Monoclonal LYM-1 antibody-dependent cytolysis by human neutrophils exposed to GM-CSF: auto-regulation of target cell attack by cathepsin G.
Murine monoclonal antibody (mAb) Lym-1 is an immunoglobulin G2a specific for certain human leukocyte antigen-DR variants expressed on the surface of malignant B cells. It has been proposed for serotherapy in patients with B lymphomas. We have previously shown that mAb Lym-1 synergizes with granulocyte macrophage-colony stimulating factor to promote Raji B-lymphoid cell lysis by human neutrophils via the intervention of neutrophil Fc receptors type II and D-mannose-inhibitable interactions between CD11b-CD18 integrins and CD66b glycoproteins. Here, we provide evidence that the process is oxygen-independent by inference related to the release of primary granules and is regulated by cathepsin G activity. The lysis was indeed reproduced by replacing normal neutrophils with cells from three patients suffering from chronic granulomatous disease, i.e., neutrophils genetically incapable of generating oxidants. Moreover, the lysis was inhibited by the serine protease inhibitor 3,4-dichloroisocoumarin and by Z-glycyl-leucyl-phenyl-chloromethyl ketone (Z-Gly-Leu-Phe-CMK), which blocks cathepsin G. Conversely, the lysis was unaffected by N-methoxysuccinyl-alanyl-alanyl-prolyl-alanyl-CMK (MeOSuc-Ala-Ala-Pro-Ala-CMK; elastase inhibitor) and MeOSuc-Ala-Ala-Pro-valine (Val)-CMK, which inhibits elastase and proteinase 3. The ability of neutrophils, engaged in cytolysis, to release cathepsin G was proved by detecting this enzymatic activity spectrophotometrically and immunocytochemically. Moreover, inhibition of cathepsin G activity by concentrations of Z-Gly-Leu-Phe-CMK, incapable of affecting elastase activity, was found to reduce the release of elastase and myeloperoxidase from neutrophils under conditions similar to those used for cytolytic assays. These findings suggest that neutrophils auto-regulate their lytic efficiency by controlling the exocytosis of primary granules via their cathepsin G activity.


A radiometric assay for glutamine:fructose-6-phosphate amidotransferase.
Glutamine:fructose-6-phosphate amidotransferase (GFAT) catalyzes the first step in the biosynthesis of amino sugars by transferring the amino group from l-glutamine to the acceptor substrate, fructose 6-phosphate, generating the products glucosamine 6-phosphate and glutamic acid. We describe a method for the synthesis and purification of the substrate, fructose 6-phosphate, and methods for a radiometric assay of human GFAT1 that can be performed in either of two formats: a small disposable-column format and a high-throughput 96-well-plate format. The method performed in the column format can detect 1 pmol of glucosamine 6-phosphate, much less than that required by previously published assays that measure GlcN 6-phosphate. The column assay demonstrates a broad linear range with low variability. In both formats, the assay is linear with time and enzyme concentration and is highly reproducible. This method greatly improves the sensitivity and speed with which GFAT1 activity can be measured and facilitates direct kinetic measurement of the transferase activity.


Enhanced Performance of Planar Perovskite Solar Cells Using Low-Temperature Solution-Processed Al-Doped SnO2 as Electron Transport Layers.
Lead halide perovskite solar cells (PSCs) appear to be the ideal future candidate for photovoltaic applications owing to the rapid development in recent years. The electron transport layers (ETLs) prepared by low-temperature process are essential for widespread implementation and large-scale commercialization of PSCs. Here, we report an effective approach for producing planar PSCs with Al3+ doped SnO2 ETLs prepared by using a low-temperature solution-processed method. The Al dopant in SnO2 enhanced the charge transport behavior of planar PSCs and increased the current density of the devices, compared with the undoped SnO2 ETLs. Moreover, the enhanced electrical property also improved the fill factors (FF) and power conversion efficiency (PCE) of the solar cells. This study has indicated that the low-temperature solution-processed Al-SnO2 is a promising ETL for commercialization of planar PSCs.


Leptin prevents fasting-mediated reductions in pulsatile secretion of luteinizing hormone and enhances its gonadotropin-releasing hormone-mediated release in heifers.
We tested the hypothesis that leptin could prevent fasting-mediated reductions in pulsatile secretion and modify GnRH-mediated release of LH in heifers approaching puberty. Thirteen crossbred, prepubertal heifers (13.5-16 mo; 280-350 kg) exhibiting frequencies of pulses of LH between 0.67 and 1 pulse/h, were assigned randomly to two groups: 1). control (n = 6), fasted for 72 h with s.c. injections of saline at 12-h intervals, and 2). leptin (n = 7), fasted for 72 h with s.c. injections of oleptin (19.2 microg/kg) at 12-h intervals. Blood samples were collected intensively for 6 h on Days 0 and 3. This was followed on Day 3 with sequential administration of physiological (0.0011 microg/kg, i.v.) and pharmacological (0.22 microg/kg, i.v.) doses of GnRH and additional blood sampling. Leptin treatment increased (P = 0.0003) plasma concentrations of leptin 5-6-fold compared to controls. Fasting caused a marked decline (P = 0.01) between Days 0 and 3 in the frequency of LH pulses in controls; however, this effect was prevented in the leptin group, with pulse frequency increasing (P < 0.008) from Day 0 to 3. Leptin treatment increased GnRH-induced release of LH at both low (P = 0.04) and high (P = 0.02) doses. Plasma insulin and insulin-like growth factor-1 were reduced by fasting and unaffected by leptin. Leptin increased mean concentrations of growth hormone. Results indicate, for the first time, that exogenous leptin can prevent fasting-mediated reductions in the frequency of LH pulses and modify GnRH-mediated release of LH in intact, prepubertal heifers.


Pathophysiological significance of a reaction in mouse gastrointestinal tract associated with delayed-type hypersensitivity.
To explore the pathophysiological significance of delayed type hypersensitivity (DTH) reaction in mouse gastrointestinal tract induced by an allergen 2,4-dinitrochlorobenzene (DNCB). BALB/c mice were randomly divided into control and DTH(1-6) groups. After sensitized by DNCB smeared on the abdominal skin, the mice were challenged with DNCB by gavage or enema. The weight, stool viscosity and hematochezia were observed and accumulated as disease active index (DAI) score; the gastrointestinal motility was represented by active charcoal propulsion rate; the colon pathological score was achieved by macropathology and HE staining of section prepared for microscopy; and the leukocyte migration inhibitory factor (LMIF) activity was determined by indirect capillary assay of the absorbance (A) of migrated leukocytes. Active charcoal propulsion rates of small intestine in the DNCB gavages groups were significantly higher than that in the control group (P<0.01). The DAI scores and pathological score in DNCB enema groups were also higher than that in the control group (P<0.05), and there were significant rises in LMIF activity in DNCB enema groups as compared with control groups (P<0.01). Mouse gastrointestinal DTH reaction could be induced by DNCB, which might facilitate the mechanism underlying the ulcerative colitis.


Risk and Protective Factors for Suicidal Behaviors Among Pacific Youth in New Zealand.
New Zealand has the second highest youth suicide rate in the OECD and particularly among Pacific New Zealanders, who have a threefold higher risk of suicide attempt compared with the general population. Protective and risk factors for suicide attempts among New Zealand Pacific adolescents were assessed using data from Youth'12, an adolescent health and well-being survey. This randomly selected nationally representative sample of New Zealand secondary school students included 1,445 Pacific high school students aged 12-17 years. One in 10 (11.6%) Pacific adolescents reported attempting suicide. Risk factors for suicide included: being female, household food insecurity, low levels of family connections and family monitoring, life dissatisfaction, having a religious affiliation, and previous suicide by a family member or friend. Of those who had made a suicide attempt, 71% also experienced both suicide ideation and self-harm. This study suggests that given the high rates of suicide ideation and attempts among Pacific young people, targeted trials for new ways of support should be prioritized for this high-risk group. The Pacific family environment, which continues to be the critical space for intervening, and the school environment, as a provider of health services, were both protective of suicide attempt.


Randomised, double blind, placebo controlled trial of inosine pranobex in rheumatoid arthritis.
In a randomised, placebo controlled, double blind study inosine pranobex was assessed as a possible second line drug in rheumatoid arthritis. Twenty four patients received inosine pranobex (3 g/day) and 26 patients received placebo for up to 24 weeks. Morning stiffness, articular index, grip strength, pain score, erythrocyte sedimentation rate, C reactive protein, IgG, IgM, and serum urate were assessed at weeks 0, 12, and 24. Baseline characteristics were similar except for a significantly higher C reactive protein in the placebo group. No significant improvement occurred in any variable: (a) when comparing week 0 with week 12 or week 24 for either group, (b) comparing active drug with placebo at week 12 or 24, or (c) taking all 50 patients as one group. Withdrawal from the study for lack of response or side effects was similar in both groups. Serum urate increased transiently but significantly with inosine pranobex (a recognised side effect). It is concluded that inosine pranobex has no second line activity in rheumatoid arthritis. Further, 50 patients effectively given placebo showed no spontaneous improvement in their disease activity.


Genetic influences on hub connectivity of the human connectome.
Brain network hubs are both highly connected and highly inter-connected, forming a critical communication backbone for coherent neural dynamics. The mechanisms driving this organization are poorly understood. Using diffusion-weighted magnetic resonance imaging in twins, we identify a major role for genes, showing that they preferentially influence connectivity strength between network hubs of the human connectome. Using transcriptomic atlas data, we show that connected hubs demonstrate tight coupling of transcriptional activity related to metabolic and cytoarchitectonic similarity. Finally, comparing over thirteen generative models of network growth, we show that purely stochastic processes cannot explain the precise wiring patterns of hubs, and that model performance can be improved by incorporating genetic constraints. Our findings indicate that genes play a strong and preferential role in shaping the functionally valuable, metabolically costly connections between connectome hubs.


SNP-based association analysis for seedling traits in durum wheat (Triticum turgidum L. durum (Desf.)).
In the present study, 150 accessions of worldwide originated durum wheat germplasm (Triticum turgidum spp. durum) were observed for major seedling traits and their growth. The accessions were evaluated for major seedling traits under controlled conditions of hydroponics at the 13th, 20th, 27th and 34th day-after germination. Biomass traits were measured at the 34th day-after germination. Correlation analysis was conducted among the seedling traits and three field traits at maturity, plant height, grain weight and 1000-grain weight observed in four consecutive years. Associations of the measured seedling traits and SNP markers were analyzed based on the mixed linear model (MLM). The results indicated that highly significant genetic variation and robust heritability were found for the seedling and field mature traits. In total, 259 significant associations were detected for all the traits and four growth stages. The phenotypic variation explained (R2) by a single SNP marker is higher than 10% for most (84%) of the significant SNP markers. Forty-six SNP markers associated with multiple traits, indicating non-neglectable pleiotropy in seedling stage. The associated SNP markers could be helpful for genetic analysis of seedling traits, and marker-assisted breeding of new wheat varieties with strong seedling vigor.


