Effects of sleep apnea and kidney dysfunction on objective sleep quality in nondialyzed patients with chronic kidney disease: an ESADA study.
Patients with chronic kidney disease (CKD) often report poor sleep quality, but they commonly exhibit OSA. The aim of this study was to evaluate the influence of OSA severity and of estimated glomerular filtration rate impairment on objective sleep quality in nondialyzed patients with CKD, defined as an estimated glomerular filtration rate <60 mL/min/1.73m². Polysomnographic sleep characteristics were compared between patients with (n = 430) and without CKD (n = 6,639) in the European Sleep Apnea Database cohort. Comparisons were repeated in 375 patients with CKD and 375 control patients without CKD matched for sleep center, age, sex, and AHI, and in 310 matched CKD and non-CKD patients without psychiatric disturbances. Among all patients with and without CKD, total sleep time was similar but sleep stage N1 (median 8.7% [IQR 4.8-18.0] vs 6.7% [3.6-12.7], respectively) and sleep stage R (12.6% [6.8-17.7] vs 14.2% [8.8-19.8], respectively) significantly differed (P < .0001). No difference in sleep characteristics was observed between matched patients either with or without psychiatric disturbances. After subdividing the matched patients according to AHI tertile (<25, ≥25 to <49, and ≥49 events/h) and estimated glomerular filtration rate (≥60, 45 to <60, <45 mL/min/1.73m²), we found a significant effect of AHI on sleep stages N2, N3, and R (P < .001), but there was no effect of CKD. In nondialyzed patients with CKD, objective sleep quality is influenced similarly by AHI as in patients without CKD but is not affected by CKD severity. Previously reported poor sleep quality in CKD may partly result from the high prevalence of OSA in CKD.


Cross-talk between lung and systemic circulation during carbon nanotube respiratory exposure. Potential biomarkers.
Nanotechnology is an emerging field that demands urgent development of adequate toxicology and risk assessment. The previous experimental data on carbon nanotube respiratory exposure strongly suggest the need for complex evaluation of potential toxicity. Our work demonstrates that after carbon nanotube deposition in the lung, acute local and systemic responses are activated and characterized by a blood gene and protein expression signature. The approach described here will foster the development of biomarkers for application in human screening of nanoparticle exposure.


Are the health needs of young people with cerebral palsy met during transition from child to adult health care?
The transition from child to adult health care is a particular challenge for young people with cerebral palsy, who have a range of needs. The measurement of reported needs, and in particular unmet needs, is one means to assess the effectiveness of services. We recruited 106 young people with cerebral palsy, before transfer from child services, along with their parents to a 3-year longitudinal study. Reported needs were measured with an 11-item questionnaire covering speech, mobility, positioning, equipment, pain, epilepsy, weight, control of movement, bone or joint problems, curvature of the back, and eyesight. Categorical principal component analysis was used to create factor scores for bivariate and regression analyses. A high level of reported needs was identified particularly for control of movement, mobility, and equipment, but these areas were generally being addressed by services. The highest areas of unmet needs were for management of pain, bone or joint problems, and speech. Analysis of unmet needs yielded two factor scores, daily living health care and medical care. Unmet needs in daily living health care were related to severity of motor impairment and to attending nonspecialist education. Unmet needs tended to increase over time but were not significantly (p > .05) related to whether the young person had transferred from child services. Reporting of unmet needs can indicate where service development is required, and we have shown that the approach to measurement can be improved. As the number of unmet health needs at the start of transition is considerable, unmet health needs after transition cannot all be attributed to poor transitional health care. The range and continuation of needs of young people with cerebral palsy argue for close liaison between adult services and child services and creation of models of practice to improve coordination.


[A study of the association between the aortic pulse wave velocity and atherosclerotic risk factors among Japanese Americans in Seattle, U.S.A].
Cardiovascular disease prevention screening was conducted among 1389 Japanese Americans in Seattle, Washington, U.S.A. from 1989 to 1994. The association between atherosclerotic risk factors and the aortic pulse wave velocity (PWV), an indicator of atherosclerosis, was examined by using multiple logistic regression method. Based on a study in 1996 by Suzuki et al. on the association between PWV and atherosclerotic indicators, abnormally high PWV was defined as 8.0 m/sec. and over for those less than 60 years of age and 9.0 m/sec. and over for those 60 years of age and older Significant odds ratios to estimate the risk for the presence of abnormally high PWV were found in age >or= 60 years (4.31, p < 0.001), hypertension (2.00, p < 0.001), diabetes (5.65, p < 0.001), current drinker (0.44, p < 0.001), ex-drinker (0.49, p < 0.05), and ex-smoker (1.82, p < 0.01) among men. Women showed a similar association: age > or = 60 years (3.03, p < 0.001), hypertension (1.94, p < 0.01), diabetes (2.47, p < 0.05), TC/HDL-C >or= 4.5 (1.98, p < 0.001), current drinker (0.47, p < 0.001), and ex-drinker (0.45, p < 0.05). Our findings are almost identical to those from other studies showing the association between coronary heart disease and its risk factors. The question of whether PWV can be a predictor of atherosclerotic diseases, particularly coronary heart disease, remains to be answered by additional studies. However, PWV may serve as a simple and valuable indicator to estimate the extent and severity of asymptomatic atherosclerosis in the large artery.


Revealing Biological Pathways Implicated in Lung Cancer from TCGA Gene Expression Data Using Gene Set Enrichment Analysis.
Analyzing biological system abnormalities in cancer patients based on measures of biological entities, such as gene expression levels, is an important and challenging problem. This paper applies existing methods, Gene Set Enrichment Analysis and Signaling Pathway Impact Analysis, to pathway abnormality analysis in lung cancer using microarray gene expression data. Gene expression data from studies of Lung Squamous Cell Carcinoma (LUSC) in The Cancer Genome Atlas project, and pathway gene set data from the Kyoto Encyclopedia of Genes and Genomes were used to analyze the relationship between pathways and phenotypes. Results, in the form of pathway rankings, indicate that some pathways may behave abnormally in LUSC. For example, both the cell cycle and viral carcinogenesis pathways ranked very high in LUSC. Furthermore, some pathways that are known to be associated with cancer, such as the p53 and the PI3K-Akt signal transduction pathways, were found to rank high in LUSC. Other pathways, such as bladder cancer and thyroid cancer pathways, were also ranked high in LUSC.


Auditory processing tests for children: normative and clinical results on the SSW test.
Staggered Spondaic Word (SSW) test results were studied in 93 normally achieving children and 97 children referred to a learning disabilities clinic. All subjects were 8-11 years of age. The SSW test was found to differentiate between the normally achieving children and those experiencing classroom learning difficulties. Further, it was found that the performance of the normally achieving group was generally better than current test norms would imply. This finding suggests the use of stricter criteria in determining when a child is at risk for central auditory processing difficulties. Results for children with classroom learning difficulties show a progression toward better performance with age, except for the Left-Competing condition. This makes it unclear whether one can or cannot expect some resolution of auditory processing difficulties by age 11.


Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling.
The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role is primarily fulfilled by professional bone marrow macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within the BMME. However, little is known about the mechanism and impact of efferocytosis on MSCs and on their function. To investigate, we performed flow cytometric analysis of neutrophil uptake by ST2 cells, a murine bone marrow-derived stromal cell line, and in murine primary bone marrow-derived stromal cells. Transcriptional analysis showed that MSCs possess the necessary receptors and internal processing machinery to conduct efferocytosis, with Axl and Tyro3 serving as the main receptors, while MerTK was not expressed. Moreover, the expression of these receptors was modulated by efferocytic behavior, regardless of apoptotic target. MSCs derived from human bone marrow also demonstrated efferocytic behavior, showing that MSC efferocytosis is conserved. In all MSCs, efferocytosis impaired osteoblastic differentiation. Transcriptional analysis and functional assays identified downregulation in MSC mitochondrial function upon efferocytosis. Experimentally, efferocytosis induced mitochondrial fission in MSCs. Pharmacologic inhibition of mitochondrial fission in MSCs not only decreased efferocytic activity but also rescued osteoblastic differentiation, demonstrating that efferocytosis-mediated mitochondrial remodeling plays a critical role in regulating MSC differentiation. This work describes a novel function of MSCs as non-professional phagocytes within the BMME and demonstrates that efferocytosis by MSCs plays a key role in directing mitochondrial remodeling and MSC differentiation. Efferocytosis by MSCs may therefore be a novel mechanism of dysfunction and senescence. Since our data in human MSCs show that MSC efferocytosis is conserved, the consequences of MSC efferocytosis may impact the behavior of these cells in the human skeleton, including bone marrow remodeling and bone loss in the setting of aging, cancer and other diseases.


Nuclear spin relaxation of sodium cations in bacteriophage Pf1 solutions.
The nuclear magnetic resonance (NMR) spectra for the I=3/2 23Na cation dissolved into filamentous bacteriophage Pf1 solutions display line splittings and relaxation times consistent with an interaction between the 23Na nuclear quadrupole moment and the electric field gradient produced by the negatively charged Pf1 particles. The 23Na NMR line splittings and relaxation rates corresponding to magnetization recovery and single, double, and triple quantum coherence decays are measured in Pf1 solutions and compared to theoretical values. The deviation of the observed dc spectral density J0 from the equal first harmonic J(omega0) and second harmonic J(2omega0) values as J(omega0)=J(2omega0) not equal to J0 in these solutions suggests that ion migration in the electric field gradient of the Pf1 particles produces an anisotropic relaxation mechanism. Correlation functions and thus spectral densities for this process are calculated from solutions to the Fokker-Planck equation for radial motion in an electric potential and used to estimate measured relaxation rates. Appropriate electric potentials are generated from the solutions to the Poisson-Boltzmann equation for a charged Pf1 particle in aqueous phase, functions that lead to theoretical estimates of NMR line splittings consistent with experimental observations.


Shrinking Lung Syndrome: A Rare Manifestation of Systemic Lupus Erythematosus.
Shrinking lung syndrome (SLS) is a pulmonary complication of systemic lupus erythematosus (SLE) characterized by dyspnea, pleuritic chest pain, and progressive decrease in lung volumes with no evidence of pleural or interstitial disease on chest CT. We present a 51-year-old female with a 14-year history of SLE with symptoms of progressive shortness of breath, pleuritic chest pains, low grade fevers, and productive cough which was unresponsive to multiple courses of antibiotics. After careful review of her course of SLE and timeline of symptoms, she was diagnosed with SLS. Even though rare, clinicians should have a high suspicion of SLS in patients with a long-term history of SLE and worsening dyspnea. Early treatment can be initiated to help reduce long-term morbidity and mortality and maintain the quality of life.


