Temperature-controlled laser-soldering system and its clinical application for bonding skin incisions.
Laser tissue soldering is a method of repairing incisions. It involves the application of a biological solder to the approximated edges of the incision and heating it with a laser beam. A pilot clinical study was carried out on 10 patients who underwent laparoscopic cholecystectomy. Of the four abdominal incisions in each patient, two were sutured and two were laser soldered. Cicatrization, esthetical appearance, degree of pain, and pruritus in the incisions were examined on postoperative days 1, 7, and 30. The soldered wounds were watertight and healed well, with no discharge from these wounds or infection. The total closure time was equal in both methods, but the net soldering time was much shorter than suturing. There was no difference between the two types of wound closure with respect to the pain and pruritus on a follow-up of one month. Esthetically, the soldered incisions were estimated as good as the sutured ones. The present study confirmed that temperature-controlled laser soldering of human skin incisions is clinically feasible, and the results obtained were at least equivalent to those of standard suturing.


Dual delivery of hepatocyte and vascular endothelial growth factors via a protease-degradable hydrogel improves cardiac function in rats.
Acute myocardial infarction (MI) caused by ischemia and reperfusion (IR) is the most common cause of cardiac dysfunction due to local cell death and a temporally regulated inflammatory response. Current therapeutics are limited by delivery vehicles that do not address spatial and temporal aspects of healing. The aim of this study was to engineer biotherapeutic delivery materials to harness endogenous cell repair to enhance myocardial repair and function. We have previously engineered poly(ethylene glycol) (PEG)-based hydrogels to present cell adhesive motifs and deliver VEGF to promote vascularization in vivo. In the current study, bioactive hydrogels with a protease-degradable crosslinker were loaded with hepatocyte and vascular endothelial growth factors (HGF and VEGF, respectively) and delivered to the infarcted myocardium of rats. Release of both growth factors was accelerated in the presence of collagenase due to hydrogel degradation. When delivered to the border zones following ischemia-reperfusion injury, there was no acute effect on cardiac function as measured by echocardiography. Over time there was a significant increase in angiogenesis, stem cell recruitment, and a decrease in fibrosis in the dual growth factor delivery group that was significant compared with single growth factor therapy. This led to an improvement in chronic function as measured by both invasive hemodynamics and echocardiography. These data demonstrate that dual growth factor release of HGF and VEGF from a bioactive hydrogel has the capacity to significantly improve cardiac remodeling and function following IR injury.


Chest pain without significant coronary stenosis after implantation of sirolimus-eluting stents.
We encountered a case of exercise-induced chest pain after the implantation of sirolimus-eluting stents (SESs). She had no history of previous chest pain, and an exercise stress test just after the implantation of the SESs was negative without any symptoms. However, six months after the implantation of the SESs, she began to experience frequent episodes of severe chest pain on effort in spite of there being no significant coronary stenosis. Interestingly, severe coronary vasoconstriction was induced by an intracoronary administration of acetylcholine, and exercise stress testing revealed positive findings with chest pain and ST-T segment depression on ECG. An intensive treatment with two types of calcium channel blockers could readily and completely abolish the exercise-induced chest pain and ST-T segment depression on the ECG. In view of these findings, we presumed that coronary microvessel dysfunction and/or exercise-induced coronary vasoconstriction leading to myocardial ischemia had appeared 6 months after the implantation of the SESs. Although the pathogenesis of this phenomenon could not be completely elucidated, the anatomical and functional abnormalities of the coronary arteries associated with the implantation of the SESs may have been one of the most important mechanisms.