Utilization of primary care among college students with mental health disorders.
Our goal was to assess whether integration of behavioral and medical services in college settings is associated with decreased use of primary care by patients with mental health diagnoses (MHDs). The cohort consisted of 80,219 patients with at least 1 MHD in 21 universities. Two levels of service integration were defined: "standard"-universities with separate electronic health records (EHR) systems and minimal clinical collaboration between services, and "enhanced"-universities with shared EHR and collaborative patient care. Frequency, the total number of primary care visits, and complexity, the total visit length for primary care per unit time, were compared by using multilevel models. Nine schools met the criteria of enhanced clinical integration; a tenth school shifted to enhanced service during the study period. Student and patient demographics and clinical diagnoses were similar between the 2 categories. When controlling for variance in age, sex, and total time in school, patients with MHDs in standard systems had 15.72% (95% confidence interval [CI]: 10.77%-20.44%) more primary care visits and 22.88% (95% CI: 21.42%-24.38%) more time than patients in enhanced systems. Students with MHDs have significantly lower utilization of primary care services in integrated health care systems, but only a minority of institutions nationally have adopted this model of care. Although further research is needed to specifically assess differences in health outcomes and perceived suffering, it is possible that reduced primary care visits in enhanced integrative service settings with robust mental health support indicates overall reduction in perceived suffering for patients/clients. (PsycINFO Database Record


Genetic variation of capsid protein VP7 in genotype g4 human rotavirus strains: simultaneous emergence and spread of different lineages in Argentina.
Rotavirus is the most-common cause of severe diarrhea in young children. Complete rotavirus characterization includes determination of the antigenic type of the two outer capsid proteins, VP7 and VP4, designated G and P types, respectively. During a nationwide rotavirus surveillance study, genotype G4 frequency increased during the second year. To evaluate further the mechanism of emergence and the relationship among G4 strains, the genetic diversity of VP7 capsid protein in these samples was studied in detail. Overall nucleotide sequence divergence ranged from less than 0.1 to 19.5%, a higher divergence than that observed for other rotavirus G types (0.1 to 9%). Sequences were classified into two major lineages (designated I and II) based on their nucleotide distances. The most heterogeneous lineage was further subdivided into four sublineages (designated Ia to Id). Most Argentine sequences were of sublineages Ib and Ic, which were confirmed to be independent sequence clusters by parsimony analysis. This study describes different lineages and sublineages within G4 strains and shows that Argentine strains are distantly related to reference strain ST3. The appearance of at least two G4 genotype (sub)lineages during 1998 demonstrates that the increased frequency of these strains was due to the synchronized emergence of different groups of strains.


Power comparison between population-based case-control studies and family-based transmission-disequilibrium tests: An empirical study.
THERE ARE TWO MAJOR CLASSES OF GENETIC ASSOCIATION ANALYSES: population based and family based. Population-based case-control studies have been the method of choice due to the ease of data collection. However, population stratification is one of the major limitations of case-control studies, while family-based studies are protected against stratification. In this study, we carry out extensive simulations under different disease models (both Mendelian as well as complex) to evaluate the relative powers of the two approaches in detecting association. The power comparisons are based on a case-control design comprising 200 cases and 200 controls versus a Transmission Disequilibrium Test (TDT) or Pedigree Disequilibrium Test (PDT) design with 200 informative trios. We perform the allele-level test for case-control studies, which is based on the difference of allele frequencies at a single nucleotide polymorphism (SNP) between unrelated cases and controls. The TDT and the PDT are based on preferential allelic transmissions at a SNP from heterozygous parents to the affected offspring. We considered five disease modes of inheritance: (i) recessive with complete penetrance (ii) dominant with complete penetrance and (iii), (iv) and (v) complex diseases with varying levels of penetrances and phenocopies. We find that while the TDT/PDT design with 200 informative trios is in general more powerful than a case-control design with 200 cases and 200 controls (except when the heterozygosity at the marker locus is high), it may be necessary to sample a very large number of trios to obtain the requisite number of informative families. The current study provides insights into power comparisons between population-based and family-based association studies.


Pro-angiogenic Activity Discriminates Human Adipose-Derived Stromal Cells From Retinal Pericytes: Considerations for Cell-Based Therapy of Diabetic Retinopathy.
Diabetic retinopathy (DR) is a frequent diabetes-associated complication. Pericyte dropout can cause increased vascular permeability and contribute to vascular occlusion. Adipose-derived stromal cells (ASC) have been suggested to replace pericytes and restore microvascular support as potential therapy of DR. In models of DR, ASC not only generated a cytoprotective and reparative environment by the secretion of trophic factors but also engrafted and integrated into the retina in a pericyte-like fashion. The aim of this study was to compare the pro-angiogenic features of human ASC and human retinal microvascular pericytes (HRMVPC) in vitro. The proliferation and the expression of ASC and HRMVPC markers were compared. Adhesion to high glucose-conditioned endothelial extracellular matrix, mimicking the diabetic microenvironment, was measured. The angiogenesis-promoting features of both cell types and their conditioned media on human retinal endothelial cells (EC) were assessed. To identify a molecular basis for the observed differences, gene expression profiling was performed using whole-genome microarrays, and data were validated using PCR arrays and flow cytometry. Based on multiplex cytokine results, functional studies on selected growth factors were performed to assess their role in angiogenic support. Despite a distinct heterogeneity in ASC and HRMVPC cultures with an overlap of expressed markers, ASC differed functionally from HRMVPC. Most importantly, the pro-angiogenic activity was solely featured by ASC, whereas HRMVPC actively suppressed vascular network formation. HRMVPC, in contrast to ASC, showed impaired adhesion and proliferation on the high glucose-conditioned endothelial extracellular matrix. These data were supported by gene expression profiles with differentially expressed genes. The vessel-stabilizing factors were more highly expressed in HRMVPC, and the angiogenesis-promoting factors were more highly expressed in ASC. The vascular endothelial growth factor receptor-2 inhibition efficiently abolished the ASC angiogenic supportive capacities, whereas the addition of angiopoietin-1 and angiopoietin-2 did not alter these effects. Our results clearly show that ASC are pro-angiogenic, whereas HRMVPC are marked by anti-angiogenic/EC-stabilizing features. These data support ASC as pericyte replacement in DR but also suggest a careful risk-to-benefit analysis to take full advantage of the ASC therapeutic features.


Lipid droplets in stress protection: distinct mechanisms of lipid droplet microautophagy.
Lipid droplets (LDs) are organelles that function as sites for lipid storage. LDs have also been implicated in the cellular response to proteotoxic or lipotoxic stress as sites for sequestering dysfunctional or excess proteins or lipids, and targeting those cargos for degradation by LD microautophagy (microlipophagy, μLP). Here, we describe two mechanisms for μLP in yeast, which are triggered by different stressors. μLP occurs at raft-like liquid ordered microdomains in the vacuolar membrane in yeast exposed to severe nutrient limitations. In contrast, in yeast exposed to ER stress or less severe nutrient limitations, LD uptake at the vacuole is liquid ordered (Lo) microdomain-independent and dependent upon vacuolar membrane remodeling mediated by endosomal sorting complexes required for transport (ESCRT).


Self-Defensive Antimicrobial Surfaces Using Polymyxin-Loaded Poly(styrene sulfonate) Microgels.
Self-defensive antimicrobial surfaces are of interest because they can inhibit bacterial colonization while minimizing unnecessary antimicrobial release in the absence of a bacterial challenge. One self-defensive approach uses self-assembly to first deposit a submonolayer coating of polyelectrolyte microgels and subsequently load those microgels by complexation with small-molecule antimicrobials. The microgel/antimicrobial complexation strength is a key parameter that controls the ability of the antimicrobial both to remain sequestered within the microgels when exposed to medium and to release in response to a bacterial challenge. Here we study the relative complexation strengths of two FDA-approved cationic antibiotics─colistin (polymyxin E) and polymyxin B─with microgels of poly(styrene sulfonate) (PSS). These polymyxins are similar cyclic polypeptides with +5 charge at pH 7.4. However, polymyxin B substitutes an aromatic ring for a dimethyl moiety in colistin, and this aromaticity can influence complexation via π and hydrophobic interactions. Coarse-grained molecular dynamics shows that the free-energy change associated with polymyxin B/PSS complexation is more negative than that of colistin/PSS complexation. Experimentally, in situ optical microscopy of microgel deswelling shows that both antibiotics load quickly from low-ionic-strength phosphate buffer. The enhanced polymyxin B/PSS complexation strength is then manifested by subsequent exposure to flowing antibiotic-free buffer with varying NaCl concentration. Microgels loaded with polymyxin B remain stably deswollen to higher salt concentrations than do colistin/PSS microgels. Importantly, exposing loaded microgels to E. coli in nutrient-free-flowing phosphate buffer shows that bacteria are killed by physical contact with the loaded microgels consistent with the contact-transfer mechanism of self-defensiveness. In vitro culture experiments show that these same surfaces, nevertheless, support the adhesion, spreading and proliferation of human fetal osteoblasts. These findings suggest a pathway to create a self-defensive antimicrobial surface effective under physiological conditions based on the nonmetabolic bacteria-triggered release of FDA-approved antibiotics.


New Doppler ultrasound signs improve the non-invasive diagnosis of cirrhosis or severe liver fibrosis.
To determine whether ultrasound and, particularly, new Doppler signs increased the diagnostic accuracy of the most accurate, currently available markers for the diagnosis of cirrhosis or severe fibrosis. Thirty-two clinical (n = 4), biochemical (n = 11) and Doppler ultrasound (n = 17) variables were recorded in 106 patients with compensated chronic liver disease. Diagnostic accuracy was evaluated by discriminant analysis; first, globally, using all variables then by stepwise analysis. (A) Diagnosis of cirrhosis. Using Doppler ultrasound, diagnostic accuracy was 92% (95% confidence interval 81-98) globally, and 89% (76-95) with three variables (spleen length, hepatic vein spectrum and maximum portal vein velocity). Based upon clinical signs, diagnostic accuracy was 86% (77-92) globally, and 85% (76-91) with one variable (firm liver). Based upon biochemical parameters, diagnostic accuracy was 80% (70-88) globally, and 81% (72-88) with two variables (hyaluronate and platelet count). Based upon all parameters, diagnostic accuracy was 91% (79-96.5) globally, and 91% (79-96.5) with four variables (firm liver, hyaluronate, platelet and hepatic vein spectrum). On an intention to diagnose basis, Doppler ultrasound provided a lower independent contribution due to missing data. (B) In the diagnosis of severe fibrosis, diagnostic accuracy was 83% (69-92) globally, and 77% (62-87) with one variable. Cirrhosis can be correctly diagnosed in approximately 90% of patients with compensated chronic liver disease using a few Doppler ultrasound signs including a new sign, the hepatic vein spectrum. Doppler ultrasound could be used for the first line diagnosis and biochemical markers, such as hyaluronate, in patients with missing Doppler ultrasound data.