Defibrotide for Patients with Hepatic Veno-Occlusive Disease/Sinusoidal Obstruction Syndrome: Interim Results from a Treatment IND Study.
Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD.


Intrapartum sonographic signs: new diagnostic tools in malposition and malrotation.
In the past years, numerous studies have been published on the use of ultrasound during labor, showing this is an effective, accurate and objective tool for the assessment of the fetal head position and station. Literature affirmed that traditional transvaginal digital examination is highly subjective and dependent on the operator's experience. On the contrary, the use of intrapartum suprapubic transabdominal ultrasound can improve accuracy in determination of fetal head position and the precise knowledge of the location of specific fetal head landmarks in relationship to maternal pelvis. Intrapartum ultrasound will assist obstetricians in the diagnosis of normal labor progression, suggesting when medical and or operative intervention should be taken in case of complications. During each fetal head movement, there is a very specific relationship between fetal head landmarks and well-identified maternal structures, so the ultrasound diagnosis is performed step by step. In this review, we summarized the clinical situation of the fetal head in the pelvis and the relative ultrasonographic signs. Moreover, we collected all the ultrasonographic measures to diagnose the fetal head progression and rotations in the birth canal.


Identification of Ulnar Artery Perforators Using Color Doppler Ultrasonography.
The ulnar artery perforator (UAP) flap, which is hairless, thin, and pliable, has been used for the reconstruction of soft tissues from the finger to the elbow. Preoperative planning is essential for a perforator flap surgery, and there are some tests to identify perforators. Color Doppler ultrasonography (US) with a high-frequency transducer helps in detecting decreased flow in smaller vessels, such as perforators. The purpose of this study was to determine the anatomical locations and origins of perforators arising from the ulnar artery using color Doppler US in healthy volunteers. Forty forearms of 20 healthy volunteers were included in the study. Perforators arising from the ulnar artery, within 100 mm proximal to the pisiform, were investigated using color Doppler US with a high-frequency transducer. A total of 205 perforators were identified. On comparing the locations in each 20 mm section from the pisiform, the largest number of perforators was 58 (28%), within 20 mm proximal to the pisiform. The axial view demonstrated 44 (21%), 64 (31%), 32 (16%), and 65 (32%) perforators in the radial, ulnar, superficial, and deep aspects of the ulnar artery, respectively. Fifty-two and 28 essential perforators were supplied by the UAPs arising from the superficial and ulnar aspect within 20 mm proximal to the pisiform and between 21 and 40 mm proximal to the pisiform, respectively, while elevating the UAP flap. This is the first study to assess the UAP using color Doppler US. Identification of UAP using color Doppler US can be used as a preoperative assessment for reliable elevation of a UAP flap.


Predicting outcomes in acute severe ulcerative colitis.
Response to corticosteroid treatment in acute severe ulcerative colitis (ASUC) has changed very little in the past 50 years. Predicting those at risk at an early stage helps stratify patients into those who may require second line therapy or early surgical treatment. Traditionally, risk scores have used a combination of clinical, radiological and biochemical parameters; established indices include the 'Travis' and 'Ho' scores. Recently, inflammatory bowel disease genetic risk alleles have been built into models to predict outcome in ASUC. Given the multifactorial nature of inflammatory bowel disease pathogenesis, in the future, composite scores integrating clinical, biochemical, serological, genetic and other '-omic' data will be increasingly investigated. Although these new genetic prediction models are promising, they have yet to supplant traditional scores, which remain the best practice. In this modern era of rescue therapies in ASUC, robust scoring systems to predict failure of ciclosporine and infliximab must be devised.


Acute Liver Failure following a Single Dose of Atezolizumab, as Assessed for Causality Using the Updated RUCAM.
Immune checkpoint inhibitors have become major therapeutic agents in oncology over the last few years. However, they are associated with a variety of potentially severe autoimmune phenomena. We present a patient with advanced adenocarcinoma of the lung, who presented with acute liver injury two weeks following his first treatment with atezolizumab, rapidly deteriorating to fulminant liver failure. A thorough evaluation of infectious, vascular, metabolic, and autoimmune etiologies did not yield any results. Liver pathology was nonspecific. Using RUCAM as a causality assessment method indicated probable connection between atezolizumab and liver damage. To our knowledge, this is the first documented report of a patient developing acute liver failure shortly after immune checkpoint inhibitor initiation.


Phylogenetic Relationship of Plant MLO Genes and Transcriptional Response of MLO Genes to Ralstonia solanacearum in Tomato.
As a broad-spectrum disease resistance factor, MLO is involved in a variety of biotic and abiotic stress responses in plants. To figure out the structural features, phylogenetic relationships, and expression patterns of MLO genes, we investigated the genome and transcriptome sequencing data of 28 plant species using bioinformatics tools. A total of 197 MLO genes were identified. They possessed 5-7 transmembrane domains, but only partially contained a calmodulin-binding domain. A total of 359 polymorphic sites and 142 haplotypes were found in 143 sequences, indicating the rich nucleotide diversity of MLO genes. The MLO genes were unevenly distributed on chromosomes or scaffolds and were mainly located at the ends, forming clusters (24.1% genes), tandem duplicates (5.7%), and segment duplicates (36.2%). The MLO genes could be classified into three groups by phylogenetic analysis. The angiosperm genes were mainly in subgroup IA, Selaginella moellendorffii genes were in subgroup IA and IIIB, Physcomitrella patens genes were in subgroup IB and IIIA, and almost all algae genes were in group II. About half of the MLO genes had homologs within and across species. The Ka/Ks values were all less than 1, varying 0.01-0.78, suggesting that purifying selection had occurred in MLO gene evolution. In tomato, RNA-seq data indicated that SlMLO genes were highly expressed in roots, followed by flowers, buds, and leaves, and also regulated by different biotic stresses. qRT-PCR analysis revealed that SlMLO genes could respond to tomato bacterial wilt, with SlMLO1, SlMLO2, SlMLO4, and SlMLO6 probably involved in the susceptibility response, whereas SlMLO14 and SlMLO16 being the opposite. These results lay a foundation for the isolation and application of related genes in plant disease resistance breeding.


Minimal energy cost to initialize a bit with tolerable error.
Landauer's principle imposes a fundamental limit on the energy cost to perfectly initialize a classical bit, which is only reached under the ideal operation with infinitely long time. The question on the cost in the practical operation for a bit has been raised under the constraint by the finiteness of operation time. We discover a raise-up of energy cost by L^{2}(ε)/τ from the Landaeur's limit (k_{B}Tln2) for a finite-time τ initialization of a bit with an error probability ε. The thermodynamic length L(ε) between the states before and after initializing in the parametric space increases monotonously as the error decreases. For example, in the constant dissipation coefficient (γ_{0}) case, the minimal additional cost is 0.997k_{B}T/(γ_{0}τ) for ε=1% and 1.288k_{B}T/(γ_{0}τ) for ε=0.1%. Furthermore, the optimal protocol to reach the bound of minimal energy cost is proposed for the bit initialization realized via a finite-time isothermal process.


Mathematical analysis of a chemostat system modeling the competition for light and inorganic carbon with internal storage.
This paper investigates a mathematical model of competition between two species for inorganic carbon and light in a well-mixed water column. The population growth of the species depends on the consumption of two substitutable forms of inorganic carbon, "CO2" (dissolved CO2 and carbonic acid) and "CARB" (bicarbonate and carbonate ions), which are stored internally. Besides, uptake rates also includes self-shading by the phytoplankton population, that is, an increase in population density will reduce light available for photosynthesis, and thereby reducing further carbon assimilation and population growth. We also incorporate the fact that carbon is lost by respiration, and the respiration rate is assumed to be proportional to the size of the transient carbon pool. Then we study the extinction and persistence of a single-species system. Finally, we show that coexistence of the two-species system is possible, depending on parameter values, and both persistence of one population.


Signal integration at the PI3K-p85-XBP1 hub endows coagulation protease activated protein C with insulin-like function.
Coagulation proteases have increasingly recognized functions beyond hemostasis and thrombosis. Disruption of activated protein C (aPC) or insulin signaling impair function of podocytes and ultimately cause dysfunction of the glomerular filtration barrier and diabetic kidney disease (DKD). We here show that insulin and aPC converge on a common spliced-X-box binding protein-1 (sXBP1) signaling pathway to maintain endoplasmic reticulum (ER) homeostasis. Analogous to insulin, physiological levels of aPC maintain ER proteostasis in DKD. Accordingly, genetically impaired protein C activation exacerbates maladaptive ER response, whereas genetic or pharmacological restoration of aPC maintains ER proteostasis in DKD models. Importantly, in mice with podocyte-specific deficiency of insulin receptor (INSR), aPC selectively restores the activity of the cytoprotective ER-transcription factor sXBP1 by temporally targeting INSR downstream signaling intermediates, the regulatory subunits of PI3Kinase, p85α and p85β. Genome-wide mapping of condition-specific XBP1-transcriptional regulatory patterns confirmed that concordant unfolded protein response target genes are involved in maintenance of ER proteostasis by both insulin and aPC. Thus, aPC efficiently employs disengaged insulin signaling components to reconfigure ER signaling and restore proteostasis. These results identify ER reprogramming as a novel hormonelike function of coagulation proteases and demonstrate that targeting insulin signaling intermediates may be a feasible therapeutic approach ameliorating defective insulin signaling.