E-cadherin expression is regulated by miR-192/215 by a mechanism that is independent of the profibrotic effects of transforming growth factor-beta.
Increased deposition of extracellular matrix (ECM) within the kidney is driven by profibrotic mediators including transforming growth factor-beta (TGF-beta) and connective tissue growth factor (CTGF). We investigated whether some of their effects may be mediated through changes in expression of certain microRNAs (miRNAs). Proximal tubular cells, primary rat mesangial cells, and human podocytes were analyzed for changes in the expression of key genes, ECM proteins, and miRNA after exposure to TGF-beta (1-10 ng/microl). Tubular cells were also infected with CTGF-adenovirus. Kidneys from diabetic apoE mice were also analyzed for changes in gene expression and miRNA levels. TGF-beta treatment was associated with morphologic and phenotypic changes typical of epithelial-mesenchymal transition (EMT) including increased fibrogenesis in all renal cell types and decreased E-cadherin expression in tubular cells. TGF-beta treatment also modulated the expression of certain miRNAs, including decreased expression of miR-192/215 in tubular cells, mesangial cells, which are also decreased in diabetic kidney. Ectopic expression of miR-192/215 increased E-cadherin levels via repressed translation of ZEB2 mRNA, in the presence and absence of TGF-beta, as demonstrated by a ZEB2 3'-untranslated region luciferase reporter assay. However, ectopic expression of miR-192/215 did not affect the expression of matrix proteins or their induction by TGF-beta. In contrast, CTGF increased miR-192/215 levels, causing a decrease in ZEB2, and consequently increased E-cadherin mRNA. These data demonstrate the linking role of miRNA-192/215 and ZEB2 in TGF-beta/CTGF-mediated changes in E-cadherin expression. These changes appear to occur independently of augmentation of matrix protein synthesis, suggesting that a multistep EMT program is not necessary for fibrogenesis to occur.


Transmission of hepatitis B virus in dialysis units: a systematic review of reports on outbreaks.
Changes in the delivery of healthcare in the developed world have resulted in frequent reporting of outbreaks of hepatitis B virus (HBV) infection in nonhospital healthcare settings, including hemodialysis units. We performed a systematic review of HBV outbreaks in dialysis units of developed and less-developed countries published between 1992 and 2014 to elucidate the most frequent mechanisms of patient-to-patient transmission of HBV in this setting. The research was performed using the PubMed Database and the Outbreak Database; studies were selected according to the PRISMA algorithm. Inclusion criteria were established before the papers were retrieved in order to avoid selection biases. 12 papers reported on 16 outbreaks that involved 118 patients on maintenance dialysis; 10 fatal cases occurred. European outbreaks were smaller compared with the others (P = 0.0046). Information on specific transmission pathways was given in many outbreaks (n = 10; 62%); multiple deficiencies in standard or hemodialysis-specific procedures was the most common route of patient-to-patient transmission of HBV (80%, 8/10). De novo HBV from HBsAg negative/HBV DNA positive blood donors was found in 2 (20%) oubreaks. Sharing of contaminated HD machines was mentioned in 1 report. Our systematic review of HBV outbreaks shows that incomplete adherence to standard and dialysis-specific infection control precautions was the most important cause of patient-to-patient transmission of HBV in dialysis units. This review should serve as a reminder to HD providers that the risk of HBV infection is still present among patients undergoing dialysis and that HBV may be easily transmitted in the dialysis setting whenever appropriate infection control practices are not strictly applied.


Biodegradable bioartificial materials made with chitosan and poly(vinyl alcohol). Part I: Physicochemical characterization.
Polymers have widespread applications in therapeutics, and their use can play important structural and functional roles in different disease conditions. Bioartificial biodegradable materials, to be used as biomaterials and, in particular, as localized drug carriers, were prepared mixing chitosan (CHI) and poly(vinyl alcohol) (PVA), then manufactured as films, and finally cross-linked with glutaraldehyde (GTA), both in the absence and in the presence of the edible plasticizer sorbitol (SOR). The materials were characterized by Fourier-transform infrared (FTIR) spectroscopy, differential scanning calorimetry (DSC), ther-mogravimetric analysis (TGA), X-ray diffraction, scanning electron microscopy (SEM), and tensile test. The FTIR spectroscopy and the X-ray diffraction indicated that the presence of CHI lowers the crystallinity of PVA, and that the cross-linking with GTA does not modify the interactions between the two polymers, but only forms bridges between the different chains. In addition, the thermodynamic parameters for PVA, evaluated from the DSC measurements, confirmed that the PVA structure was less crystalline in the blends than in the pure state. The addition of SOR as a plasticizer to the CHI/PVA blends generally improved the characteristics of the films, making the cross-linked films less brittle, as confirmed by the SEM measurements and by the mechanical test. The TGA measurements confirmed the presence of chemical interactions between the polymers, as indicated by the DSC measurements. On the whole, the physicochemical properties of the blends showed the strong interactions existing between the component materials.