Inactivation of BAD by IKK inhibits TNFα-induced apoptosis independently of NF-κB activation.
The IκB kinase complex (IKK) is a key regulator of immune responses, inflammation, cell survival, and tumorigenesis. The prosurvival function of IKK centers on activation of the transcription factor NF-κB, whose target gene products inhibit caspases and prevent prolonged JNK activation. Here, we report that inactivation of the BH3-only protein BAD by IKK independently of NF-κB activation suppresses TNFα-induced apoptosis. TNFα-treated Ikkβ(-/-) mouse embryonic fibroblasts (MEFs) undergo apoptosis significantly faster than MEFs deficient in both RelA and cRel due to lack of inhibition of BAD by IKK. IKK phosphorylates BAD at serine-26 (Ser26) and primes it for inactivation. Elimination of Ser26 phosphorylation promotes BAD proapoptotic activity, thereby accelerating TNFα-induced apoptosis in cultured cells and increasing mortality in animals. Our results reveal that IKK inhibits TNFα-induced apoptosis through two distinct but cooperative mechanisms: activation of the survival factor NF-κB and inactivation of the proapoptotic BH3-only BAD protein.


Covalent ISG15 conjugation to CHIP promotes its ubiquitin E3 ligase activity and inhibits lung cancer cell growth in response to type I interferon.
The carboxyl terminus of Hsp70-interacting protein (CHIP) acts as a ubiquitin E3 ligase and a link between the chaperones Hsp70/90 and the proteasome system, playing a vital role in maintaining protein homeostasis. CHIP regulates a number of proteins involved in a myriad of physiological and pathological processes, but the underlying mechanism of action via posttranslational modification has not been extensively explored. In this study, we investigated a novel modulatory mode of CHIP and its effect on CHIP enzymatic activity. ISG15, an ubiquitin-like modifier, is induced by type I interferon (IFN) stimulation and can be conjugated to target proteins (ISGylation). Here we demonstrated that CHIP may be a novel target of ISGylation in HEK293 cells stimulated with type I IFN. We also found that Lys143/144/145 and Lys287 residues in CHIP are important for and target residues of ISGylation. Moreover, ISGylation promotes the E3 ubiquitin ligase activity of CHIP, subsequently causing a decrease in levels of oncogenic c-Myc, one of its many ubiquitination targets, in A549 lung cancer cells and inhibiting A549 cell and tumor growth. In conclusion, the present study demonstrates that covalent ISG15 conjugation produces a novel CHIP regulatory mode that enhances the tumor-suppressive activity of CHIP, thereby contributing to the antitumor effect of type I IFN.


The repair of large incisional hernias.
An old technique for the repair of incisional hernias, but with the use of Marlex mesh instead of fascia lata, was used in eight cases, with good results for the limited time the patients have been observed. The operation involves the use of a multifingered sheet of Marlex mesh, a material with characteristics that make it ideal for repair of large hernias.


Peripheral CCL2 induces inflammatory pain via regulation of Ih currents in small diameter DRG neurons.
The C-C motif chemokine ligand 2 (CCL2) has been implicated in chronic pain, but its exact mechanism of peripheral sensitization is unknown. In this study, we aimed to clarify the mechanism of CCL2 regulation of ion channels. Our behavioral experiments revealed that ZD7288, a blocker of Ih current, can inhibit CFA and CCL2-mediated mechanical and thermal nociceptive sensitization. Furthermore, patch clamp studies demonstrated that CFA-induced peripheral sensitization primarily affects the excitability of small-diameter DRG neurons. Further studies revealed that inflammatory pain caused by CFA or incubation of DRG with CCL2 mainly affected Ih currents in small-diameter DRG neurons, which were blocked by co-incubation CCR2 antagonist INCB3344 or adenylate cyclase inhibitor SQ22536. Immunohistochemical staining showed that both intraplantar injection of CFA as well as DRG injection of CCL2 resulted in significant upregulation of CCR2+/HCN2+ expression. In conclusion, we suggest in the inflammatory pain state, CCL2 can act on small-diameter DRG neurons, leading to upregulation of HCN2 expression and consequently Ih, which in turn leads to neuronal hyperexcitability.


The UK Centre for Astrobiology: A Virtual Astrobiology Centre. Accomplishments and Lessons Learned, 2011-2016.
The UK Centre for Astrobiology (UKCA) was set up in 2011 as a virtual center to contribute to astrobiology research, education, and outreach. After 5 years, we describe this center and its work in each of these areas. Its research has focused on studying life in extreme environments, the limits of life on Earth, and implications for habitability elsewhere. Among its research infrastructure projects, UKCA has assembled an underground astrobiology laboratory that has hosted a deep subsurface planetary analog program, and it has developed new flow-through systems to study extraterrestrial aqueous environments. UKCA has used this research backdrop to develop education programs in astrobiology, including a massive open online course in astrobiology that has attracted over 120,000 students, a teacher training program, and an initiative to take astrobiology into prisons. In this paper, we review these activities and others with a particular focus on providing lessons to others who may consider setting up an astrobiology center, institute, or science facility. We discuss experience in integrating astrobiology research into teaching and education activities. Key Words: Astrobiology-Centre-Education-Subsurface-Analog research. Astrobiology 18, 224-243.


A copper-based layered coordination polymer: synthesis, magnetic properties and electrochemical performance in supercapacitors.
A copper-based layered coordination polymer ([Cu(hmt)(tfbdc)(H2O)]; hmt = hexamethylenetetramine, tfbdc = 2,3,5,6-tetrafluoroterephthalate; Cu-LCP) has been synthesized, and it has been structurally and magnetically characterized. The Cu-LCP shows ferromagnetic interactions between the adjacent copper(II) ions. Density functional theory calculations on the special model of Cu-LCP support the occurrence of ferromagnetic interactions. As an electrode material for supercapacitors, Cu-LCP exhibits a high specific capacitance of 1274 F g(-1) at a current density of 1 A g(-1) in 1 M LiOH electrolyte, and the capacitance retention is about 88% after 2000 cycles.


CT of acquired cystic kidney disease and renal tumors in long-term dialysis patients.
The kidneys of long-term dialysis patients frequently demonstrate multiple small acquired cysts and renal cell tumors on pathologic examination. The original kidneys of 30 long-term dialysis patients and six renal transplant patients were evaluated by computed tomography to determine the incidence of these abnormalities. Among dialysis patients, 43.3% had diffuse bilateral cysts, while 16.7% had occasional cysts (fewer than five per kidney), and 40% showed no renal cysts. Seven solid renal tumors were detected in four dialysis patients with renal cysts. Acquired cystic kidney disease tends to result in renal enlargement, is more common in patients who have been maintained on dialysis for prolonged periods, and may lead to spontaneous renal hemorrhage. The six transplant patients showed no evidence of renal cysts, and all had markedly shrunken kidneys. Acquired cystic disease and renal cell tumors in the original kidneys of dialysis patients may be due to biologically active substances that are not cleared effectively by dialysis but that are removed by normally functioning transplant kidneys.


Relation of metabolic syndrome with long-term mortality in acute and stable coronary disease.
Past studies examining the effects of the metabolic syndrome (MS) on prognosis in postangiography patients were limited in size or were controversial in results. The aim of the study was to examine the association of the MS and the risk for long-term mortality in a large cohort of patients undergoing coronary angiography for various clinical indications. Medical history, physical examination, and laboratory values were used to diagnose patients with the MS. Cox regression models were used to analyze the effect of MS on long-term all-cause mortality. We prospectively recruited 3,525 consecutive patients with a mean age of 66 ± 22 years (range 24 to 97) and 72% men. Thirty percent of the cohort had MS. Patients with MS were more likely to have advanced coronary artery disease and acute coronary syndrome (p <0.001). Patients with MS had more abnormalities in their metabolic and inflammatory biomarkers regardless of their clinical presentation. A total of 495 deaths occurred during a mean follow-up period of 1,614 ± 709 days (median 1,780, interquartile range 1,030 to 2,178). MS was associated with an increased risk of death in the general cohort (hazard ratio [HR] 1.27, 95% confidence interval [CI] 1.01 to 1.56, p = 0.02). MS had a significant effect on mortality in stable patients (HR 1.55, 95% CI 1.1 to 2.18, p = 0.01), whereas it did not have a significant effect on mortality in patients with acute coronary syndrome (HR 1.11, 95% CI 0.86 to 1.44, p = 0.42). In conclusion, MS is associated with increased mortality in postangiography patients. Its adverse outcome is mainly seen in patients with stable angina.


Severe hypertriglyceridemia and acute pancreatitis during pregnancy: treatment with gemfibrozil.
To describe the effect of gemfibrozil therapy during pregnancy in a woman with severe hypertriglyceridemia. We present a case report, with details of lipid levels throughout several attempted pregnancies, and discuss other similar published studies. In a 22-year-old woman, severe acute pancreatitis due to hypertriglyceridemia developed during her first pregnancy. After a prolonged hospital course, the outcome was fetal demise. The patient was subsequently treated with gemfibrozil, which controlled the hypertriglyceridemia. A second pregnancy ended with a therapeutic abortion at 1 month because of the possible risk of pancreatitis. Gemfibrozil therapy was instituted but subsequently discontinued when she was discovered to be pregnant again, at approximately 10 weeks of gestation; the potential risks involved with the use of this drug during pregnancy were unknown. Because of the patient's strong desire to maintain the pregnancy, gemfibrozil treatment was resumed 1 week later in order to help prevent recurrent pancreatitis. The patient ultimately delivered a fullterm healthy boy, and she had no recurrence of pancreatitis or other complications. In selected patients at high risk for pancreatitis, the potential risk of gemfibrozil use during pregnancy may be offset by its benefits in the management of severe hypertriglyceridemia.