Ler interdomain linker is essential for anti-silencing activity in enteropathogenic Escherichia coli.
Enteropathogenic Escherichia coli (EPEC) expresses a type III secretion system (T3SS) required for pathogenesis. Regulation of the genes encoding the T3SS is complex; two major regulators control transcription, the silencer H-NS, and the related H-NS-like protein Ler. Our laboratory is interested in understanding the molecular differences that distinguish the anti-silencer Ler from H-NS, and how Ler differentially regulates EPEC virulence genes. Here, we demonstrate that mutated Ler proteins either containing H-NS alpha-helices 1 and 2, missing from Ler, or truncated for the 11 aa C-terminal extension compared with the related H-NS protein, did not appreciably alter Ler function. In contrast, mutating the proline at position 92 of Ler, in the conserved C-terminal DNA binding motif, eliminated Ler activity. Inserting 11 H-NS-specific amino acids, 11 alanines or 6 alanines into the Ler linker severely impaired the ability of Ler to increase LEE5 transcription. To extend our analysis, we constructed six chimeric proteins containing the N terminus, linker region or C terminus of Ler in different combinations with the complementary domains of H-NS, and monitored their in vivo activities. Replacing the Ler linker domain with that of H-NS, or replacing the Ler C-terminal, DNA binding domain with that of H-NS eliminated the ability of Ler to increase transcription at the LEE5 promoter. Thus, the linker and C-terminal domains of Ler and H-NS are not functionally equivalent. Conversely, replacing the H-NS linker region with that of Ler caused increased transcription at LEE5 in a strain deleted for hns. In summary, the interdomain linker specific to Ler is necessary for anti-silencing activity in EPEC.


Evaluation of the toxicity of local anaesthetic agents in man.
Etidocaine given by intravenous infusion has been compared, using a double-blind technique, with bupivacaine and lignocaine in respect of toxic symptoms and signs. The degree of toxicity is affected considerably by the rate of drug infusion. At 10 mg/min subjects could tolerate twice the dose of etidocaine as bupivacaine. Tolerance to etidocaine was less at 20 mg/min but still compared favourably with bupivacaine at 10 mg/min. Considering the difference in potency of the two agents it was considered that the therapeutic ratios would not be substantially different. Lignocaine at 20 mg/min was better tolerated than etidocaine. Venous plasma concentration during these experiments showed a more rapid decrease in the case of etidocaine compared with bupivacaine, but the concentrations were unhelpful in predicting the toxic effects. Similarly electroencephalography revealed no abnormalities in spite of marked subjective and objective signs of toxicity.


Suicide risk in attention-deficit/hyperactivity disorder.
ADHD (Attention-deficit/hyperactivity disorder) is a common neurodevelopmental disorder that manifests itself during childhood with various combinations of symptoms, including inattention, hyperactivity and impulsivity. Research has shown that psychiatric comorbidities play an important role in the development of suicidal behavior and, recently, there has been a growing interest in a possible association between ADHD and suicide during both childhood and adulthood. Furthermore, some authors have shown a relationship between pharmacological treatments and suicide in patients affected by ADHD. We conducted a selective review of current literature to explore the factors which contribute to suicidal behavior and self-harm in those with ADHD. We performed a PubMed/MEDLINE, Scopus, PsycLit, and PsycINFO search to identify all articles and book chapters on the topic up to 2017. Several studies have showed that ADHD may be correlated with an increased suicide ideation and attempts. Although differences in studies design and samples made the results difficult to compare and interpret, many studies indicate an association between ADHD and suicidal behavior. It remains controversial whether there is a direct relationship or whether the association depends on the increased prevalence of pre-existing comorbid conditions and individual and family dysfunctional factors.


Labor force participation and family formation: a study of working mothers.
Drawing upon a sample of 638 mothers aged 18 to 40, with at least some marital work experience, significant associations were found between the extent, kind, and timing of employment and a series of family formation variables. Generally lower fertility, longer first birth intervals, and earlier use of birth control were associated with the longest work durations, the highest status jobs, and work before the birth of the first child. The data failed, however, to differentiate desired family size.


Can agrobiont spiders (Araneae) avoid a surface with pesticide residues?
Integrated pest management includes the use of various pesticides that can have a detrimental effect on spiders. A pesticide can express its activity directly or via residues. Most of the attention paid to the impact of pesticides on spiders has investigated the effects of direct exposure. Our aim in this study was to investigate the residual activity (repellency and toxicity) of selected pesticides on six principal species of spider occurring in an apple orchard. Four of these species (Clubiona spp., Pardosa spp., Philodromus spp., Xysticus spp.) are hunting spiders, and two species (Dictyna spp., Theridion spp.) are web-building. We were interested to see whether these spiders could avoid a surface with residues and to examine their susceptibilities to fresh and 1-day-old residues. For this purpose we conducted laboratory experiments using three types of pesticide, an organophosphate, phosalone (Zolone), a pyrethroid, permethrin (Ambush) and Bacillus thuringiensis (Bt; Novodor), which were applied to paper discs or branches. Spiders could choose to stay on any treated paper/branch within a dish. Except for Theridion spp., all species were repelled by fresh residues but not by 1-day-old residues. Clubiona spp., Dictyna spp., Pardosa spp. and Xysticus spp were repelled by phosalone and permethrin residues only, whereas Philodromus spp. specimens were repelled also by Bt residues. Theridion spp. avoided contact with residues by making a web on any available branch. Regarding toxicity, neither fresh nor 1-day-old residues of phosalone or Bt caused significant mortality to any spider species. In contrast, both fresh and 1-day-old residues of permethrin caused significant mortality to all species except for Theridion spp. In conclusion, spiders can recognise and avoid only fresh residues, although older residues might still be toxic to them.


Testing Geology with Biology: Plate Tectonics and the Diversification of Microhylid Frogs in the Papuan Region.
Studies of the Papuan region have provided fundamental insights into the evolutionary processes generating its exceptional biodiversity, but the influence of geological processes merits further study. Lying at the junction of five tectonic plates, this region has experienced a turbulent geological history that has not only produced towering mountains allowing elevational specialization and island archipelagos with varying degrees of isolation promoting vicariance, but also active margins where land masses have collided and been subsequently rifted apart creating a mosaic of intermixed terranes with vastly different geological histories. Asterophryine frogs are a hyperdiverse clade representing half the world's microhylid diversity (over 360 species) centered on New Guinea and its satellite islands. We show that vicariance facilitated by geological history explains this far and wide distribution of a clade that should have poor dispersal abilities. We recovered a mainland tectonic unit, the East Papua Composite Terrane (EPCT), as the center of origin for Asterophryinae and no fewer than 71 instances of what appear to be long-distance dispersal events, 29 of which are between mainland regions, with 42 from the mainland to the islands, some presently as far as 200 km away from source populations over open ocean. Furthermore, we find strong support for a "Slow and Steady" hypothesis for the formation of the northern margin of New Guinea by many separate accretion events during the Miocene, over other major geological alternatives, consistent with the 20 M year age of the clade and arrival via the EPCT. In addition, the historical biogeography of our frogs strongly supports an affiliation of the Louisiade Archipelago and Woodlark Island with the Owen Stanley Range on the EPCT, and the recent proximity of the large New Britain Island. Our results show that Asterophryinae did not have to repeatedly and independently disperse across large ocean barriers to the offshore islands, against the predictions of island biogeography theory, but that the current distribution can be explained through vicariance and short-distance oceanic dispersal as historical land connections disappeared and islands slowly became separated from each other. We show that islands have a life history, changing in distance from other land masses, with consequent opportunities for dispersal, isolation, and cladogenesis of their biotas. More broadly, we can begin to see how the geological history of the Papuan region can result in the rapid accumulation and staggering number of extant species.


Phosphorylation of αB-Crystallin Involves Interleukin-1β-Mediated Intracellular Retention in Retinal Müller Cells: A New Mechanism Underlying Fibrovascular Membrane Formation.
Chronic inflammation plays a pivotal role in the pathology of proliferative diabetic retinopathy (PDR), in which biological alterations of retinal glial cells are one of the key elements. The phosphorylation of αB-crystallin/CRYAB modulates its molecular dynamics and chaperone activity, and attenuates αB-crystallin secretion via exosomes. In this study, we investigated the effect of phosphorylated αB-crystallin in retinal Müller cells on diabetic mimicking conditions, including interleukin (IL)-1β stimuli. Human retinal Müller cells (MIO-M1) were used to examine gene and protein expressions with real-time quantitative PCR, enzyme linked immunosorbent assay (ELISA), and immunoblot analyses. Cell apoptosis was assessed by Caspase-3/7 assay and TdT-mediated dUTP nick-end labeling staining. Retinal tissues isolated from the Spontaneously Diabetic Torii (SDT) fatty rat, a type 2 diabetic animal model with obesity, and fibrovascular membranes from patients with PDR were examined by double-staining immunofluorescence. CRYAB mRNA was downregulated in MIO-M1 cells with the addition of 10 ng/mL IL-1β; however, intracellular αB-crystallin protein levels were maintained. The αB-crystallin serine 59 (Ser59) residue was phosphorylated with IL-1β application in MIO-M1 cells. Cell apoptosis in MIO-M1 cells was induced by CRYAB knockdown. Immunoreactivity for Ser59-phosphorylated αB-crystallin and glial fibrillary acidic protein was colocalized in glial cells of SDT fatty rats and fibrovascular membranes. The Ser59 phosphorylation of αB-crystallin was modulated by IL-1β in Müller cells under diabetic mimicking inflammatory conditions, suggesting that αB-crystallin contributes to the pathogenesis of PDR through an anti-apoptotic effect.


[Effect of coenzyme Q10 supplementation on apoptosis, free radical oxidative processes and proteome pool of microsomal and cytosol fractions of hepatocytes using food ration with different lipid component].
Our aim was to analyze biochemical mechanism in regulation and adaptation to feeding with omega-3 and omega-6 PUFA plus coenzyme Q10-based diet in rats. The rats were supplemented with Co Q10 (100 mg/kg b.wt.) for 12 month. Male rats were fed a control, control + Q10, fish oil + Q10 palm oil + Q10 and flax oil + Q10 diet. The learning and tests were monitored in 1st, 3rd, 6th and 12th month after the start of feeding. There was studied the content of lipid peroxidation products in the liver, the level of their potential substrates polyunsaturated fatty acids of omega-3 and omega-6 families and MEC (metabolism effectiveness coefficient) index value. Growth of relative number of hepatocyte in the state of late apoptosis has been detected in rats receiving fish oil, linseed oil and palm oil as compared to the control group at the age of 1 and 3 months. In later period no differences in the invested indices, that can be the result of impact of CoQ10 and adaptation of organism to diet. Proteomic studies of microsomal fraction of hepatocytes in rats have found differences in the manifestation of catalase and cetochrome b5, associated both with age of animals and type of fat in diet. Proteomic analysis of cytosolic fraction revealed the expression of c-type lectin in the later stages of ontogeny. The levels of lipid peroxidation markers obtain to minimum at 3 month in serum and at 6 month in liver. The specific proteomic changes of influence of diet composition were identified during the research.


