene expression during development. One of the great difficulties in this field is uncertainty as to whether the mutations which are associated with persistent gamma chain production or, for the matter, the experimental models which have been used to study the differential expression of the fetal and adult globin genes, have any real relevance to an understanding of the normal switching process. Probably they do, but only with respect to one aspect of what must be an extremely complex multi-step regulatory system. The consistent changes in chromatin and methylation state of the beta globin gene cluster which are associated with activation of the different gene loci at different stages of development provide an anatomical explanation for the activity of these loci but tell us nothing about their mode of regulation. However, the gene or chromosome transfer experiments suggest that there may be developmental-stage specific trans regulatory factors which may be involved in the regulation of these genes, presumably by interacting in some way with chromatin. This is a very promising lead. Equally interesting is the possibility that the upstream mutations which are being found in some of the forms of non-deletion HPFH could provide a clue as to the site of these interactions. Thus at least we have an indication of what might be the most productive area of investigation for trying to characterize the mechanisms of regulation at the chromosomal level. This may be as far as we can go in the immediate future. The central question remains, however. How is the differential expression of the globin genes during development actually timed? All we know at the moment is that it is related fairly closely to gestational age. The only experimental data relating to this question is derived from the sheep transplant model, and suggests that there might be some form of "developmental clock' built into the hemopoietic stem cell. Here we are in considerable difficulties because we don't have an obvious experimental model with which to analyze time-related events. None of the forms of HPFH is, strictly speaking, a heterochronic mutation.(ABSTRACT TRUNCATED AT 400 WORDS)


SMAD4 mutations in colorectal cancer probably occur before chromosomal instability, but after divergence of the microsatellite instability pathway.
Loss of chromosome 18q21 is well documented in colorectal cancer, and it has been suggested that this loss targets the DCC, DPC4/SMAD4, and SMAD2 genes. Recently, the importance of SMAD4, a downstream regulator in the TGF-beta signaling pathway, in colorectal cancer has been highlighted, although the frequency of SMAD4 mutations appears much lower than that of 18q21 loss. We set out to investigate allele loss, mutations, protein expression, and cytogenetics of chromosome 18 copy number in a collection of 44 colorectal cancer cell lines of known status with respect to microsatellite instability (MSI). Fourteen of thirty-two MSI(-) lines showed loss of SMAD4 protein expression; usually, one allele was lost and the other was mutated in one of a number of ways, including deletions of various sizes, splice site changes, and missense and nonsense point mutations (although no frameshifts). Of the 18 MSI(-) cancers with retained SMAD4 expression, four harbored missense mutations in the 3' part of the gene and showed allele loss. The remaining 14 MSI(-) lines had no detectable SMAD4 mutation, but all showed allele loss at SMAD4 and/or DCC. SMAD4 mutations can therefore account for about 50-60% of the 18q21 allele loss in colorectal cancer. No MSI(+) cancer showed loss of SMAD4 protein or SMAD4 mutation, and very few had allelic loss at SMAD4 or DCC, although many of these MSI(+) lines did carry TGFBIIR changes. Although SMAD4 mutations have been associated with late-stage or metastatic disease, our combined molecular and cytogenetic data best fit a model in which SMAD4 mutations occur before colorectal cancers become aneuploid/polyploid, but after the MSI(+) and MSI(-) pathways diverge. Thus, MSI(+) cancers may diverge first, followed by CIN(+) (chromosomal instability) cancers, leaving other cancers to follow a CIN(-)MSI(-) pathway.


Four-class classification of skin lesions with task decomposition strategy.
This paper proposes a new computer-aided method for the skin lesion classification applicable to both melanocytic skin lesions (MSLs) and nonmelanocytic skin lesions (NoMSLs). The computer-aided skin lesion classification has drawn attention as an aid for detection of skin cancers. Several researchers have developed methods to distinguish between melanoma and nevus, which are both categorized as MSL. However, most of these studies did not focus on NoMSLs such as basal cell carcinoma (BCC), the most common skin cancer and seborrheic keratosis (SK) despite their high incidence rates. It is preferable to deal with these NoMSLs as well as MSLs especially for the potential users who are not enough capable of diagnosing pigmented skin lesions on their own such as dermatologists in training and physicians with different expertise. We developed a new method to distinguish among melanomas, nevi, BCCs, and SKs. Our method calculates 828 candidate features grouped into three categories: color, subregion, and texture. We introduced two types of classification models: a layered model that uses a task decomposition strategy and flat models to serve as performance baselines. We tested our methods on 964 dermoscopy images: 105 melanomas, 692 nevi, 69 BCCs, and 98 SKs. The layered model outperformed the flat models, achieving detection rates of 90.48%, 82.51%, 82.61%, and 80.61% for melanomas, nevi, BCCs, and SKs, respectively. We also identified specific features effective for the classification task including irregularity of color distribution. The results show promise for enhancing the capability of the computer-aided skin lesion classification.


Impact of cooking, proving, and baking on the (poly)phenol content of wild blueberry.
Accumulating evidence suggests that diets rich in (poly)phenols may have positive effects on human health. Currently there is limited information regarding the effects of processing on the (poly)phenolic content of berries, in particular in processes related to the baking industry. This study investigated the impact of cooking, proving, and baking on the anthocyanin, procyanidin, flavonol, and phenolic acid contents of wild blueberry using HPLC with UV and fluorescence detection. Anthocyanin levels decreased during cooking, proving, and baking, whereas no significant changes were observed for total procyanidins. However, lower molecular weight procyanidins increased and high molecular weight oligomers decreased during the process. Quercetin and ferulic and caffeic acid levels remained constant, whereas increases were found for chlorogenic acid. Due to their possible health benefits, a better understanding of the impact of processing is important to maximize the retention of these phytochemicals in berry-containing products.