Nucleophosmin leukemogenic mutant activates Wnt signaling during zebrafish development.
Nucleophosmin (NPM1) is a ubiquitous multifunctional phosphoprotein with both oncogenic and tumor suppressor functions. Mutations of the NPM1 gene are the most frequent genetic alterations in acute myeloid leukemia (AML) and result in the expression of a mutant protein with aberrant cytoplasmic localization, NPMc+. Although NPMc+ causes myeloproliferation and AML in animal models, its mechanism of action remains largely unknown. Here we report that NPMc+ activates canonical Wnt signaling during the early phases of zebrafish development and determines a Wnt-dependent increase in the number of progenitor cells during primitive hematopoiesis. Coherently, the canonical Wnt pathway is active in AML blasts bearing NPMc+ and depletion of the mutant protein in the patient derived OCI-AML3 cell line leads to a decrease in the levels of active β-catenin and of Wnt target genes. Our results reveal a novel function of NPMc+ and provide insight into the molecular pathogenesis of AML bearing NPM1 mutations.


EEG functional connectivity and brain-to-brain coupling in failing cognitive strategies.
Cooperation behavior is a core question of study on social neuroscience. In the present study, inter-brain functional connectivity and cognitive performance were considered during joint which was failing. The cognitive performance and the EEG (brain oscillations from delta to beta) underlying the execution of joint-actions were recorded when dyads of participants executed synchronicity game and received reinforcing negative feedbacks A pre-feedback condition (cooperation) and a control condition (individual task, T0) were provided as well as a check for possible learning effect (time series analysis). Finally, correlation analysis was considered to assess the relation between behavioral and physiological levels. Results showed that the external feedback was able to modulate participants' responses in both behavioral and neural components with increased RTs and ERs after the negative reinforcement. Similarly, a reduced inter-brain connectivity was found, mainly localized within the superior frontal regions, and for low-frequency bands (delta and theta). In contrast pre-feedback condition showed the best performance in terms of both behavioral and brain-to-brain coupling activity. Moreover, the presence of significant correlations between RTs and inter-brain connectivity revealed that the failing cooperation induces significant negative effects on the cognitive and brain strategy in comparison with cooperative (pre-feedback) and individual (control) condition. The present study provides significant contribution to the identification of patterns of cognitive behavior and functional connectivity when social reinforcement is provided within dyads of participants by using a hyperscanning approach.


Genomic organization and the tissue distribution of alternatively spliced isoforms of the mouse Spatial gene.
The stromal component of the thymic microenvironment is critical for T lymphocyte generation. Thymocyte differentiation involves a cascade of coordinated stromal genes controlling thymocyte survival, lineage commitment and selection. The "Stromal Protein Associated with Thymii And Lymph-node" (Spatial) gene encodes a putative transcription factor which may be involved in T-cell development. In the testis, the Spatial gene is also expressed by round spermatids during spermatogenesis. The Spatial gene maps to the B3-B4 region of murine chromosome 10 corresponding to the human syntenic region 10q22.1. The mouse Spatial genomic DNA is organised into 10 exons and is alternatively spliced to generate two short isoforms (Spatial-alpha and -gamma) and two other long isoforms (Spatial-delta and -epsilon) comprising 5 additional exons on the 3' site. Here, we report the cloning of a new short isoform, Spatial-beta, which differs from other isoforms by an additional alternative exon of 69 bases. This new exon encodes an interesting proline-rich signature that could confer to the 34 kDa Spatial-beta protein a particular function. By quantitative TaqMan RT-PCR, we have shown that the short isoforms are highly expressed in the thymus while the long isoforms are highly expressed in the testis. We further examined the inter-species conservation of Spatial between several mammals and identified that the protein which is rich in proline and positive amino acids, is highly conserved. The Spatial gene generates at least five alternative spliced variants: three short isoforms (Spatial-alpha, -beta and -gamma) highly expressed in the thymus and two long isoforms (Spatial-delta and -epsilon) highly expressed in the testis. These alternative spliced variants could have a tissue specific function.


Expression of the glucokinase gene in mule duck liver and glucokinase activities in chicken and mule duck livers.
The presence of glucokinase (GK), a critical enzyme controlling glucose homeostasis, particularly liver glucose utilization in mammals, has long been a matter of debate in avian species because a number of investigators have failed to detect GK activity in the livers of chickens and several other avian species. In this study, we cloned a partial GK cDNA from mule duck livers and measured GK-like activity in the livers of mule ducks and broiler chickens under 2 nutritional states. Liver samples from 5-wk-old meal-fed male broiler chickens (Ross) were obtained from overnight-fasted chickens (BC) and 5 h after an oral saccharose load (6 mL/kg of BW of a 50% saccharose solution) given just before the meal (BS). Liver samples from 15-wk-old mule ducks were collected after an overnight fast (DC) and 12 h after the last overfeeding meal (DO). A partial cDNA ( approximately 600 bp) was obtained from duck livers. It presented 99% identity with chicken partial GK cDNA (gi 44888789) and 82% identity with human GK (gi 15967158). Chicken liver weights represented 1.8 and 3.3% of BW, respectively, for BC and BS (n = 8, P < 0.05). Glucokinase and low-Michaelis constant hexokinase (HK) activity levels were similar in BC (respectively, 0.88 and 1.00 mU/mg of protein). In response to the meal load, GK activity increased significantly (+57%), whereas HK decreased (-46%) in BS. Duck liver weights represented 1.4 and 7.6% of BW, respectively, for DC and DO (n = 8, P < 0.05). In DC livers, GK activity was significantly higher than HK activity (respectively, 1.76 and 0.63 mU/mg of protein). Both activities were significantly increased in DO (2 times, n = 8, P < 0.05). In conclusion, GK is present in ducks as well as chickens, and it is nutritionally regulated in avian species as well as in mammals. Further work will determine whether the higher liver GK activity and GK:HK ratio in DC compared with BC is related to age or BW or linked to the high lipogenic capacity of the duck liver.


Imaging modalities in patients with slipped capital femoral epiphysis.
Slipped capital femoral epiphysis (SCFE) is a frequent disorder of the adolescent hip, which may lead to avascular necrosis (AVN) of the femoral head, chondrolysis and early osteoarthritis due to the post-slip deformity of the proximal femur. To warrant the best possible outcome for the affected (and contralateral) hip, early diagnosis and proper treatment are needed. A review of the literature was undertaken to identify today's role of available imaging modalities in the management of SCFE. This review outlines the relevancy of different imaging modalities such as radiography, ultrasound, CT, MRI and bone scintigraphy in the treatment of SCFE patients. While standard radiography is the first-choice imaging modality for patients with suspected SCFE, ultrasound and advanced imaging modalities may aid in surgical planning, diagnosis of complications such as AVN and treatment follow-up.


The Underlying Structure of Comorbid Mental Health and Substance Use Disorders in Prison Populations.
High rates of mental disorders have been reported for prison populations. Understanding patterns of comorbidity may be essential for the development of adequate treatment interventions. The present study aimed to assess the underlying structure of comorbidity between mental health and substance use disorders in prison populations. Current mental disorders were assessed using the Mini-International Neuropsychiatric Interview in a cross-sectional observational study of 427 individuals consecutively committed to prison facilities in Santiago, Chile. Five alternative structural models were tested using confirmatory factor analysis (CFA). Latent class analysis of comorbid mental health and substance use disorders was carried out. CFA indicated the best fit for a bifactor model with a general psychopathology P factor and specific internalizing and externalizing factors. Borderline personality disorder loaded highest on the P factor (0.85). The latent comorbidity structure showed a four-class solution representing one class without relevant comorbidities (48% prevalence) and three classes representing the following comorbidities: (1) externalizing disorders including substance use and antisocial personality disorder (31%), (2) internalizing disorders including anxiety disorders (10%), and (3) all types of disorders co-occurring (11%). Major depression and borderline personality disorder were present across all three latent classes of comorbidity. Prison mental health services need to serve a highly comorbid population. Specific approaches may be useful for an externalizing and an internalizing spectrum of disorders. An important group of individuals with all types of mental disorders co-occurring may need new approaches in treatment development.


Too important to miss out? Documentation of care in critical care nursing.
1. In critical care settings, time may be limited for the documentation of care in the care plan. 2. Implementation of the nursing process involves responsiveness both to clients' clinical needs and their informed choices. 3. The care plan is not wholly indispensable to individualised, holistic care, but is integral to the full professional implementation of the nursing process.


Life years lost among patients with a given disease.
A number of suggested measures of life years lost among patients with a given disease are reviewed, and some new ones are proposed. The methods are all phrased in the framework of a (Markov or non-Markov) illness-death model in combination with a population life table. The methods are illustrated using data on Danish male patients with bipolar disorder, and some recommendations are given. Copyright © 2017 John Wiley & Sons, Ltd.


The functional analysis of auditory discrimination.
Mammals have evolved the ability to acquire auditory discriminations. The characteristics of this discriminative ability presumably fit the natural conditions under which discriminations are normally acquired. The purpose of this paper is to review experiments which were directed at showing that auditory discriminations are most rapidly acquired when natural features are incorporated into the experiments. The experiments were also directed at discovering the underlying characteristics of the discriminative ability. When animals were trained to discriminate the position of a sound source in which natural features were incorporated into the experiment, the discrimination was acquired in one trial. Manipulation of the natural features suggested that one trial acquisition depends upon the following. (1) Stimulus novelty; the effect of reinforcement is stronger in the presence of novel than familiar stimuli. (2) Specific behavioral effect of reinforcement; the effect of reinforcing a response in the presence of a novel auditory stimulus is to increase the strength of approaching and manipulating the sound source.


On-site Determination of Trace Arsenic by Reflection-Absorption Colorimetry of Molybdenum Blue Collected on a Membrane Filter.
An on-site determination method for trace arsenic has been developed by collecting it as molybdenum blue (MB) in the presence of tetradecyldimethylbenzylammonium chloride on a mixed cellulose ester membrane filter and by measuring reflection absorbance (RA) of MB on the filter using a laboratory-made palm-top size reflection-absorbance colorimeter with a red light-emitting diode. The value of RA was proportional to the amount of arsenic up to 0.5 μg with a detection limit of 0.01 μg. The proposed method was successfully applied to soil extract and hot-spring water samples.