Efficacy of prolonged administration of intravenous erythromycin in an ambulatory setting as treatment of severe gastroparesis: one center's experience.
Intravenous erythromycin is a potent gastric prokinetic with demonstrated efficacy in the acute therapy of gastroparesis; long-term oral therapy has been limited by tolerance and modest efficacy. Our aim was to review our experience with prolonged administration of intravenous erythromycin in an ambulatory setting as therapy for severe gastroparesis, refractory to usual dietary and oral prokinetic regimens. We conducted a retrospective analysis of patients with gastroparesis treated with intravenous erythromycin for at least 1 month. Information on demographics; origin of gastroparesis; dosage, duration, and route of administration; clinical outcome in the short- and longer-term; and complications were determined. Eleven patients received a total of 14 courses of intravenous erythromycin for a median of 6.5 months (range, 1 to 19 months) at a median dosage of 300 mg/day (range, 150 to 1,000 mg/day). One patient received no benefit, two had complete responses, and all others reported some benefit. Two had dramatic relapse on cessation of therapy and subsequently improved on its resumption. Parenteral nutrition could be discontinued in one of four patients. There were four episodes of line sepsis; two required catheter removal. A nonocclusive thrombus developed at the site of a central line in one patient. Secondary infections or antibiotic resistance were not encountered. Prolonged administration of intravenous erythromycin in an ambulatory setting is feasible, well tolerated, and effective in patients with severe gastroparesis.


Downregulation of EIF5A2 by miR-221-3p inhibits cell proliferation, promotes cell cycle arrest and apoptosis in medulloblastoma cells.
Recently, miR-221-3p expression has been reported to be down-regulated in medulloblastoma (MB), but its functional effects remains unclear. In this study, quantitative real-time PCR (qRT-PCR) revealed significantly decreased miR-221-3p in MB cell lines. Transfection of miR-221-3p mimics reduced, or inhibitor increased cell proliferation in MB cells using MTT assay. Flow cytometry analysis indicated miR-221-3p overexpression promoted, while knockdown alleviated G0/G1 arrest and apoptosis. Luciferase reporter assay confirmed miR-221-3p directly targets the EIF5A2 gene. Moreover, restoration of EIF5A2 in the miR-221-3p-overexpressing DAOY cells significantly alleviated the suppressive effects of miR-221-3p on cell proliferation, cell cycle and apoptosis. Furthermore, miR-221-3p overexpression decreased CDK4, Cyclin D1 and Bcl-2 and increased Bad expression, which was reversed by EIF5A2 overexpression. These results uncovered the tumor suppressive role of miR-221-3p in MB cell proliferation at least in part via targeting EIF5A2, suggesting that miR-221-3p might be a potential candidate target for diagnosis and therapeutics of MB.


Fabrication and characterization of transparent nanocomposite films based on poly (lactic acid)/polyethylene glycol reinforced with nano glass flake.
Developing new biodegradable packaging with superior properties and advanced functionalities is one of the most emerging research areas of interest in food packaging. In this study, PLA/PEG-based nanocomposite films incorporated with different amounts of nano glass flake (NGF) (0, 0.5, 1, and 2 phr) were fabricated via casting solution for applications in food packaging. The ATR-FTIR displayed no chemical interaction between the PLA/PEG-based matrix and NGF particles. The scanning electron microscopy (SEM) observations exhibited a relatively smooth and homogeneous surface without defects. Incorporation of the NGF into the PLA/PEG-based matrix did not affect the color and opacity of the fabricated films. The prepared nanocomposite films were highly transparent and exhibited superior properties such as increased hydrophobicity, appreciable oxygen barrier properties, and enhanced thermal stability. Dynamic mechanical thermal analysis (DMTA) and differential scanning calorimetry (DSC) analysis confirmed the existence of a single glass-transition temperature (Tg) as evidence of miscibility. According to the research results, the PLA/PEG/NGF1 nanocomposite film significantly offered the best overall performance. This work has developed new insight into the potential application of nano glass flakes in food packaging.