Therapeutic use of classic psychedelics to treat cancer-related psychiatric distress.
Cancer is highly prevalent and one of the leading causes of global morbidity and mortality. Psychological and existential suffering is common in cancer patients, associated with poor psychiatric and medical outcomes. Promising early-phase clinical research (1960s to early 1970s) suggested a therapeutic signal for serotoninergic psychedelics (e.g. psilocybin, LSD) in treating cancer-related psychiatric distress. After several decades of quiescence, research on psychedelic-assisted therapy to treat psychiatric disorders in cancer patients has resumed within the last 2 decades in the US and Europe. This review article is based on a systematic search of clinical trials from 1960-2018 researching the therapeutic use of psychedelic treatment in patients with serious or terminal illnesses and related psychiatric illness. The search found 10 eligible clinical trials, with a total of 445 participants, with the vast majority of the patients having advanced or terminal cancer diagnoses. Six open label trials, published between 1964 and 1980 (n = 341), suggested that psychedelic therapy (mostly with LSD) may improve cancer-related depression, anxiety, and fear of death. Four RCTs trials were published between 2011 and 2016 (n = 104), mostly with psilocybin treatment (n = 92), and demonstrated that psychedelic-assisted treatment can produce rapid, robust, and sustained improvements in cancer-related psychological and existential distress.


Modelling the impact on avoidable cardiovascular disease burden and costs of interventions to lower SBP in the England population.
The burden of disease from cardiovascular disease (CVD) remains significant in England. Blood pressure remains an important risk factor. Health gain through public health measures and improving treatment compliance are potentially likely to be high. We assess the impact of known cost-effective interventions in terms of the avoidable CVD burden and costs by comparing these strategies to the current situation. We modelled avoidable CVD outcomes simulating the English population aged over 16 years with Excel spreadsheets for the current prevention/treatment and following various interventions over a 10-year time frame. The outcome measures were avoidable incident heart disease and stroke events, deaths and disability-adjusted life years (DALYs). Costs are reported from the health service perspective. We analysed relative cost-effectiveness, undertook sensitivity analysis and measured relative impacts of different strategies on avoidable burden of disease. The assessed interventions have a potential to reduce the current burden of disease between 70 000 and about 1 million DALYs over the 10-year frame. Although all interventions were cost-effective, some (e.g. Salt reduction in the population and 'Dietary Approaches to Stop Hypertension-sodium', which modelled the impact of salt reduction and dietary approaches) were cost-saving. The cost-effectiveness of treatment strategies was sensitive to drug costs. Evidence-based interventions appropriately scaled up for both prevention and treatment of blood pressure lead to important additional potential health gains. There was noticeable variance in cost-effectiveness and impact among the different interventions at a population level. Taking into account impact, priority should be given to prevention to reduce blood pressure at a population level through reduced salt consumption.


Histopathological and ultrastructural observations of metacercarial infections of Diplostomum phoxini (Digenea) in the brain of minnows Phoxinus phoxinus.
The spatial distribution and histopathological changes induced by metacercariae of the digenean trematode Diplostomum phoxini (Faust, 1918) in the brains of European minnows Phoxinus phoxinus (L.) from the River Endrick, Scotland, were studied by light and electron microscopy. Post-mortem examination of a sample of 34 minnows revealed that 50% (n = 17) of the population was infected with 13.7 +/- 2.6 (mean +/- SE; range 1 to 38) metacercariae per infected host. Serial histological sections of the infected minnow brains revealed that the metacercariae were unevenly distributed throughout the brain, with aggregations occurring in the cerebellum, the medulla oblongata and the optic lobes. In fish with highest intensities of infection, over 40% of the cerebellar area and about 30% of the medulla oblongata area were occupied by larvae. Metacercariae disrupt the integrity of brain tissue, with individuals being found in small pockets surrounded by cellular debris. Metacercariae were rarely encountered on the surface of the brain. Electron microscopic examination of infection sites revealed that the granular layer surrounding metacercariae was necrotic, exhibited nuclear degradation and was marked by vacuolation of the cytoplasm. Rodlet cells, the only inflammatory cell types recorded in this study, were found only in parasitized brains and in close proximity to the teguments of metacercariae. It is hypothesised that secretions released from the teguments of metacercariae are a counter response to protect the metacercariae from the fish brain's cellular defence mechanisms.


Targeting osteoblastic casein kinase-2 interacting protein-1 to enhance Smad-dependent BMP signaling and reverse bone formation reduction in glucocorticoid-induced osteoporosis.
The underlying mechanism of the reduced bone formation during the development of glucocorticoid-induced osteoporosis (GIO) remains unclear. Here, we found that the highly expressed CKIP-1 together with lowly expressed total and phosphorylated Smad1/5 in bone samples was accompanied by either the reduced serum bone formation markers in GIO patients or the decreased bone formation in GIO mice. In vitro studies showed that the highly expressed CKIP-1 could promote Smad1 ubiquitination to suppress the Smad-dependent BMP signaling and inhibit osteogenic differentiation and mineral deposition in MC3T3-E1 cells during glucocorticoid treatment. Further, the reduced bone formation in GIO mice could not only be prevented by osteoblasts-specific Ckip-1 ablation, but also be attenuated after osteoblasts-specific Smad1 overexpression. Moreover, osteoblasts-targeting CKIP-1 siRNA treatment also attenuated the bone formation reduction in GIO mice. These study suggest that the highly expressed CKIP-1 in osteoblasts could suppress the Smad-dependent BMP signaling and contribute to the bone formation reduction in GIO. Targeting osteoblastic CKIP-1 would be a novel bone anabolic strategy for GIO patients.