Applications of Extended Reality in Ophthalmology: Systematic Review.
Virtual reality, augmented reality, and mixed reality make use of a variety of different software and hardware, but they share three main characteristics: immersion, presence, and interaction. The umbrella term for technologies with these characteristics is extended reality. The ability of extended reality to create environments that are otherwise impossible in the real world has practical implications in the medical discipline. In ophthalmology, virtual reality simulators have become increasingly popular as tools for surgical education. Recent developments have also explored diagnostic and therapeutic uses in ophthalmology. This systematic review aims to identify and investigate the utility of extended reality in ophthalmic education, diagnostics, and therapeutics. A literature search was conducted using PubMed, Embase, and Cochrane Register of Controlled Trials. Publications from January 1, 1956 to April 15, 2020 were included. Inclusion criteria were studies evaluating the use of extended reality in ophthalmic education, diagnostics, and therapeutics. Eligible studies were evaluated using the Oxford Centre for Evidence-Based Medicine levels of evidence. Relevant studies were also evaluated using a validity framework. Findings and relevant data from the studies were extracted, evaluated, and compared to determine the utility of extended reality in ophthalmology. We identified 12,490 unique records in our literature search; 87 met final eligibility criteria, comprising studies that evaluated the use of extended reality in education (n=54), diagnostics (n=5), and therapeutics (n=28). Of these, 79 studies (91%) achieved evidence levels in the range 2b to 4, indicating poor quality. Only 2 (9%) out of 22 relevant studies addressed all 5 sources of validity evidence. In education, we found that ophthalmic surgical simulators demonstrated efficacy and validity in improving surgical performance and reducing complication rates. Ophthalmoscopy simulators demonstrated efficacy and validity evidence in improving ophthalmoscopy skills in the clinical setting. In diagnostics, studies demonstrated proof-of-concept in presenting ocular imaging data on extended reality platforms and validity in assessing the function of patients with ophthalmic diseases. In therapeutics, heads-up surgical systems had similar complication rates, procedural success rates, and outcomes in comparison with conventional ophthalmic surgery. Extended reality has promising areas of application in ophthalmology, but additional high-quality comparative studies are needed to assess their roles among incumbent methods of ophthalmic education, diagnostics, and therapeutics.


Buprenorphine maintenance: office-based treatment with addiction clinic support.
Buprenorphine has already been registered in 27 European countries for maintenance therapy in opioid-dependent patients. In our office-based prescription study we applied sublingual buprenorphine, initiating the treatment at the addiction clinic with subsequent treatment at the offices of general practitioners (GPs) to evaluate its efficacy and feasibility in two different treatment settings. Sixty opioid-dependent patients were studied for a period of 15 weeks. The first 3 weeks of treatment initiation took place at the addiction clinic, followed by 12 weeks of treatment by GPs. Mean outcome measures were retention rate and additional consumption of illicit substances in addition to the evaluation of whether buprenorphine can be prescribed successfully by GPs. The retention rate was 57% (n = 34). No significant differences occurred between the treatment phases at the specialized addiction unit and the GPs' offices. During the 15-week period a significant improvement in well-being and a significant reduction in craving for heroin (p < 0.001) and cocaine (p < 0.001) could be calculated for patients stabilized on a mean dose of 16 mg buprenorphine. Furthermore a significant reduction in additional consumption of opioids (p < 0.001) was found. Our results show the involvement of office-based prescription, which should further encourage colleagues to treat opioid-dependent subjects with buprenorphine to make more treatment options for this target group available.


Congenital hypofibrinogenaemia: a presymptomatic detection of an extremely rare bleeding disorder in preterm twins.
Twenty-eight-week-old preterm monochorionic-diamniotic twins were admitted to the neonatal intensive care unit secondary to low birth weight and mild respiratory distress syndrome. A low fibrinogen level of less than 0.5 g/L was detected following an abnormal full blood count. They required fibrinogen transfusions until 32 weeks corrected gestation to maintain adequate fibrinogen levels. Parental screening revealed that their mother had a previously undiagnosed hypofibrinogenaemia. Of note, her only symptom was menorrhagia. This may have implications on further pregnancies as it can be associated with spontaneous miscarriage and post-partum haemorrhage. Congenital hypofibrinogenaemia is a rare disorder and there are no reported cases from Ireland. A higher degree of suspicion for screening is required to detect new cases and demonstrates the benefits of checking parental levels in such situations.


Evidence-based financial management.
Like the practice of evidence-based medicine, evidence-based financial management can be used by providers to improve results. The concept provides a framework that managers and researchers can use to help direct efforts in gathering and using evidence to support management decisions in health care.


Accessing stored knowledge of familiar people from faces, names and voices: a review.
Recent findings from neuropsychology and experimental psychology appear incompatible with the claim that feelings of familiarity about known people require activation of amodal person identity nodes. Evidence suggests that there are modality-specific effects after the point at which faces, names and voices have been found familiar. It therefore appears that activation of distinct modality-specific face, name and voice processing systems can signal that a known person is familiar. There is no convincing evidence, however, of modular effects on the way that information about familiar people is represented in semantic memory. Instead, semantic information about people appears to be stored separately from other forms of knowledge such as knowledge of objects. Anatomical evidence suggests that amodal person-specific semantic knowledge is stored in the right anterior temporal lobe where it has close connections with modality specific recognition systems. Failures to retrieve names in proper name anomia may be caused by impairments to the links between semantic knowledge in the right anterior temporal lobe and lexical representations in the left temporal pole.


CRISPR Editing in Biological and Biomedical Investigation.
The CRISPR (clustered regularly interspaced short palindromic repeat)-Cas (CRISPR-associated protein) system, a prokaryotic RNA-based adaptive immune system against viral infection, is emerging as a powerful genome editing tool in broad research areas. To further improve and expand its functionality, various CRISPR delivery strategies have been tested and optimized, and key CRISPR system components such as Cas protein have been engineered with different purposes. Benefiting from more in-depth understanding and further development of CRISPR, versatile CRISPR-based platforms for genome editing have been rapidly developed to advance investigations in biology and biomedicine. In biological research area, CRISPR has been widely adopted in both fundamental and applied research fields, such as genomic and epigenomic modification, genome-wide screening, cell and animal research, agriculture transforming, livestock breeding, food manufacture, industrial biotechnology, and gene drives in disease agents control. In biomedical research area, CRISPR has also shown its extensive applicability in the establishment of animal models for genetic disorders, generation of tissue donors, implementation of antimicrobial and antiviral studies, identification and assessment of new drugs, and even treatment for clinical diseases. However, there are still several problems to consider, and the biggest concerns are the off-target effects and ethical issues of this technology. In this prospect article, after highlighting recent development of CRISPR systems, we outline different applications and current limitations of CRISPR in biological and biomedical investigation. Finally, we provide a perspective on future development and potential risks of this multifunctional technology. J. Cell. Biochem. 119: 52-61, 2018. © 2017 Wiley Periodicals, Inc.


Chondrogenesis in a cell-polymer-bioreactor system.
Chondrogenesis was studied under controlled in vitro conditions using a cell-polymer-bioreactor system. Bovine calf articular chondrocytes were seeded onto biodegradable polymer scaffolds and cultured in rotating bioreactor vessels. Concomitant increases in the amounts of glycosaminoglycan (GAG) and type II collagen resulted in cell-polymer constructs with continuous cartilaginous matrix over their entire cross sections (6.7 mm diameter x 5 mm thick) after 40 days of cultivation. As compared to natural calf cartilage, constructs had comparable cellularities, 68% as much GAG and 33% as much type II collagen per gram wet weight. The progression of chondrogenesis in chondrocyte-polymer constructs was similar to that suggested previously for precursor cells in vitro and developing limbs in vivo. In particular, the polymer scaffold provided a three-dimensional structure that could be seeded with chondrocytes at high cell densities in order to establish cell-to-cell contacts and initiate cartilage tissue development, whereas the bioreactor vessel provided a permissive microenvironment for chondrogenesis. This work demonstrates the promise of using tissue engineered constructs for in vitro studies of cell interactions and differentiation.


Differential expression of three hypoxia-inducible factor-alpha subunits in pulmonary arteries of rat with hypoxia-induced hypertension.
Hypoxia inducible transcription factor (HIF)-1alpha plays an important role in the development of hypoxic pulmonary hypertension, but little is known about HIF-2alpha and HIF-3alpha with respect to transcriptional regulation by hypoxia. To examine the expression patterns of all HIF-alpha subunits (HIF-1alpha, HIF-2alpha and HIF-3alpha) in pulmonary arteries of rats undergoing systemic hypoxia, five groups of healthy male Wistar rats were exposed to normoxia (N) and hypoxia for 3 (H3), 7 (H7), 14 (H14) and 21 (H21) d respectively. Mean pulmonary arterial pressure (mPAP), vessel morphometry and right ventricular hypertrophy index were measured. Lungs were inflation fixed for immunohistochemistry and in situ hybridization, and homogenized for Western blot. mPAP increased significantly after 7 d of hypoxia [(18.4+/-0.4) vs. (14.4+/-0.4) mmHg, H7 vs. N], reached its peak after 14 d of hypoxia, then remained stable. Pulmonary artery remodeling and right ventricular hypertrophy developed significantly after 14 d of hypoxia. During normoxia, HIF-1alpha and HIF-3alpha staining were slightly positive regarding mRNA levels. A substantial alteration of HIF-1alpha and HIF-3alpha staining occurred in pulmonary arteries after 14 d and 7 d of hypoxia, respectively, but HIF-2alpha staining showed an inversed trend after 14 d of hypoxia. Protein levels of all HIF-alpha subunits except HIF-3alpha showed a marked increase corresponding to the duration of hypoxia, which was obtained by Western blot. Our study found that HIF-1alpha, HIF-2alpha and HIF-3alpha may not only confer different target genes, but also play key pathogenetic roles in hypoxic-induced pulmonary hypertension.


Morphological and biochemical characterization of the membranous hepatitis C virus replication compartment.
Like all other positive-strand RNA viruses, hepatitis C virus (HCV) induces rearrangements of intracellular membranes that are thought to serve as a scaffold for the assembly of the viral replicase machinery. The most prominent membranous structures present in HCV-infected cells are double-membrane vesicles (DMVs). However, their composition and role in the HCV replication cycle are poorly understood. To gain further insights into the biochemcial properties of HCV-induced membrane alterations, we generated a functional replicon containing a hemagglutinin (HA) affinity tag in nonstructural protein 4B (NS4B), the supposed scaffold protein of the viral replication complex. By using HA-specific affinity purification we isolated NS4B-containing membranes from stable replicon cells. Complementing biochemical and electron microscopy analyses of purified membranes revealed predominantly DMVs, which contained viral proteins NS3 and NS5A as well as enzymatically active viral replicase capable of de novo synthesis of HCV RNA. In addition to viral factors, co-opted cellular proteins, such as vesicle-associated membrane protein-associated protein A (VAP-A) and VAP-B, that are crucial for viral RNA replication, as well as cholesterol, a major structural lipid of detergent-resistant membranes, are highly enriched in DMVs. Here we describe the first isolation and biochemical characterization of HCV-induced DMVs. The results obtained underline their central role in the HCV replication cycle and suggest that DMVs are sites of viral RNA replication. The experimental approach described here is a powerful tool to more precisely define the molecular composition of membranous replication factories induced by other positive-strand RNA viruses, such as picorna-, arteri- and coronaviruses.