Long-term Mortality and Disability in Cryptococcal Meningitis: A Systematic Literature Review.
Cryptococcal meningitis (CM) is the primary cause of meningitis in adults with human immunodeficiency virus (HIV) infection and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3-month) impact of CM (Cryptococcus neoformans and Cryptococcus gattii) on mortality and disability in HIV-infected and non-HIV-infected adults. Although the quality of current evidence is limited, the long-term impact of CM on survival and disability seems to be high. One-year mortality ranged from 13% in an Australian non-HIV-infected C. gattii-infected cohort to 78% in a Malawian HIV-infected cohort treated with fluconazole monotherapy. One-year impairment proportions among survivors ranged from 19% in an Australian C. gattii cohort to >70% in a Taiwanese non-HIV- and HIV-infected cohorts. Ongoing early therapeutic interventions, early detection of impairments and access to rehabilitation services may significantly improve patients' survival and quality of life.


Cluster, function and promoter: analysis of yeast expression array.
Gene clusters could be derived based on expression profiles, function categorization and promoter regions. To obtain thorough understanding of gene expression and regulation, the three aspects should be combined in an organic way. In this study, we explored the possible ways to analyze the large-scale gene expression data. Three approaches were used to analyze yeast temporal expression data: 1) start from clustering on the expression profiles followed by function categorization and promoter analysis, 2) start from function categorization followed by clustering on expression profiles and promoter analysis, and 3) start from clustering on the promoter region followed by clustering on expression profiles. For clustering analysis on the time-series data, we developed a largest-first algorithm, which provide a mechanism for quality control on clusters. For promoter analysis, we developed a core-extension algorithm.


Correlation between femoral tunnel length and tunnel position in ACL reconstruction.
The position of the femoral tunnel affects the osseous geometry available for drilling during anterior cruciate ligament (ACL) reconstruction. The length of the tunnel changes with changes in the tunnel position and may have implications for femoral fixation. Forty-seven patients with a single-bundle ACL reconstruction underwent computed tomography (CT) evaluation to generate three-dimensional (3D) CT bone models. With use of a previously described anatomic coordinate system, the center of the femoral tunnel was quantified in the posterior-anterior and proximal-distal dimensions on 3D CT. Tunnel length was defined as the distance between the centers of the intra-articular and extra-articular tunnel apertures. The reconstructed knees were dichotomized by anatomy and technique into anatomic (n = 20) and nonanatomic (n = 27) groups as well as according to whether they had undergone medial portal drilling (n = 20) or transtibial drilling (n = 27) for analysis. In addition, a review of the literature on the relationship between tunnel length and tendon-to-bone healing was performed. Femoral tunnels drilled with nonanatomic footprints were longer (mean [and standard deviation], 43.6 ± 8.5 mm; range, 28.2 to 60.7 mm) than tunnels drilled with anatomic footprints (31.0 ± 6.3 mm; 21.2 to 42.5 mm) (p < 0.001). Tunnels drilled transtibially (44.4 ± 7.6 mm; 32.5 to 60.7 mm) were significantly longer than tunnels drilled through the medial portal (29.8 ± 5.0 mm; 21.2 to 40.3 mm) (p < 0.001). There was a strong correlation between tunnel length and posterior-anterior femoral tunnel position (r = 0.78, p < 0.05), with more anterior tunnel positioning associated with greater tunnel length. There was no correlation between posterior-distal femoral tunnel position and tunnel length (r = -0.05; p = 0.74). There was no consensus in the literature regarding adequate tunnel length for biologic fixation. Femoral tunnels drilled with anatomic footprints had sufficient length for adequate femoral fixation. Femoral tunnels positioned anterior to the native insertion of the ACL were longer than those in anatomic position. The results of this study can help the surgeon to consider the relationship between tunnel position and subsequent tunnel length in ACL reconstruction.