Rilpivirine use in the Swiss HIV cohort study: a prospective cohort study.
Rilpivirine is safe and effective in HIV-naïve patients with low baseline HIV-RNA or in switch strategy. It offers the advantages of few drug-drug interactions and a favourable toxicity profile. We aimed to determine the reasons for prescribing the rilpivirine (RPV)/tenofovir disoproxil (TDF)/emtricitabine (FTC) co-formulation within the Swiss HIV Cohort Study and to assess its effectiveness and safety over a 24 months period. All individuals enrolled in the Swiss HIV Cohort Study who initiated a RPV/TDF/FTC co-formulation between April 2013 and March 2014 were included. Primary outcomes were the HIV-RNA viral load (copies/mL) and CD4 cell count (cells/mm3) at 6, 12 and 24 months. Reasons for a switch to RPV/TDF/FTC were evaluated through a standardized questionnaire. We also assessed discontinuation and reasons for discontinuation of RPV/TDF/FTC until October 30, 2015. Of 644 individuals who started the RPV/TDF/FTC co-formulation, only 7.5% were treatment-naïve. At 24 months, viral suppression (HIV-RNA <50 copies/mL) was achieved in 100% and 96.7% of cART-naïve and cART-experienced patients respectively. The switch to RPV was mainly done for simplification (44.6%) and to overcome central nervous system toxicity symptoms due to efavirenz (24%). Six months after switch, 74.8% of patients reported an improvement of psycho-neurological symptoms with continued improvement at 12 months for almost 80%. However, one quarter of patients reported a discontinuation of RPV/TDF/FTC on October 30, 2015 after a median time of 18.4 months. Reasons for discontinuation included physician decision (5.3%) and side-effects (3.9%) mainly related to the central nervous system and to renal toxicity. The RPV/TDF/FTC co-formulation was safe and effective throughout 24 months of follow-up but barely prescribed for HIV-naïve patients. Despite excellent virological suppression among both treatment-naïve and -experienced patients, we observed a high rate of treatment discontinuation.


Is SS-A/Ro52 a hydrogen peroxide-sensitive signaling molecule?
SS-A/Ro52 (Ro52) protein is one of the targets of autoantibodies in Sjogren's syndrome and systemic lupus erythematosus. Ro52 structurally belongs to the RING-B-box/coiled-coil family, which appears to carry out diverse functions, but the physiological function of Ro52 remains largely unknown. Here, the authors demonstrate that hydrogen peroxide but not other oxidative stressors induced translocation of Ro52 protein from the cytoplasm to the nucleus and this phenomenon was attenuated by inhibition of MAP kinases, ERK in particular. These findings raise the possibility that SS-A/Ro52 may function as a hydrogen peroxide-selective, oxidative stress-sensitive signaling molecule that is activated via the MAP kinase pathway.


Accuracy of the Xpert® MTB/RIF assay for the diagnosis of extra-pulmonary tuberculosis in South Korea.
The Xpert(®) MTB/RIF assay has been endorsed by the World Health Organization for the detection of pulmonary and extra-pulmonary tuberculosis (EPTB). To determine the accuracy of the Xpert assay in diagnosing EPTB in South Korea, a country with an intermediate TB burden. We retrospectively reviewed the medical records of 1429 patients in whom the Xpert assay using EPTB specimens was requested between 1 January 2011 and 31 October 2013 in a tertiary referral hospital in South Korea. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) for the diagnosis of EPTB and detection of rifampicin (RMP) resistance were calculated. Using culture as gold standard, the sensitivity, specificity, PPV and NPV of the assay were respectively 67.7%, 98.1%, 60% and 98.6%. Using a composite reference standard, the sensitivity, specificity, PPV and NPV were respectively 49.3%, 100%, 100% and 95.1%. The sensitivity, specificity, PPV and NPV for the detection of RMP resistance among specimens with positive results for Mycobacterium tuberculosis were respectively 80%, 100%, 100% and 97.7%. The Xpert assay showed acceptable sensitivity in certain groups and excellent specificity in diagnosing EPTB and detecting RMP resistance in an intermediate TB burden country.


Effects of hepatic portal infusion of deionized water on metabolic and hormonal responses to exercise in rats.
The present study was conducted to investigate the in vivo effects of an intrahepatic infusion of deionized water during exercise in rats. Adrenodemedullated male Sprague-Dawley rats were continuously infused for 30 min either at rest or during treadmill exercise (26 m/min, 0% grade). Rats were randomly assigned to one of three infusion conditions (52 micro ul/min) with either deionized water (PW) or saline (PS; NaCl; 0.9%) via the hepatic portal vein or deionized water through the jugular vein (JW). The exercise period caused a significant (P < 0.05) decrease in liver glycogen and relative liver water content and peripheral and portal blood glucose and insulin while increasing peripheral and portal glucagon and K+ plasma concentrations. These responses, with the exception of K+, were not influenced by the different types of infusions. The increase in K+ during exercise was significantly (P < 0.05) higher in JW rats than in the PW and PS groups. Both the infusion and exercise protocols did not significantly alter the liver weight-to-body weight ratio, plasma osmolality, free fatty acids, beta-hydroxybutyrate, Na+, Cl-, vasopressin, and catecholamine concentrations. It is concluded that an hepatic portal infusion of deionized water does not specifically alter the metabolic and hormonal responses to exercise in rats.


[Analysis of the efficacy of Twin-block appliance on maxillofacial growth of six pairs of monozygotic twins].
The purpose of this study was to investigate the efficacy of Twin-block appliance on maxillofacial growth by using monozygotic twins. 6 pairs of non-high angle monozygotic twins aged 12.2 with class II division 1 malocclusion were selected from 32 pairs of twins. In the first year Twin A of each pair was functionally treated using Twin-block appliance; meanwhile, Twin B underwent non-extracted fixed treatment without any treatment procedure which might cause changes like functional appliances such as Class II elastics. The difference of the cephalometric changes of maxilla and mandible before and after treatment between Twin A and Twin B was compared using paired-t test. Compared with those of Twin A after one year treatment, SNA, Cd-A and Cd-Go of Twin B had little chang (P>0.05), but Cd-S' reduced (P<0.05), Cd-Gn and SNB increased (P=0.01), (Cd-Gn)-(Cd-A) and ANB increased (P<0.05) significantly. Twin-block appliance can stimulate forward mandibular growth and cause forward mandibular displacement, but has little effect on ramus height and maxillary growth.


An unusually medial axillary arch muscle.
In the left upper limb of an adult male cadaver a triangular muscular slip, 3.5 cm long and 2.5 cm wide, arose from the lower border of latissimus dorsi just proximal to its tendon of insertion. It was inserted by a slender 6 cm long tendon mainly into the coracoid process of the scapula. Three short fibrous strands radiated from this slender tendon to gain attachments to pectoralis minor and the common tendon of origin of the short head of biceps brachii and coracobrachialis. In addition 2 flat tendinous bands attached the margin of this muscular slip to teres major. The thoracodorsal nerve entered the main bulk of latissimus dorsi close to the muscular slip but did not supply a separate branch to the latter. This is an axillary arch muscle in an unusually medial location.


Prognostic Predictors of Visual Outcome in Open Globe Injury: Emphasis on Facial CT Findings.
The present prognostic models for open globe injuries have a limited ability to predict visual outcome before a comprehensive ophthalmologic examination or operation because they depend on the data derived from the ophthalmologic examination and intraoperative findings. The purpose of our study was to determine the specific CT and preoperative clinical data that can predict the prognosis of open globe injury. We analyzed the relationship of 29 variables derived from clinical and CT data from 97 globe injuries with visual acuity at 1 month. A prediction model was derived from 49 globe injuries by regression analysis, followed by receiver operating characteristic curve analysis of the best CT predictor. Four variables with significance on a regression model were the following: posterior segment hemorrhage (β = -0.93, P < .0001), presenting visual acuity (β = 0.28, P = .042), orbital emphysema (β = 0.46, P = .0018), and complex facial fracture (β = -0.43, P = .009). Receiver operating characteristic analysis of the posterior segment hemorrhage predicted profound vision loss (light perception or no light perception) with an area under the curve of 0.97. The receiver operating characteristic table indicated that grade III posterior segment hemorrhage has a strong positive predictive value of 100% for profound vision loss. On the other hand, the absence of posterior segment hemorrhage has a strong positive predictive value of 93% for mild-to-severe vision loss (visual acuity better than light perception). Radiologists, with the help of CT and preoperative clinical data, can predict visual acuity after open globe injury.


Proximal tubule-derived colony stimulating factor-1 mediates polarization of renal macrophages and dendritic cells, and recovery in acute kidney injury.
Infiltrating cells play an important role in both the development of and recovery from acute kidney injury (AKI). Macrophages and renal dendritic cells are of particular interest because they can exhibit distinctly different functional phenotypes, broadly characterized as proinflammatory (M1) or tissue reparative (M2). Resident renal macrophages and dendritic cells participate in recovery from AKI in response to either ischemia/reperfusion or a model of selective proximal tubule injury induced by diphtheria-toxin-induced apoptosis in transgenic mice expressing the human diphtheria toxin receptor on proximal tubule cells. Colony-stimulating factor-1 (CSF-1) is an important factor mediating the recovery from AKI, and CSF-1 can stimulate macrophage and dendritic cell proliferation and polarization during the recovery phase of AKI. The kidney, and specifically the proximal tubule, is a major source of intrarenal CSF-1 production in response to AKI. We induced selective deletion of proximal tubule CSF-1 to determine its role in expansion and proliferation of renal macrophages and dendritic cells and in recovery from AKI. In both models of AKI, there was decreased M2 polarization, delayed functional and structural recovery, and increased tubulointerstitial fibrosis. Thus, intrarenal CSF-1 is an important mediator of macrophage/dendritic cell polarization and recovery from AKI.


Altered pattern of replication of human chromosomes in a human fibroblast-mouse cell hybrid.
The pattern of terminal replication of the human chromosomes in a clone of hybrids between diploid human fibroblasts and mouse cells was analyzed by autoradiography. An average of 10 human chromosomes was present in the hybrid cells. Several of these chromosomes were found to terminate replication in a different order from the same chromosomes in the parental human fibroblasts. Chromosomes 4 and 5 completed replication later in the hybrid than in the fibroblasts (relative to the other human chromosomes). In contrast, chromosomes 7, 12, and 15 completed replication earlier in the hybrid than in the fibroblasts. These results suggest that the sequence of terminal chromosome replication in human fibroblasts is not irreversibly programmed into each chromosome.