Rheology of a 2D granular film.
We study experimentally the rheology of a macroscopic particle-laden soap film, designated as a "Granular Film", in the simple shear configuration. Macroscopic particles are dispersed in a soap film, while being large enough that they bridge both fluid interfaces. We simultaneously perform macroscopic rheological measurements with a classical rheometer and investigate interactions at the particle scale with a camera underneath the film. The determination of the velocity field of the grains reveals the presence of an inhomogeneous shear within the granular film. Trying to correlate both measurements unveils the non-locality of the rheology of the granular film: similar to what has been observed in a dry granular material, we find an highly-sheared zone close to the moving wall contrasting with a large quasistatic area. This behavior can be accounted for through extended kinetic theory and correlated with a transition in the dominant component of the stress.


Libyostrongylus infections in ostriches--a brief review with particular reference to their detection in New Zealand.
Following the recent discovery of Libyostrongylus douglassii in ostriches in New Zealand, information relating to this nematode is reviewed. Amongst some of the topics considered are the parasite's distribution and prevalence, its life cycle and survival, and its diagnosis and control. Of particular interest from a New Zealand perspective is the potential for the parasite to infect other ratites, especially the kiwi. While the current evidence suggests that this may be unlikely to occur, the possibility that it might be able to do so cannot be ruled out entirely.


Inhibitory Effects of Wheat Sprouts Extract on RANKL-Induced Osteoclast Differentiation via Suppressing MAPK and NFATc1 Signaling Pathways.
The maintenance of bone is dependent on both osteoclasts, which break down bone, and osteoblasts, which build new bone. Various bone-related disorders, including osteoporosis, can occur as a result of an imbalance between these two cell types. Prolonged use of currently available bone resorption inhibitors may show side effects. Therefore, developing a novel preventive material which effectively inhibits osteoclast differentiation could be beneficial. This study planned to investigate the inhibitory effect of wheat sprout ethanolic extracts (Saegeumgang [SGG] and Arriheuk [ARH]) on the differentiation of osteoclasts induced by RANKL, as well as the mechanisms why fundamental to these effects. The effects of SGG and ARH on bone resorption and osteoclast differentiation were evaluated using RAW 264.7 cells and assessed through TRAP cell count, pit formation, and activity. The expressions of mRNA and protein were accomplished using western blotting, and reverse transcription quantitative polymerase chain reaction analyses were conducted. SGG and ARH were found to suppress osteoclast differentiation in RANKL-stimulated RAW264.7 cells without causing cytotoxic effects. In addition, treatment with SGG and ARH led to a reduction in the number of cells with positive staining for TRAP and TRAP activity. SGG and ARH treatment dose-dependently decreased the pit area in pit formation assays, showing a notable reduction compared to the pit area created by mature osteoclasts. SGG and ARH inhibited osteoclast activity by 84.9% and 95.7% at 200 μg/mL, respectively. In addition, SGG and ARH suppressed the transcriptional activation of various osteoclast-related genes, such as RANK, NFATc1, cathepsin K, c-Fos, TRAP, matrix metallopeptidase-9, dendritic cell-specific transmembrane protein, ATPase H+ transporting v0 subunit d2, and osteoclast-associated receptor in RAW264.7 cells treated with RANKL. SGG and ARH extracts were found to affect the expression of NFATc1 and genes that are specific to osteoclasts during osteoclast differentiation, suggesting their potential use as functional foods or as therapeutic interventions targeting bone health.


Coincidence of granulomatosis and polyangiitis with atypical clinical manifestation and antiphospholipid syndrome.
Granulomatosis and angiitis (GPA) is a multisystemic disease characterized by a granulomatous inflammation, tissue necrosis, and vasculitis of small and medium-sized blood vessels. Although the disease has a predilection for the upper respiratory tract, lungs, and kidneys, any organ system may be affected. Here, we present a case of generalized GPA manifested initially by necrotizing isolated parotitis and later by pulmonary-renal syndrome. Simultaneously with pulmonary hemorrhage, our patient developed an antiphospholipid syndrome (APS) presenting with deep vein thrombosis and strongly positive lupus anticoagulant. To the best of our knowledge the coincidence of parotitis and pulmonary-renal syndrome due to GPA and APS has never been reported previously. Concomitant venous thromboembolism may be life-threatening in a patient with GPA. Early diagnosis and institution of the proper therapy are critical in order to prevent organ damage.


A retrospective review of the Pediatric Development Clinic implementation: a model to improve medical, nutritional and developmental outcomes of at-risk under-five children in rural Rwanda.
As more high-risk newborns survive the neonatal period, they remain at significant medical, nutritional, and developmental risk. However, no follow-up system for early intervention exists in most developing countries. In 2014, a novel Pediatric Development Clinic (PDC) was implemented to provide comprehensive follow-up to at-risk under-five children, led by nurses and social workers in a district hospital and surrounding health centers in rural Rwanda. At each PDC visit, children undergo clinical/nutritional assessment and caregivers participate in counseling sessions. Social assessments identify families needing additional social support. Developmental assessment is completed using Ages and Stages Questionnaires. A retrospective medical record review was conducted to evaluate the first 24 months of PDC implementation for patients enrolled between April 2014-December 2015 in rural Rwanda. Demographic and clinical characteristics of patients and their caregivers were described using frequencies and proportions. Completion of different core components of PDC visits were compared overtime using Fisher's Exact test and p-values calculated using trend analysis. 426 patients enrolled at 5 PDC sites. 54% were female, 44% were neonates and 35% were under 6 months at enrollment. Most frequent referral reasons were prematurity/low birth weight (63%) and hypoxic-ischemic encephalopathy (34%). In 24 months, 2787 PDC visits were conducted. Nurses consistently completed anthropometric measurements (age, weight, height) at all visits. Some visit components were inconsistently recorded, including adjusted age (p = 0.003), interval growth, danger sign assessment, and feeding difficulties (p < 0.001). Completion of other visit components, such as child development counseling and play/stimulation activities, were low but improved with time (p < 0.001). It is feasible to implement PDCs with non-specialized providers in rural settings as we were able to enroll a diverse group of high-risk infants. We are seeing an improvement in services offered at PDCs over time and continuous quality improvement efforts are underway to strengthen current gaps. Future studies looking at the outcomes of the children benefiting from the PDC program are underway.


Identification of Candidate Genes Responsible for Stem Pith Production Using Expression Analysis in Solid-Stemmed Wheat.
The wheat stem sawfly (WSS) is an economically important pest of wheat in the Northern Great Plains. The primary means of WSS control is resistance associated with the single quantitative trait locus (QTL) , which controls most stem solidness variation. The goal of this study was to identify stem solidness candidate genes via RNA-seq. This study made use of 28 single nucleotide polymorphism (SNP) makers derived from expressed sequence tags (ESTs) linked to contained within a 5.13 cM region. Allele specific expression of EST markers was examined in stem tissue for solid and hollow-stemmed pairs of two spring wheat near isogenic lines (NILs) differing for the QTL. Of the 28 ESTs, 13 were located within annotated genes and 10 had detectable stem expression. Annotated genes corresponding to four of the ESTs were differentially expressed between solid and hollow-stemmed NILs and represent possible stem solidness gene candidates. Further examination of the 5.13 cM region containing the 28 EST markers identified 260 annotated genes. Twenty of the 260 linked genes were up-regulated in hollow NIL stems, while only seven genes were up-regulated in solid NIL stems. An -methyltransferase within the region of interest was identified as a candidate based on differential expression between solid and hollow-stemmed NILs and putative function. Further study of these candidate genes may lead to the identification of the gene(s) controlling stem solidness and an increased ability to select for wheat stem solidness and manage WSS.


Evaluation of the analgesic efficacy of EMLA cream in volunteers with differing skin pigmentation undergoing venipuncture.
Lidocaine/prilocaine cream (EMLA) applied to intact skin for 60 minutes has been shown to reduce venipuncture pain. Recent studies have suggested that lidocaine/prilocaine cream is less effective on heavily pigmented skin. The objective of this study was to evaluate the topical anesthetic efficacy of lidocaine/prilocaine cream in volunteers with varying skin pigmentation types. Sixty volunteers were enrolled into each of three groups based on skin pigmentation history. Subjects were randomized to receive lidocaine/prilocaine cream onto the antecubital fossa of one arm and placebo cream on the comparable location of the other arm for either 60, 90, or 120 minutes prior to venipuncture. Assessments of perceived pain associated with each venipuncture were made by the subject using a visual analog scale. Lidocaine/prilocaine cream applied for 60 minutes significantly (P < .0001) reduced the pain of venipuncture compared to placebo regardless of the skin pigmentation type. Pain reduction did not differ significantly across skin types (P = .7986). Additional exposure up to 120 minutes did not change the efficacy of EMLA cream. Lidocaine/prilocaine cream is a safe and effective topical anesthetic for reducing pain associated with venipuncture in individuals, regardless of skin pigmentation.


Evidence for a Novel Phylotype of Pseudomonas syringae Causing Bacterial Leaf Blight of Cantaloupe in China.
Bacterial leaf blight (BLB) has caused severe yield losses in cantaloupe (Cucumis melo L.) in the major melon-growing regions of China since the beginning of the twentieth century. Historically, Pseudomonas syringae pv. lachrymans was considered to be the causal agent of BLB of cantaloupe and angular leaf spot of cucumber. In the process of characterizing bacteria isolated from cantaloupe, we observed that putative P. syringae pv. lachrymans yielded negative results in P. syringae pv. lachrymans-specific PCR assays. This suggested that the P. syringae pv. lachrymans-like strains from cantaloupe were distinct from those recovered from cucumber. To investigate the differences between P. syringae pv. lachrymans-like strains isolated from cantaloupe and cucumber, 13 P. syringae strains isolated from cantaloupe [12 from China and 1 from Zimbabwe (NCPPB2916)] and 7 additional P. syringae reference strains were analyzed by catabolic profiling, phylogenetic analysis by multilocus sequence analysis (MLSA) and pathogenicity tests on cantaloupe leaflets. Catabolic profiling and MLSA based on 10 housekeeping genes and 2 hypersensitive response and pathogenicity (hrp) genes allowed us to differentiate strains isolated from cantaloupe and cucumber. Pseudomonas syringae pv. lachrymans strains isolated from cucumber clustered with genomospecies 2, and 13 P. syringae strains isolated from cantaloupe belonged to genomospecies 1. While all cantaloupe strains were closely related to P. syringae pv. aptata, they could be differentiated from this pathovar based on metabolic tests and MLSA. Pathogenicity tests showed that all strains isolated from cantaloupe and cucumber were only pathogenic on their original hosts. Based on these observations we conclude that P. syringae pv. lachrymans strains recovered from cantaloupe in China represent a novel phylotype.