How young children learn from examples: descriptive and inferential problems.
Three experiments with preschool- and young school-aged children (N = 75 and 53) explored the kinds of relations children detect in samples of instances (descriptive problem) and how they generalize those relations to new instances (inferential problem). Each experiment initially presented a perfect biconditional relation between two features (e.g., all and only frogs are blue). Additional examples undermined one of the component conditional relations (not all frogs are blue) but supported another (only frogs are blue). Preschool-aged children did not distinguish between supported and undermined relations. Older children did show the distinction, at least when the test instances were clearly drawn from the same population as the training instances. Results suggest that younger children's difficulties may stem from the demands of using imperfect correlations for predictions. Older children seemed sensitive to the inferential problem of using samples to make predictions about populations.


Delivering Cognitive Behavior Therapy to Young Adults With Symptoms of Depression and Anxiety Using a Fully Automated Conversational Agent (Woebot): A Randomized Controlled Trial.
Web-based cognitive-behavioral therapeutic (CBT) apps have demonstrated efficacy but are characterized by poor adherence. Conversational agents may offer a convenient, engaging way of getting support at any time. The objective of the study was to determine the feasibility, acceptability, and preliminary efficacy of a fully automated conversational agent to deliver a self-help program for college students who self-identify as having symptoms of anxiety and depression. In an unblinded trial, 70 individuals age 18-28 years were recruited online from a university community social media site and were randomized to receive either 2 weeks (up to 20 sessions) of self-help content derived from CBT principles in a conversational format with a text-based conversational agent (Woebot) (n=34) or were directed to the National Institute of Mental Health ebook, "Depression in College Students," as an information-only control group (n=36). All participants completed Web-based versions of the 9-item Patient Health Questionnaire (PHQ-9), the 7-item Generalized Anxiety Disorder scale (GAD-7), and the Positive and Negative Affect Scale at baseline and 2-3 weeks later (T2). Participants were on average 22.2 years old (SD 2.33), 67% female (47/70), mostly non-Hispanic (93%, 54/58), and Caucasian (79%, 46/58). Participants in the Woebot group engaged with the conversational agent an average of 12.14 (SD 2.23) times over the study period. No significant differences existed between the groups at baseline, and 83% (58/70) of participants provided data at T2 (17% attrition). Intent-to-treat univariate analysis of covariance revealed a significant group difference on depression such that those in the Woebot group significantly reduced their symptoms of depression over the study period as measured by the PHQ-9 (F=6.47; P=.01) while those in the information control group did not. In an analysis of completers, participants in both groups significantly reduced anxiety as measured by the GAD-7 (F1,54= 9.24; P=.004). Participants' comments suggest that process factors were more influential on their acceptability of the program than content factors mirroring traditional therapy. Conversational agents appear to be a feasible, engaging, and effective way to deliver CBT.


A large meta-analysis of the global prevalence rates of S. aureus and MRSA contamination of milk.
Past reports have indicated a high prevalence of milk contaminated with Staphylococcus aureus (S. aureus) and methicillin-resistant Staphylococcus aureus (MRSA), but the pooled prevalence rates of S. aureus and MRSA in pasteurized and boiled cow's milk, raw cow's milk, and raw Caprinae milk (raw sheep's milk and raw goat's milk) and across different periods, continents, economic conditions and purchase locations remain inconsistent. We searched relevant articles published in PubMed, EMBASE, and Web of Science before July 2016. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement was used to evaluate the quality of 93 included studies. We observed that the pooled prevalence rates of S. aureus contamination in pasteurized and boiled cow's milk, raw cow's milk, and raw Caprinae milk were 15.4% (95% CI, 6.1-27.5%), 33.5% (95% CI, 29.5-37.7%) and 25.8% (95% CI, 17.5-35.0%), respectively. The pooled prevalence rates of MRSA contamination were 4.9% (95% CI, 0.0-15.7%), 2.3% (95% CI, 1.3-3.6%), and 1.1% (95% CI, 0.5-1.8%), respectively. The prevalence of S. aureus contamination in raw cow's milk increased over time. However, the pooled prevalence of raw cow's milk contaminated with S. aureus was lowest in European studies. These findings give an indication of the consequence of better milk regulation in Europe. High S. aureus prevalence rates in raw milk collected from farms and processing companies pose a potential threat to consumers. The implementation of good hygiene practices, appropriate health knowledge, and food safety principles at the farm level, as well as the prudent use of antibiotics in veterinary medicine and heat treatment before drinking, are necessary to reduce the potential risk of S. aureus and MRSA contamination.


An advanced approach for rapid visual identification of Liposcelis bostrychophila (Psocoptera: Liposcelididae) based on CRISPR/Cas12a combined with RPA.
Liposcelis bostrychophila Badonnel (Psocoptera: Liposcelididae) is a booklouse pest that is a threat to commodity storage security worldwide. Accurate and sensitive methods of L. bostrychophila on-site identification are essential prerequisites for its effective management. Evidence suggests that L. bostrychophila contains 3 intraspecific biotypes that are morphologically indistinguishable but can be discriminated at the level of mitochondrial genome organization and sequences. The traditional molecular identification methods, such as DNA barcoding and PCR-RFLP, are instrumentally demanding and time-consuming, limiting the application of the identification in the field. Therefore, this study developed a new CRISPR/Cas12a-based visual nucleic acid system based on the mitochondrial gene coding for NADH dehydrogenase subunit 2 (nad2), combined with recombinase polymerase amplification (RPA) to accurately identify L. bostrychophila from 4 other common stored-product booklice, and also differentiate 3 biotypes of this species at the same time. The entire identification process could be completed at 37 °C within 20 min with high sensitivity. The system could stably detect at least 1 ng/μl of DNA template. The green fluorescence signal produced by the trans-cleaving of the single-stranded DNA reporter could be observed by the naked eye under blue light. Additionally, the suggested system combined with the crude DNA extraction method to extract DNA rapidly, enabled identification of all developmental stages of L. bostrychophila. With crude DNA, this novel diagnostic system successfully identified an unknown booklouse by holding the reaction tubes in the hand, thus can be considered as an accurate, rapid, highly sensitive, and instrument-flexible method for on-site visual identification of L. bostrychophila.


Starburst Diblock Polyprodrugs: Reduction-Responsive Unimolecular Micelles with High Drug Loading and Robust Micellar Stability for Programmed Delivery of Anticancer Drugs.
Polymeric prodrug based on therapeutic nanomedicine has demonstrated great promise for effective tumor growth inhibition, however, the drawbacks of low drug-loading and weak micellar stability limit its application for clinical cancer therapy. Herein, a reduction-responsive starburst block copolymer prodrug CCP [β-cyclodextrin (β-CD)-PCPTXX-POEGMA, XX: SS or CC] has been developed for cancer therapy. And CCP is composed of β-CD-Br core with multiple reactive sites, as well as a diblock copolymer containing hydrophobic polymerized camptothecin (PCPT) prodrug chain and hydrophilic poly[(ethylene glycol) methyl ether methacrylate] (OEGMA) chain. A family of CCP polymeric prodrugs with different drug loading contents (up to 25%) and various sizes of unimolecular micelles (UMs) (around 30 nm) were obtained by adjusting the block ratio of PCPTXX and POEGMA. On account of the amphiphilic structure feature, CPP could take shape water-soluble UMs in aqueous medium with excellent micellar stability. Under imitatively reductive tumor microenvironment, anticancer drug CPT could rapidly escape from CCP UMs in terms of disulfide bond breakage. However, this behavior is strongly refrained in the physiological environment. In vitro and in vivo outcome confirmed that CCP UMs showed excellent performance of sufficient tumor accumulation, high-efficiency tumor growth inhibition and low-toxicity for healthy tissues. Based on these gratifying therapeutic efficacy, it is believed that as-present starburst prodrug strategy can offer a brand-new insight for high-efficiency therapeutic nanoplatforms for chemotherapy application.


Evaluating the response to antioestrogen toremifene treatment in DMBA induced rat mammary carcinoma.
Evaluation of the treatment response to hormonal therapy in experimental mammary carcinoma models usually consists of recording the changes in tumour volume or in number of tumours. We performed quantitative histology on dimethylbenz[a]anthracene(DMBA) induced rat mammary carcinoma treated with the antioestrogen toremifene. The inhibition of growth of the treated regressing tumours was not only associated with inhibition of mitosis and reduction of the neoplastic epithelium, but toremifene seemed to reduce all main tissue components. The percentual area fractions of epithelium and stroma were equal in the untreated and the treated tumours. The estimated absolute volumes of epithelium, stroma and glandular luminae as well as the mitotic index were significantly reduced during toremifene treatment in those tumours which were responding by regression to the treatment. The findings indicate growth inhibiting effect on both epithelium and stroma or on interactions between epithelium and stroma. Adding quantitative histology to the gross response analysis in experimental animal models is feasible and may elucidate the mechanisms of action of a novel hormonal treatment.


Experimental design-based optimization of lipid nanocarrier as delivery system against Mycobacterium species: in vitro and in vivo evaluation.
The study aimed to optimize self-nanoemulsifying drug delivery system using experimental design using excipients holding innate anti-mycobacterium activities followed with characterizations for responses such as optical clarity (Y1), zone of inhibition (ZOI) against Mycobacterium smegmatis strains (Y2, Y3), and globular size (Y4). The optimized formulations (OF1-OF3) were further characterized for responses and evaluated for zeta potential, minimum inhibition concentration (MIC) against non-pathogenic and tubercular strains, morphological (electron microscopy and atomic force microscopy), and confocal laser scanning microscopy (CLSM) studies. The desirability analysis suggested that the predicted values of the OF1 for the responses Y1, Y2, Y3, and Y4 were 0.137, 22.77 mm, 21.9 mm, and 191.11 nm, respectively. The morphological assessment confirmed the in vitro studies and established the inhibition mechanism as evidenced with oozing, ablation, and cell-wall fragmentation followed with cell disruption. The OF1, OF2, and OF3 showed an MIC value at 8.8 ± 0.56 mg/ml, 12.5 ± 0.22 mg/ml, and 15.0 ± 0.4 mg/ml, respectively, corroborating effectiveness against tubercular strain. CLSM studies revealed 75.1, 80.3, and 88.7% as an intense fluorescence intensity of OF1, OF2, and OF3, respectively, as compared with dye solution (∼53%). Conclusively, it can be inferred that the delivery of anti-tubercular drugs might be reassessed using excipients with inherent anti-mycobacterium activities.