Association between serum uric acid and metabolic syndrome components in prepubertal obese children (Tanner Stage I) from Nuevo León, Mexico - a preliminary study.
Metabolic syndrome (MetS) is a major risk factor for cardiovascular disease and diabetes. Previous studies in obese children demonstrating a positive association between serum uric acid (sUA) and components of MetS are confounded by lack of uniformity in age and pubertal status of children. Therefore, we have examined the role of sUA in MetS and its components in pre-pubertal children (Tanner Stage I, age ≤ 9 years). Pre-pubertal obese children (32 boys, 27 girls, age 6-9 years) were recruited from Nuevo Leon, Mexico. For comparison, an equal number of children with normal body mass index (BMI) in the same age range (22 Boys, 39 girls, age 6-9 years) were also recruited from the same community. Presence of MetS and its components was defined according to the criteria of International Diabetes Federation. Fasting blood was analyzed for lipids, glucose, insulin, and uric acid. Among the obese children, sUA was positively associated with insulin resistance and hypertriglyceridemia and negatively associated with high density lipoprotein-cholesterol (HDLc). Subjects were three times more likely to have a MetS diagnosis per one unit (md/dL) difference in sUA. Of the 59 obese pre-pubertal children, 20 were classified as having MetS defined by the presence of abdominal obesity and two or more of other components described under methods. Of these, 57.1% (20/61) had sUA between 5.1 and 7.1 mg/dl. The findings of this study clearly indicate a positive relationship between uric acid and MetS and its components in pre-pubertal obese children with Tanner stage I and ≤9 years of age.


Retinal microincarceration with penetrating diathermy in the management of giant retinal tears.
A technique for repair of giant retinal breaks with detachment involves the performance of lensectomy-sector iridectomy, vitrectomy, and scleral buckling behind the equator. Total fluid-gas exchange is performed while the patient is turned to the prone position on a rotating table. Penetrating diathermy is used to fix the retina and to create retinal microincarceration while air is simultaneously injected into the eye.


Antibacterial Activity of Polymers: Discussions on the Nature of Amphiphilic Balance.
The purpose of this Viewpoint is to discuss the molecular design principles that guide development of synthetic antimicrobial polymers, especially those intended to mimic the structure of host defense peptides (HDPs). In particular, we focus on the principle of "amphiphilic balance" as it relates to some recently developed polyphosphoniums with somewhat atypical structure. We find that the fundamental concept of amphiphilic balance is still applicable to these new polymers, but that the method to achieve such balance is somewhat unique. We then briefly outline the future challenges and opportunities in this field.


A 'Disease Severity Index' to identify individuals with Subjective Memory Decline who will progress to mild cognitive impairment or dementia.
Subjective memory decline (SMD) is a heterogeneous condition. While SMD might be the earliest sign of Alzheimer's disease (AD), it also occurs in aging and various neurological, medical, and psychiatric conditions. Identifying those with higher risk to develop dementia is thus a major challenge. We tested a novel disease severity index generated by multivariate data analysis with numerous structural MRI measures as input. The index was used to identify SMD individuals with high risk of progression to mild cognitive impairment (MCI) or AD. A total of 69 healthy controls, 86 SMD, 45 MCI, and 38 AD patients were included. Subjects were followed up for 7.5 years. Clinical, cognitive, PET amyloid imaging and APOE ε4 data were used as outcome variables. The results showed that SMD evidenced cognitive performance intermediate between healthy controls and MCI. The disease severity index identified eleven (13%) SMD individuals with an AD-like pattern of brain atrophy. These individuals showed lower cognitive performance, increased CDR-SOB, higher amyloid burden and worse clinical progression (6.2 times higher likelihood to develop MCI, dementia or die than healthy controls). The current disease severity index may have relevance for clinical practice, as well as for selecting appropriate individuals for clinical trials.


Molecular Profiling: A Case of ZBTB16-RARA Acute Promyelocytic Leukemia.
Several variant RARA translocations have been reported in acute promyelocytic leukemia (APL) of which the t(11;17)(q23;q21), which results in a ZBTB16-RARA fusion, is the most widely identified and is largely resistant to therapy with all-trans retinoic acid (ATRA). The clinical course together with the cytogenetic and molecular characterization of a case of ATRA-unresponsive ZBTB16-RARA APL is described. Additional mutations potentially cooperating with the translocation fusion product in leukemogenesis have been hitherto unreported in ZBTB16-RARA APL and were sought by application of a next-generation sequencing approach to detect those recurrently found in myeloid malignancies. This technique identified a solitary, low level mutation in the CEBPA gene. Molecular profiling of additional mutations may provide a platform to individualise therapeutic management in patients with this rare form of APL.


Simultaneous Formation of a Self-Wrinkled Surface and Silver Nanoparticles on a Functional Photocuring Coating.
Bioinspired functional surface with micro/nanostructures are particularly attractive because of the potential for outstanding characteristics, such as self-cleaning, self-replenishing and antibiosis. Here, we presented a facile approach to fabricate a functional photocuring coating with both a self-wrinkling patterned surface and incorporated silver nanoparticles (Ag NPs). Fluorinated polymeric photoinitiator (FPPI) and silver precursor (TFAAg) can self-assemble together on the air/acrylate interface to form a top layer of photocuring liquid resin. Under UV irradiation, a wrinkled pattern was formed as a result of the mismatch in shrinkage caused by photopolymerization between the top layer and the bulk layer. Simultaneously, Ag NPs with sizes of 15 ± 8 nm in diameter were in situ generated in the photocuring coating through the photoreduction of TFAAg. Their number density is higher in the top layer than in the bulk. Scanning electron microscope (SEM) and atomic force microscope (AFM) measurements revealed that the characteristic wavelength (λ) and amplitude (A) of the wrinkled morphology increased with growing concentration of FPPI, and that the generation of Ag NPs led to the wrinkle-to-fold transition. Furthermore, the obtained functional coatings possess a low surface energy and self-replenishing and antibiosis capabilities as a result of the synergistic effect of the wrinkled surface covered by FPPI and Ag NPs.


Amniotic fluid beta 2-microglobulin (beta 2-m) as an index of fetal maturity.
Amniotic fluid beta 2 microglobulin (beta 2-m) levels were measured by radioimmunoassay in 78 pregnant women between the 14th and the 42nd week of gestation. 62 were healthy subjects, while eight were affected by EPH gestosis, seven by diabetes (cl. B-F) associated with Rh immunization in one case, one by hydramnios. There was no significant correlation either between beta 2-m and creatinine (n = 18), or between beta 2-m and lecithin sphingomyelin ratio (L/S) (n = 16), although low concentrations of beta 2-m were usually observed after the 35th week of gestation. It is noteworthy that only in one case out of seven with amniotic levels less than 5 microgram/ml L/S ratio was less than 2.


Dynamics of Charged Excitons and Biexcitons in CsPbBr3 Perovskite Nanocrystals Revealed by Femtosecond Transient-Absorption and Single-Dot Luminescence Spectroscopy.
Metal-halide perovskite nanocrystals (NCs) are promising photonic materials for use in solar cells, light-emitting diodes, and lasers. The optoelectronic properties of these devices are determined by the excitons and exciton complexes confined in their NCs. In this study, we determined the relaxation dynamics of charged excitons and biexcitons in CsPbBr3 NCs using femtosecond transient-absorption (TA), time-resolved photoluminescence (PL), and single-dot second-order photon correlation spectroscopy. Decay times of ∼40 and ∼200 ps were obtained from the TA and PL decay curves for biexcitons and charged excitons, respectively, in NCs with an average edge length of 7.7 nm. The existence of charged excitons even under weak photoexcitation was confirmed by the second-order photon correlation measurements. We found that charged excitons play a dominant role in luminescence processes of CsPbBr3 NCs. Combining different spectroscopic techniques enabled us to clarify the dynamical behaviors of excitons, charged excitons, and biexcitons.


Emotional, behavioral, and cognitive status of children with cerebral gigantism.
Eleven children with cerebral gigantism or Sotos' syndrome were assessed regarding their cognitive, emotional, and behavioral status. The children demonstrated high rates of emotional and behavioral disorders, but no specific pattern or personality style was detected. On the cognitive assessments, all of the children presented with cognitive impairment or mental retardation, the range of which was variable. As with other syndromes associated with developmental delay, there was a wide range of expression of problems.


Multifocal Surgically Induced Necrotizing Scleritis Following Strabismus Surgery: A Case Report.
To present clinical findings of a 28-year-old woman with multifocal surgically induced necrotizing scleritis following uncomplicated strabismus surgery. A 28-year-old woman underwent uncomplicated strabismus surgery of her right eye for sensory exotropia under general anesthesia (6 mm right medial rectus muscle resection and 8 mm right lateral rectus muscle recession). Retrospective, observational case report and literature review. One month after strabismus surgery, the patient presented with surgically induced necrotizing scleritis in the nasal aspect of sclera. Bacterial culture of the bed of the scleral melt showed no growth and all laboratory evaluation was normal. The scleritis completely resolved after initiation of systemic corticosteroids and oral azathioprine. Three weeks later (after tapering dose of systemic medication), the patient returned with large area of necrotizing scleritis in the same eye, but this time in the temporal aspect of sclera. To our knowledge, this is the first documented case of multifocal surgically induced necrotizing scleritis occurring after strabismus surgery. This study also highlights the fact that scleritis may recur even in an area distant from the site of surgery, despite initial control. It seems that maybe with a longer course of treatment it is less likely to recur, and tapering medications should be carefully managed.