Baseline Expression of Exosomal miR-92a-3p and miR-221-3p Could Predict the Response to First-Line Chemotherapy and Survival in Metastatic Colorectal Cancer.
The status of predictive biomarkers in metastatic colorectal cancer is currently underdeveloped. Our study aimed to investigate the predictive value of six circulating exosomal miRNAs derived from plasma (miR-92a-3p, miR-143-3p, miR-146a-5p, miR-221-3p, miR-484, and miR-486-5p) for chemosensitivity, resistance patterns, and survival. Thirty-one metastatic colorectal cancer patients were selected before receiving first-line irinotecan- or oxaliplatin-based chemotherapy. Blood samples were harvested at baseline and 4-6 months after the initiation of chemotherapy. The levels of exosomal expression for each miRNA were analyzed by qPCR. Our results for patients receiving first-line FOLFOX showed significantly higher baseline levels of miR-92a-3p (p = 0.007 **), miR-146a-5p (p = 0.036 *), miR-221-3p (p = 0.047 *), and miR-484 (p = 0.009 **) in non-responders (NR) vs. responders (R). Of these, miR-92a-3p (AUC = 0.735), miR-221-3p (AUC = 0.774), and miR-484 (AUC = 0.725) demonstrated a predictive ability to discriminate responses from non-responses, regardless of the therapy used. Moreover, Cox regression analysis indicated that higher expression levels of miR-92a-3p (p = 0.008 **), miR-143-3p (p = 0.009 **), miR-221-3p (p = 0.016 *), and miR-486-5p (p = 0.019 *) at baseline were associated with worse overall survival, while patients expressing higher baseline miR-92a-3p (p = 0.003 **) and miR-486-5p (p = 0.003 **) had lower rates of progression-free survival. No predictive values for candidate microRNAs were found for the post-chemotherapy period. In line with these findings, we conclude that the increased baseline exosomal expression of miR-92a-3p and miR-221-3p seems to predict a lack of response to chemotherapy and lower OS. However, further prospective studies on more patients are needed before drawing practice-changing conclusions.


Numerical Investigation of Coil Configurations That Provide Ultra-High Packing Density of Saccular Aneurysms.
BACKGROUND: The long-term outcome of endovascular coiling of cerebral aneurysms is directly related to the packing density at time of treatment. In general, the highest packing density achievable is only about 45% due to the quasi-random distribution of currently available coils within aneurysms. We investigated whether packing densities could be maximized via more ordered coil configurations. METHODS: Three different coil configurations - circular loops, planar spirals, and spherical helices - were investigated. The packing densities achievable in maximally filling the volume of an exemplar human basilar aneurysm with each coil configuration were calculated numerically. Coil packing simulations were also carried out for aneurysms idealized as spheres over diameters ranging from 2 to 30 mm. RESULTS: The packing densities with the loop, spiral, and spherical helix configurations were 82%, 60%, and 73%, respectively, for the human aneurysm model; the numbers of coils required were 693, 34, and 13, respectively. Simulations within idealized aneurysms suggest that aneurysms cannot be packed to more than 91% with coils of constant circular cross-section. The spherical helix configuration provides a constant packing density (coefficient of variation 0.4%) over the range of aneurysm diameters studied as compared to the two other configurations (coefficients of variation 9% and 8%). CONCLUSIONS: Coil configurations that allow for ordered filling of cerebral aneurysms can potentially provide packing densities that are twice those currently achieved. The spherical helix configuration seems to be the most technically feasible and stable configuration of the three coil types investigated.


Comments on operations for lower limb lymphoedema.
Good results have been obtained from surgical operations for lymphoedema of the lower limbs using skin flaps with a blood supply to cover the muscles following reduction of swollen subcutaneous tissue. The Charles operation using free skin grafts for cover is reserved for tropical elephantiasis or patients with local skin in bad condition. A variety of other procedures of physiologic intent have given disappointing results and been abandoned. The results of 74 operations are reviewed with a view to improving still further the results. The mortality rate was nil and there were only minor complications.


An audit of antibiotic prescribing by vocational dental practitioners.
To investigate antibiotic prescribing of a group of vocational dental practitioners (VDPs) and assess the implications for postgraduate education. A prospective audit was carried out by VDPs in general dental practice in 2003. A total of seven vocational training schemes comprising 64 VDPs took part. Most showed some awareness of the indications for therapeutic prescribing but the prescribing patterns of a number were influenced by the pressure of time and workload and difficulty in making a definitive diagnosis. There were wide variations in the therapeutic antibiotic regimens used, with most not conforming to the guidelines available. The majority of VDPs showed a good understanding of the requirement for prescribing prophylactic antibiotics for patients with a cardiac defect but a number also prescribed when there were no medical indications to do so. From this audit it is clear that, on occasions, the prescribing of antibiotics by VDPs was not consistent with current knowledge and within the guidelines available. This calls into question the efficacy of present undergraduate teaching or the retention of knowledge. The results suggest that formal education on antibiotic prescribing in general dental practice should take place during the VT year.


Acute renal failure associated with an accidental overdose of colchicine.
A 47-year-old man with a history of polyarticular gout was admitted to the nephrology service because of severe renal insufficiency (creatinine 6.25 mg/dl). Three days before admission he had a pain crisis in his knees and ankles and self-administered 20 x 1 mg granules of colchicine p.o. over a period of 4 - 5 hours together with six suppositories each containing 100 mg of indomethacin. The patient began vomiting within 24 hours, experienced diarrhea which persisted for three days and then came to the hospital. The patient reported oliguria during the preceding 24 hours. In hospital, attempts to correct water and electrolyte balance were initiated. The patient became stabilized hemo-dynamically, the diarrhea disappeared within 24 hours, diuresis resumed and the renal function progressively improved. Leukopenia and thrombopenia were diagnosed, the transaminases increased: AST = 79 U/l, ALT = 132 U/l on the eighth day after taking the colchicine. The serology for hepatitis A, B, C and HIV viruses was negative; the serology for CMV and VEB revealed a previous infection. After being discharged from hospital 11 days after admission, the patient presented with the following parameters: hematocrit 39%, leukocytes 5,920/microl (3 470 neutrophils), prothrombin time 13 seconds, urea 44 mg/dl, creatinine 1.29 mg/dl, AST 16 U/l and ALT 35 U/l. The patient mistakenly ingested 20 mg ofcolchicine p.o. (0.22 mg/kg). The intoxication was associated with gastroenterocolitis, dehydration and renal failure during the first three days after ingestion. The patient also developed leukopenia, thrombopenia and mild hepatocellular injury. Renal failure due to colchicine intoxication is due to various factors such as depletion of volume/hypotension, rhabdomyolysis and multiorgan failure. In this case, the hypovolemia was probably the fundamental cause of the acute renal insufficiency as demonstrated by the quick recovery after administering fluids. It is possible that indomethacin may have enhanced the toxic effect of colchicine on the kidneys and bone marrow. Some colchicine intoxications, as in this case, are caused by an error in interpreting the dose for treating an acute attack of gout. A way to prevent these errors would be to use a low-dose treatment protocol.


Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF(V600E) mutation and expression.
Pediatric cortical glioneuronal benign tumors mainly include gangliogliomas (GG) [differential diagnoses pilocytic astrocytomas (PA) and pleomorphic xanthoastrocytomas (PXA)] and dysembryoplastic neuroepithelial tumor (DNT). DNT include the specific form and the controversial non-specific form that lack the specific glioneuronal element. Our aims were to search for BRAF(V600E) mutation and CD34 expression in DNT, PXA, GG and PA to correlate BRAF(V600E) mutation with BRAF(V600E) expression and to evaluate their diagnostic and prognostic values. Ninety-six children were included. BRAF(V600E) mutation was studied by sequencing and immunohistochemistry; CD34 expression was analyzed by immunohistochemistry. BRAF(V600E) mutation was detected in PXA (60%), GG (38.7%), DNT (30%, including 3/11 specific and 3/9 non-specific forms) and PA (12.5%). BRAF(V600E) expression was recorded in PXA (60%), GG (45.2%) and DNT (30%). CD34 expression was recorded in PXA (60%), GG (58.1%), DNT (25%) and PA (12.5%). Neither CD34 expression nor BRAF(V600E) status was predictive of prognosis, except for PA tumors where CD34 expression was associated with a shorter overall survival. In conclusion, DNT shared with PXA and GG, BRAF(V600E) mutation and/or CD34 expression, which represent molecular markers for these tumors, and we recommend searching for CD34 expression and BRAF(V600E) mutation in all DNT, especially the non-specific forms.


Surface passivation and interface properties of bulk GaAs and epitaxial-GaAs/Ge using atomic layer deposited TiAlO alloy dielectric.
High quality surface passivation on bulk-GaAs substrates and epitaxial-GaAs/Ge (epi-GaAs) layers were achieved by using atomic layer deposited (ALD) titanium aluminum oxide (TiAlO) alloy dielectric. The TiAlO alloy dielectric suppresses the formation of defective native oxide on GaAs layers. X-ray photoelectron spectroscopy (XPS) analysis shows interfacial arsenic oxide (As(x)O(y)) and elemental arsenic (As) were completely removed from the GaAs surface. Energy dispersive X-ray diffraction (EDX) analysis and secondary ion mass spectroscopy (SIMS) analysis showed that TiAlO dielectric is an effective barrier layer for reducing the out-diffusion of elemental atoms, enhancing the electrical properties of bulk-GaAs based metal-oxide-semiconductor (MOS) devices. Moreover, ALD TiAlO alloy dielectric on epi-GaAs with AlGaAs buffer layer realized smooth interface between epi-GaAs layers and TiAlO dielectric, yielding a high quality surface passivation on epi-GaAs layers, much sought-after for high-speed transistor applications on a silicon platform. Presence of a thin AlGaAs buffer layer between epi-GaAs and Ge substrates improved interface quality and gate dielectric quality through the reduction of interfacial layer formation (Ga(x)O(y)) and suppression of elemental out-diffusion (Ga and As). The AlGaAs buffer layer and TiAlO dielectric play a key role to suppress the roughening, interfacial layer formation, and impurity diffusion into the dielectric, which in turn largely enhances the electrical property of the epi-GaAs MOS devices.


Dynamical origin of enhanced conformational searches of Tsallis statistics sampling.
The characteristic sampling dynamics of importance samplings driven by the Tsallis weight [C. Tsallis, J. Stat. Phys. 52, 479 (1988)] has been analyzed in terms of recently developed Langevin stochastic model by considering the effects of the density of states and the potential smoothing of the Tsallis transformation. Our study reveals that the fixed points, which are determined by the crossing points of the statistical temperature and the Tsallis effective temperature, play a critical role in overall dynamics of the Tsallis statistics sampling. The dynamical origin of enhanced conformational searches of the Tsallis weight has been investigated by unveiling the intimate relationship between the sampling dynamics and the stability change of corresponding fixed points. Based on this stochastic analysis, we propose one effective method to realize a broad energy distribution in the Tsallis statistics sampling by determining optimal Tsallis parameters systematically based on preliminary canonical samplings. The effectiveness of our method has been validated in the folding simulation of Met-Enkephalin and liquid-solid transition simulation of Lennard-Jones cluster systems.


Fibrocyte measurement in peripheral blood correlates with number of cultured mature fibrocytes in vitro and is a potential biomarker for interstitial lung disease in Rheumatoid Arthritis.
Interstitial lung disease (ILD) can be a severe extra-articular disease manifestation in Rheumatoid Arthritis (RA). A potential role of fibrocytes in RA associated ILD (RA-ILD) has not previously been described. We present a modified faster method for measuring circulating fibrocytes, without intracellular staining. The results are compared to the traditional culture method, where the number of monocytes that differentiate into mature fibrocytes in vitro are counted. The results are following compared to disease activity in patients with severe asthma, ILD, RA (without diagnosed ILD) and RA with verified ILD (RA-ILD). CD45+ CD34+ CD11b+ (7-AAD- CD3- CD19- CD294-) cells were isolated by cell sorting and stained for pro-collagen type 1. Thirty-nine patients (10 RA, 9 ILD and 10 with severe asthma, 10 with RA-ILD) and 10 healthy controls (HC) were included. Current medication, disease activity, pulmonary function test and radiographic data were collected. Circulating fibrocytes were quantified by flow cytometry. Peripheral blood mononuclear cells were isolated and cultured for 5 days and the numbers of mature fibrocytes were counted. 90.2% (mean, SD = 1.5%) of the sorted cells were pro-collagen type 1 positive and thereby fulfilled the criteria for being circulating fibrocytes. The ILD and RA-ILD groups had increased levels of circulating fibrocytes compared to HC (p < 0.05). Levels of circulating fibrocytes correlated overall to number of monocytes that subsequently in vitro differentiated to mature fibrocytes (r = 0.81, p < 0.001). RA patients with pathologically reduced diffusion capacity for carbon monoxide adjusted for hemoglobin (DLCOc) in both the RA and in the combined RA + RA-ILD group, had significantly higher levels of both circulating and number of cultured mature fibrocytes (both p < 0.05). In both groups, the level of circulating fibrocytes and number of mature fibrocytes in culture also correlated to a reduction in DLCOc (r = -0.61 an r = -0.58 both p < 0.05). We presented a fast and valid method for measuring circulating fibrocytes using flow cytometry on lysed peripheral blood. Further, we showed for the first time, that the level of circulating fibrocytes correlated with the number of peripheral blood mononuclear cells, that differentiated into mature fibrocytes in vitro. Reduced DLCOc was correlated with high levels of circulating and mature fibrocytes in RA, which have not been reported previously. In such, this study suggests that fibrocytes may exhibit an important role in the pathogenesis of RA-ILD, which requires further clarification in future studies. ClinicalTrials.gov : NCT02711657 , registered 13/3-2016, retrospectively registered.


[Novel techniques in the treatment of rectal cancer].
Rectal cancer is the eighth and tenth most common kind of cancer in men and women, respectively, with an increasing frequency of occurrence. Together with cancer of the large intestine it forms the third most common cancer entity. Surgical therapy is the most important form of treatment of rectal cancer; in combination with adjuvant therapy it will cure a significant proportion of the patients and provide relief for tumor-induced hemorrhagic and obstructive symptoms. The operation has usually been conducted as an open surgery with the use of simple instruments. In recent times, the operative techniques have become more versatile, and mini-invasive techniques have resulted in quicker recovery of the patients from the operation.


Studies on leukocyte migration inhibiton: the role of E rosette-forming cells in specific antigen-induced inhibition of migration.
The role of E rosette-forming cells in leukocyte migration inhibition was investigated with human buffy coat cells fractionated by combined E rosette formation and Ficoll-Hypaque (FH) density gradient centrifugation. The migration of unfractionated dextran-sedimented leukocytes and FH-separated mononuclear cells (MN) were equally inhibited in the presence of Escherichia coli somatic antigen (E. coli), purified protein derivative of tuberculin (PPD) and influenza virus antigen (Flu). Polymorphonuclear leukocytes (PMN) separated from whole leukocytes by one FH density gradient fractionation contained greater than 1.0% E rosette-forming cells and were inhibited by E. coli and PPD. PMN submitted to three transits of FH (DF III) contained less than or equal to 0.02% E rosette forming cells and were unaffected by each of the three antigens. The migration of mixtures of 10% MN and 90DF III cells were inhibited in the presence of specific antigen, while MN depleted of E rosette-forming cells (less than or equal to 0.5%) pooled with equal numbers of DF III cells did not respond to any antigen by migration inhibition. These results show that PMN purified by three transits of FH are unable to respond to specific antigen by inhibition of migration from microcapillary tubes, and specific antigen-induced inhibition of migration of peripheral blood leukocytes does not occur in the absence of D rosette-forming cells in normal subjects.


Radio-immunological study of the regulation of interleukin-2 production in peripheral blood mononuclear cell cultures from normal subjects and rheumatoid arthritis patients.
A radio-immunoassay for human T cell growth factor, also called Interleukin-2 (IL-2), has been carried out using a recombinant IL-2 preparation as tracer and a polyclonal rabbit antiserum. The assay is highly specific for IL-2: there is no cross-reaction with either type I and II interferons, epidermal growth factor or tumor necrosis factor alpha. Using the sequential saturation procedure the limit of sensitivity was 0.5 U/ml. Intra- and between-assay coefficients of variation were 8 and 11%, respectively. With this assay, IL-2 recovery in serum and peripheral blood mononuclear cell culture (P.B.M.C.) medium was 79 and 95%, respectively. In serum of 109 normal subjects and 102 rheumatoid arthritis patients mean IL-2 concentrations (+/- SD) were 1.5 +/- 0.5 U/ml and 1.4 +/- 0.4 U/ml respectively. The IL-2 production by P.B.M.C. in vitro was also studied. In unstimulated cultures, IL-2 release remained undetectable, i.e. below 0.5 U/ml. After stimulation of mononuclear cells from 36 normal subjects with increasing amounts of phytohemagglutinin (PHA), the 3H-thymidine incorporation followed a bell-shaped curve, the maximum response being observed at a 2.5 micrograms/ml PHA concentration. After a 72-hr mononuclear cell stimulation, IL-2 release increases with PHA concentrations ranging from 0 to 10 micrograms/ml. In patients with rheumatoid arthritis (R.A.), P.B.M.C. incorporated 3H-thymidine as in normal subjects. In contrast, mean +/- SEM IL-2 production by P.B.M.C. from patients with inactive RA (5 +/- 0.9) and active disease (1 +/- 0.5) was significantly lower than that from normal subjects (12 +/- 0.7 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)


Antagonism of cytotoxic chemotherapy in neuroblastoma cell lines by 13-cis-retinoic acid is mediated by the antiapoptotic Bcl-2 family proteins.
13-cis-Retinoic acid (13-cis-RA) is given at completion of cytotoxic therapy to control minimal residual disease in neuroblastoma. We investigated the effect of combining 13-cis-RA with cytotoxic agents employed in neuroblastoma therapy using a panel of 6 neuroblastoma cell lines. The effect of 13-cis-RA on the mitochondrial apoptotic pathway was studied by flow cytometry, cytotoxicity by DIMSCAN, and protein expression by immunoblotting. Pretreatment and direct combination of 13-cis-RA with etoposide, topotecan, cisplatin, melphalan, or doxorubicin markedly antagonized the cytotoxicity of those agents in 4 out of 6 tested neuroblastoma cell lines, increasing fractional cell survival by 1 to 3 logs. The inhibitory concentration of drugs (IC(99)) increased from clinically achievable levels to nonachievable levels, greater than 5-fold (cisplatin) to greater than 7-fold (etoposide). In SMS-KNCR neuroblastoma cells, 13-cis-RA upregulated expression of Bcl-2 and Bcl-xL RNA and protein, and this was associated with protection from etoposide-mediated apoptosis at the mitochondrial level. A small molecule inhibitor of the Bcl-2 family of proteins (ABT-737) restored mitochondrial membrane potential loss and apoptosis in response to cytotoxic agents in 13-cis-RA treated cells. Prior selection for resistance to RA did not diminish the response to cytotoxic treatment. Thus, combining 13-cis-RA with cytotoxic chemotherapy significantly reduced the cytotoxicity for neuroblastoma in vitro, mediated at least in part via the antiapoptotic Bcl-2 family of proteins.


Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline.
A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.


Monoclonal antibodies reactive with the breast carcinoma-associated mucin core protein repeat sequence peptide also recognise the ovarian carcinoma-associated sebaceous gland antigen.
The monoclonal antibody (Mab) OM-1, which defines the ovarian carcinoma-associated sebaceous gland antigen (SGA), and Mab F36/22, which defines the ductal carcinoma antigen (DCA), were tested for reactivity against a synthetic peptide representing the repeat twenty amino acid sequence of the human polymorphic epithelial mucin core protein plus four amino acids of the adjacent sequence (p1-24). OM-1 bound strongly to the peptide by direct dot blot assay and ELISA and the minimum epitope for OM-1 was shown to be APDTRP(A) by inhibition assay. F36/22 reacted weakly with the peptide under the same conditions and its affinity for peptide in solution was relatively very low. Mab OC125, which defines the ovarian cancer-associated antigen CA125, did not react with the p1-24 peptide. Five other anti-mucin Mabs (HMFG1, HMFG2, BC1, BC2, BC3), previously shown to bind to the p1-24 peptide, reacted strongly with SGA by direct binding and in a sandwich assay with OM-1 as the capture Mab. F36/22 was weakly positive under the same conditions suggesting that both peptide and SGA do not express the optimal epitope for F36/22 binding. These results indicate that SGA and possibly DCA have the repeat sequence core protein of the breast carcinoma-associated human polymorphic epithelial mucin.