Electron beam induced etching of carbon nanotubes enhanced by secondary electrons in oxygen.
Multi-walled carbon nanotubes (CNTs) are subjected to electron-beam-induced etching (EBIE) in oxygen. The EBIE process is observed in situ by environmental transmission electron microscopy. The partial pressure of oxygen (10 and 100 Pa), energy of the primary electrons (80 and 200 keV), and environment of the CNTs (suspended or supported on a silicon nitride membrane) are investigated as factors affecting the etching rate. The EBIE rate of CNTs was markedly promoted by the effects of secondary electrons that were emitted from a silicon nitride membrane under irradiation by primary electrons. Membrane supported CNTs can be cut by EBIE with a spatial accuracy better than 3 nm, and a nanogap of 2 nm can be successfully achieved between the ends of two suspended CNTs.


Relationship between N-linked oligosaccharide chains of human serum immunoglobulin G and serum tumor markers with non-small cell lung cancer progression.
It has been demonstrated that increased expression of the sialyl Le(x) sugar chains on cancer cells influences cellular adhesion to vascular-endothelial cells. Therefore, it was thought that alterations in the sugar chain structure of E-cadherin, a calcium dependent adhesion molecule, influence the metastasis of cancer cells. In this study, N-linked oligosaccharides of human serum immunoglobulin G (IgG) were analyzed in 12 patients with non-small cell lung cancer (NSCLC) (6 localized cancer: 3 adenocarcinomas and 3 squamous cell carcinomas; 6 metastatic cancer: 3 adenocarcinomas and 3 squamous cell carcinomas) and 10 healthy controls using fluorophore-associated carbohydrate electrophoresis (FACE). The relationship between changes in sugar chain structure and serum concentrations of carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA21-1) were evaluated. CEA levels in the sera were determined using an enzyme immunoassay, and CYFRA21-1 levels were determined using an enzyme chemiluminescent immunoassay. Fri (monogalactosyl IgG oligosaccharides) and Fr2 (digalactosyl IgG oligosaccharides) decreased, while Fr4 (agalactosyl IgG oligosaccharides) significantly increased (p < 0.01-0.05) with NSCLC progression. The Fr4/Fr1+Fr2 ratio increased with NSCLC progression, and the ratios in localized and metastatic NSCLC were significantly higher than in healthy controls (p < 0.01 and p < 0.01, respectively). There was a strong correlation between serum CEA levels and Fr4 (r = 0.91) and a significant correlation between serum CEA levels and the Fr4/Fr1+Fr2 ratio (r = 0.83, p < 0.05) in patients with lung adenocarcinoma. There was a significant correlation between serum CYFRA21-1 levels and Fr4 (r = 0.88, p < 0.001) and a positive correlation between serum CYFRA21-1 levels and the Fr4/Fr1+Fr2 ratio (r = 0.38) in patients with lung squamous cell carcinoma. The analysis of serum IgG N-linked oligosaccharide chain structures by FACE may be an auxiliary indicator of serum tumor markers for monitoring NSCLC progression.


Having it all: national benefit equity and local payment parity in Medicare.
The Medicare Payment Advisory Commission (MedPAC) has identified two important problems with the Medicare+Choice (M+C) program: nationwide geographic inequity in government-financed benefits, and unequal government payments for M+C plans versus fee-for-service (FFS) Medicare in the same market area. MedPAC concludes that both problems cannot be solved simultaneously. We argue that both problems could be solved if Congress discontinued its policy of underwriting the cost of FFS Medicare. Instead, Congress should define a national entitlement benefit package and have all health plans submit bids on the package in each market area. The government's premium contribution should be equal to the lowest bid submitted by a qualified health plan in each market area. The contribution could be adjusted for health risk, the special obligations of FFS Medicare, and welfare enhancements associated with FFS Medicare that are valued by both beneficiaries and taxpayers but unrelated to beneficiaries' health status.


Pediatric contact lenses: case reports.
Contact lenses may be a useful, even essential, treatment modality for children with a variety of optometric needs. Many clinicians who are experienced and capable contact lens practitioners but do not specialize in the care of children may refrain from considering contact lenses as a treatment option because of a host of perceived problems. Most of these concerns can be readily overcome with patience, planning, and education. Five cases are presented to illustrate specific clinical problems and the clinical application of contact lenses in the pediatric population. The case reports illustrate the clinical application of contact lens fitting in children with a variety of clinical needs. The use of contact lenses in children is an ongoing process, requiring great flexibility and creativity on the part of the optometrist. Educating the child and the family is an integral part of the treatment. The use of contact lenses in children is both an opportunity and a challenge that may result in great satisfaction for the child, the family, and the optometrist.


The impact of proximal femoral morphology on failure strength with a mid-head resection short-stem hip arthroplasty.
Mid-head resection short-stem hip arthroplasty is a conservative alternative to conventional total hip replacement and addresses proximal fixation challenges in patients not suitable for hip resurfacing. It is unclear whether proximal femoral morphology impacts the ultimate failure load of mid-head resection implanted femurs, thus the aim of this study was to investigate the effect of native neck-shaft angle (NSA) and coronal implant alignment on proximal femoral strength. In total, 36 synthetic femurs with two different proximal femoral morphologies were utilized in this study. Of them, 18 femurs with a varus NSA of 120° and 18 femurs with a valgus NSA of 135° were each implanted with a mid-head resection prosthesis. Femurs within the two different femoral morphology groups were divided into three equal coronal implant alignment groups: 10° valgus, 10° varus or neutral alignment. Prepared femurs were tested for stiffness and to failure in axial compression. There was no significant difference in stiffness nor failure load between femurs implanted with valgus-, varus- or neutrally aligned implants in femurs with a NSA of 120° (p = 0.396, p = 0.111, respectively). Femurs implanted in valgus orientation were significantly stiffer and failed at significantly higher loads than those implanted in varus alignment in femurs with a NSA of 135° (p = 0.001, p = 0.007, respectively). A mid-head resection short-stem hip arthroplasty seems less sensitive to clinically relevant variations of coronal implant alignment and may be more forgiving upon implantation in some femoral morphologies, however, a relative valgus component alignment is recommended.


[Mitral valve prolapse].
Mitral valve prolapse (MVP) is a common finding in everyday clinical practice. However, despite simple diagnostics, clinicians remain interested in it due to its undetermined prevalence, various etiology, clinical features and echocardiographic findings. MVP exists as a primary condition and is commonly associated with tissue diseases of familial origin. It is more common in people with asthenic constitution and congenital thoracic abnormalities. Secondary etiology occurs in rheumatic processes on mitral valve, hypertrophic cardiomyopathy and ischemic heart disease. The prevalence varies between 0.33-17%. Clinical manifestations are different and in most patients asymptomatic. The diagnosis is established by anamnesis, physical examination, M-mode and 2-dimen-sional transthoracic and transesophageal echocardiography, left ventriculography and direct histopathologic investigation of mitral apparatus. Although MVP is a benign condition, there are certain complications such as infective endocarditis, severe mitral regurgitation, heart failure, cerebral and coronary embolism events, arrhythmias and sudden death. Complications mostly occur in patients with heart murmurs and mitral insufficiency in contrast to patients with cusps.


Evidence of carcinogenicity in humans of water-soluble nickel salts.
Increased risks of nasal cancer and lung cancer in nickel refiners have been investigated scientifically and discussed since they were detected in the 1930s. Nickel compounds are considered to be the main cause of the cancer excess. Parts of the nickel producing industry and their consultants oppose the classification of water-soluble nickel salts as human carcinogens, and argue that the risk in exposed workers should be ascribed to other occupational exposures and smoking. Respiratory cancer risks in Welsh, Finnish, and Norwegian nickel refiners add to the evidence of carcinogenicity of water-soluble nickel. In Norwegian refiners, the first epidemiological study in 1973 identified high risks of lung cancer and nasal cancer among long-term electrolysis workers. Risk analyses based on exposure estimates developed in the 1980s supported the view that water-soluble nickel compounds were central in the development of cancer. Recently, new exposure estimates were worked out for the same cohort based on personal monitoring of total nickel and chemical determination of four forms of nickel. Additional data have been collected on life-time smoking habits, and on exposure to arsenic, asbestos, sulphuric acid mists, cobalt, and occupational lung carcinogens outside the refinery. After adjustment for these potential confounding exposures in case-control analyses, the risk pattern added to the evidence of an important role of water-soluble nickel compounds as causes of lung cancer. These Norwegian cancer studies rely on national Cancer Registry data, considered close to complete from 1953 onwards; and on National Population Register data continuously updated with mortality and emigration. Canadian mortality studies--perceived to offer the strongest support to the industry position not to recognise carcinogenicity of water-soluble nickel--appear to suffer from limitations in follow-up time, loss to follow-up, absence of risk analysis with individual exposure estimates, no confounder control, and a likely underestimation of cancer mortality. Rejection to recognise water-soluble nickel as a human carcinogen seems to contradict material epidemiological evidence that demonstrates a strong association between water-soluble nickel compounds and risks of lung cancer and nasal cancer. Independent international scientific bodies have classified nickel compounds as carcinogenic to humans, inclusive of water-soluble nickel.


Latent profile analysis of a cohort of patients with eating disorders not otherwise specified.
This article examined possible ways of classifying eating disorders not otherwise specified (EDNOS) using latent profile analysis (LPA). Of 687 patients being seen for an evaluation for an eating disorder, 284 were classified as having anorexia nervosa (AN) or bulimia nervosa (BN). LPA was performed on the remaining 403 cases (EDNOS). Five clusters were identified that characterized individuals who appeared to be: (1) subsyndromal restrictor AN patients that denied a great deal of eating disorder (ED) psychopathology; (2) subsyndromal ED patients, some but not all of whom were low weight; (3) subsyndromal BN with higher rates of vomiting than binge-eating; (4) primarily overweight individuals with low levels of ED pathology; or (5) overweight patients who most resembled binge eating disorder (BED). Most EDNOS cases resembled AN, BN, or BED cases and can be conceptualized several ways, one of which is to see them as existing on a continuum with the DSM-IV ED.


Career Development in Transitional Work Settings: A Qualitative Investigation Among Veterans and Vocational Counselors.
Veterans living with mental health conditions have ambitious career goals and want support to find employment that meets their interests and preferences. Despite calls from researchers to "invest" and "commit" to career development research and practice for individuals living with psychiatric conditions, we still do not have empirically tested models for facilitating career development among individuals with mental health conditions, especially veterans. This qualitative study investigates the career development needs and recommended intervention strategies of veterans living with mental health conditions. Vocational counselors from the Veterans Health Administration (VHA) and veterans receiving vocational rehabilitation services (N = 13) participated in semi-structured focus groups. Findings illuminate the tasks, barriers, interventions, implementation strategies, and transitional work context that hinder and support career development of veterans with mental health conditions. Findings offer theoretical and applied guidance to researchers and counselors regarding career development of veterans living with mental health conditions.