Improving Anticoagulation Measurement Novel Warfarin Composite Measure.
Percent time in therapeutic range (TTR) and international normalized ratio (INR) variability both measure warfarin control and are associated with outcomes independently. Here, we examine the advantages of a warfarin composite measure (WCM), which summarizes the 2 when measuring patient outcomes. We also examine how the measure chosen would affect anticoagulation clinic performance rankings. We constructed WCM using an equally weighted method, adding standardized TTR to standardized log-transformed INR variability using 103 897 warfarin-experienced patients from 100 anticoagulation clinics. We examined the association of WCM with ischemic stroke, major bleeding, and fatal bleeding, using a subset of patients with atrial fibrillation (n=40 404). We divided patients into quintiles based on their level of control for TTR, log INR variability, and WCM. We calculated the hazard ratios for ischemic stroke, major bleeding, and fatal bleeding stratified by these quintiles. WCM hazard ratios for stroke and fatal bleeding showed the largest difference between excellent control and poorest control quintile compared with TTR and log INR variability, but not for major bleeding. In addition, we compared site rankings obtained using each of our 3 performance measures. Kappa scores for identifying outlier and nonoutlier clinics between WCM and its components were moderate (κ=0.56 for TTR and κ=0.62 for log INR variability) but was weak between TTR and log INR variability (κ=0.13). WCM produces the largest range of risk for warfarin complications, widening the floor ceiling effects that limit the use of TTR and INR variability as separate measures. Anticoagulation clinics ranking changed considerably according to the anticoagulation measure that was selected.


Hebb repetition effects for non-verbal visual sequences: determinants of sequence acquisition.
We report four experiments premised upon the work of Horton et al. [(2008). Hebb repetition effects in visual memory: The roles of verbal rehearsal and distinctiveness. Quarterly Journal of Experimental Psychology, 61(12), 1769-1777] and Page et al. [(2013). Repetition-spacing and item-overlap effects in the Hebb repetition task. Journal of Memory and Language, 69(4), 506-526], and explore conditions under which the visual Hebb repetition effect is observed. Experiment 1 showed that repetition learning is evident when the items comprising the non-repeated (filler) sequences and the repeated (Hebb) sequences are different (no-overlap). However, learning is abolished when the filler and Hebb sequences comprise the same items (full-overlap). Learning of the repeated sequence persisted when repetition spacing was increased to six trials (Experiment 2), consistent with that shown for verbal stimuli (Page et al., 2013). In Experiment 3, it was shown that learning for the repeated sequence is accentuated when the output motor response at test is also repeated for the Hebb sequence, but only under conditions of no-overlap. In Experiment 4, repetition spacing was re-examined with a repeated motor output response (a closer methodological analogue to Page et al., 2013). Under these conditions, the gradient of Hebb repetition learning for six trial repetition intervals was markedly similar to that for three trial intervals. These findings further support the universality of the Hebb repetition effect across memory and are discussed in terms of evidence for amodality within-sequence memory.


[Decreased incidence in HIV infection and changed sex behavior in a cohort of homosexual men in Amsterdam].
Prevalence and incidence of HIV were studied in two cohorts of homosexual men in Amsterdam between 1980 and 1987. The cumulative incidence of HIV infection increased from a weighted 2.2% in 1980 to 39% in 1987. In that year the observed incidence was less than 1%. The estimated annual HIV incidence was 3% in 1981, rose to 8.8% in 1984 and decreased gradually to 0% in 1987. This decline was assumed to be linked to a strong reduction of high risk sexual behaviour among the men under study.


Soluble donor DNA and islet injury after transplantation.
A large proportion of clinical islet transplant recipients fail to initially achieve or sustain meaningful independence from exogenous insulin use. We hypothesized that immediate allograft injury is a key constraint on independence from exogenous insulin use. Standard human leukocyte antigen genotyping was reviewed to identify nonshared polymorphisms between 21 prospectively recruited islet transplant recipients from a single institution and their respective donors. Human leukocyte antigen polymorphism-specific quantitative polymerase chain reaction was used to quantify donor DNA shed into blood by injured islets from serial sera acquired over the first 10 days postprocedure and examined for correlation with achievement of insulin independence. Nearly fourfold higher serum concentrations of donor DNA were detected in subjects whose grafts failed to generate insulin independence. The median for the average area under the curve in recipients who did and did not achieve insulin independence was 12 (range, 1-61) and 45 (range, 14-255) donor genome equivalents (gEq)-day/mL (p=0.03), respectively. These findings represent the first direct testing of allograft injury in humans undergoing islet cell transplantation. Injury to donor islets very soon after transplantation may represent an important barrier to achieving insulin independence other than adaptive immune responses targeting allografts at later times. In addition, soluble donor DNA merits further development as a quantifiable biomarker to evaluate new interventions aimed at mitigating immediate islet injury.


Evaluation of the outcomes of ice application for the control of pain associated with chest tube irritation.
The aim of this study was to evaluate the effectiveness of the use of ice for the control of pain associated with chest tube irritation. The randomized and single-blinded study consisted of 40 patients (20 in the control and 20 in the study group) who underwent thoracotomy with chest tube placement. The same general anesthesia protocol was used for all patients, and the procedure was performed by the same surgery team. Procedures such as decortication and thoracic wall resection were not included in the study. Standard postoperative analgesic methods were applied to all patients. Additionally, ice (in flexible and bendable cold gel packs wrapped in fine cloth sheaths) was applied to the chest tube insertion site at the 24th, 28th, 36th, and 40th postoperative hours for 20 minutes. To assess the effectiveness of ice application, Verbal Category Scale and Behavioral Pain Scale methods were used to measure the severity of pain. Average pain severity scores during the mobilization activities, including coughing and walking, were compared and found to be significantly lower in the study group patients who received cold therapy than in the control group patients (p < .05). Additionally, analgesic consumption was lower in the study group than in the control group patients (p < .05). As a result, the application of ice to the chest tube insertion site reduced pain associated with irritation along with the need for analgesics.


The influence of gender on early adverse events, hospital charges and length of stay after shoulder arthroplasty.
To identify differences in demographics, diagnosis, arthroplasty type, early adverse events, length of stay, and hospital costs between men and women undergoing shoulder arthroplasty. We used a nationally representative U.S. population database to determine annual rates of shoulder arthroplasty (SA) in patients (2002-2011). Early adverse events, length-of-stay and hospitalization costs were determined, and compared between patient genders. A cohort of 372,753 patients underwent total-SA (TSA) (59.7% females). Females were significantly older, more often had Medicare insurance, had a higher proportion of fracture diagnosis, more often underwent hemiarthroplasty (HA), and had significantly lower odds of any adverse event, MI, and sepsis, but higher odds of peripheral nerve injury. Females had significantly greater hospital lengths of stay for all combined procedures, and isolated TSA, reverse-TSA, and HA. Hospital costs were significantly lower in females for all combined procedures and HA. Male patients had significantly higher odds of adverse events, death, MI, and sepsis following SA. Female patients had significantly longer lengths of stay but lower hospital charges following SA.


Thrombocytopenia associated with carbamazepine: case report and review.
A case of thrombocytopenia associated with carbamazepine use is reported, and previous reports of adverse hematologic effects in patients taking carbamazepine are discussed. With increasing use of carbamazepine in the treatment of affective disorders, psychiatrists will need to be aware of the drug's hematologic side effects, and institute appropriate monitoring procedures.


Forecasting Cytokine Storms with New Predictive Biomarkers.
T cells genetically modified with CD19 chimeric antigen receptors have produced impressive clinical responses in patients with refractory B-cell malignancies, but therapeutic responses are often accompanied by cytokine release syndrome (CRS), which can cause significant morbidity and mortality. Teachey and colleagues have identified predictive biomarkers for this complication that may allow testing of earlier intervention with agents such as the IL6 receptor blocker tocilizumab to evaluate whether CRS can be ameliorated without jeopardizing clinical responses. Cancer Discov; 6(6); 579-80. ©2016 AACR.See related article by Teachey et al., p. 664.


Cartilage oligomeric matrix protein induction of chronic arthritis in mice.
To develop a new mouse model for arthritis using cartilage oligomeric matrix protein (COMP) and to study the role of major histocompatibility complex (MHC) and Ncf1 genes in COMP-induced arthritis (COMPIA). Native (pentameric) and denatured (monomeric) COMP purified from a rat chondrosarcoma was injected into mice with Freund's adjuvant to induce arthritis. C3H.NB, C3H.Q, B10.P, B10.Q, (B10.Q x DBA/1)F1, (BALB/c x B10.Q)F1, Ncf1 mutated, H-2Aq, H-2Ap, and human DR4+-transgenic mice were used. Anti-COMP antibodies and COMP levels in the immune sera were analyzed, and passive transfer of arthritis with purified immune sera was tested. Immunization with rat COMP induced a severe, chronic, relapsing arthritis, with a female preponderance, in the mice. The disease developed in C3H.NB mice, but not in B10.P mice, although they share the same MHC haplotype. Both H-2q and H-2p MHC haplotypes allowed the initiation of COMPIA. Using H-2Aq-transgenic and H-2Ap-transgenic mice, we demonstrated a role of both the Aq and Ep class II molecules in this model. Interestingly, the introduction of a mutation in the Ncf1 gene, which is responsible for the reduced oxidative burst phenotype, into the COMPIA-resistant B10.Q mouse strain rendered them highly susceptible to arthritis. In addition, the transfer of anti-COMP serum was found to induce arthritis in naive mice. Mice transgenic for the rheumatoid arthritis (RA)-associated DR4 molecule were found to be highly susceptible to COMPIA. Using rat COMP, we have developed a new and unique mouse model of chronic arthritis that resembles RA. This model will be useful as an appropriate and alternative model for studying the pathogenesis of RA.