Deletion of a Golgi protein in Trypanosoma cruzi reveals a critical role for Mn2+ in protein glycosylation needed for host cell invasion and intracellular replication.
Trypanosoma cruzi is a protist parasite and the causative agent of American trypanosomiasis or Chagas disease. The parasite life cycle in its mammalian host includes an intracellular stage, and glycosylated proteins play a key role in host-parasite interaction facilitating adhesion, invasion and immune evasion. Here, we report that a Golgi-localized Mn2+-Ca2+/H+ exchanger of T. cruzi (TcGDT1) is required for efficient protein glycosylation, host cell invasion, and intracellular replication. The Golgi localization was determined by immunofluorescence and electron microscopy assays. TcGDT1 was able to complement the growth defect of Saccharomyces cerevisiae null mutants of its ortholog ScGDT1 but ablation of TcGDT1 by CRISPR/Cas9 did not affect the growth of the insect stage of the parasite. The defect in protein glycosylation was rescued by Mn2+ supplementation to the growth medium, underscoring the importance of this transition metal for Golgi glycosylation of proteins.


Cell shape changes and transmembrane receptor uncoupling induced by tertiary amine local anesthetic.
Tertiary amine local anesthetics (dibucaine, tetracaine, procaine, etc.) modify cell morphology, concanavalin A (Con A)-mediated agglutinability and redistribution of Con A receptors. Con A agglutination of untransformed mouse 3T3 cells was enhanced at low concentrations of local anesthetics, and the dynamics of fluorescent-Con A indicated that ligand-induced clustering was increased in the presence of the drugs. In contast, these drugs inhibited Con A-induced receptor capping on mouse spleen cells. These effects can be duplicated by combinations of vinblastine (or colchicine) and cytochalasin B suggesting that local anesthetics act on microtubule and microfilament assemblies which are involved in the trans-membrane control of cell surface receptor mobility and distribution. It is proposed that tertiary amine local anesthetics displace plasma membrane-bound Ca2+, resulting in disengagement of microfilament systems from the plasma membrane and increased cellular Ca2+ concentration to levels which disrupt microtubular organization. The possible involvement of cellular Ca2+ in cytoskeletal destruction by local anesthetics was investigated utilizing Ca2+-specific ionophores A23187 and X537A. In media containing Ca2+ and cytochalasin B these ionophores caused effects similar to tertiary amine local anesthetics.


Release of tissue plasminogen activator and its fast-acting inhibitor in defective fibrinolysis.
Releasable tissue plasminogen activator (t-PA) and the fast inhibitor of t-PA were measured in 18 controls and a pedigree with venous thrombosis. The functional assay was performed by a technique that destroys the t-PA inhibitor when blood is drawn. It was found that activator and inhibitor levels varied widely in the control group. One patient demonstrated inhibitor levels, on two different occasions, of 2.82 and 3.54 IU of t-PA per milliliter of plasma, as compared with a releasable activator level of 1.87 IU/mL. The t-PA antigen levels of this patient and the remainder of the pedigree were essentially normal for all seven subjects. Thus, it is suggested that the previously reported fibrinolytic disorder in this pedigree represents an imbalance between activator and inhibitor levels rather than an actual deficiency of t-PA.


A high-throughput proteomic approach provides distinct signatures for thyroid cancer behavior.
Well-differentiated thyroid cancer (WDTC) is the most frequent form of endocrine neoplasia. One of the main challenges in the management of this disease is distinguishing low-risk patients who can be treated by surgical resection of the lesion from those with a high likelihood of recurrence who need a more extensive approach, including total thyroidectomy and radioiodine ablation. A tissue microarray (TMA) comprising 410 cases of WDTC was constructed with risk estimates for the following features: extrathyroidal extension, lymph node metastases, and vascular invasion. The variables examined were morphologic classification, candidate genetic, and proteomic biomarkers. BRAF (Raf kinase type B) mutant carriers showed increased risk of developing invasion compared with wild-type (WT) cases. However, when classified morphologically, classic papillary thyroid carcinomas (PTC) showed much higher risk estimates for invasive features compared with follicular variant PTCs (FVPTC); within these morphologic subgroups, BRAF mutational status did not provide independent risk estimates. Staining intensities for membranous galectin-3 (Gal3), HBME-1, and CK19 and nuclear Gal3 were statistically validated as markers of aggressive behavior. Estrogen receptor beta (ERβ) was overexpressed in lesions with invasive behavior. The utility of these biomarkers remained statistically significant in the FVPTC. In contrast, a different set of biomarkers proved effective in classic PTC where upregulation of cyclin D1, loss of p27, and overexpression of ERβ were associated with invasive behavior. Different proteomic signatures validate the distinction of classic and FVPTC and provide a practical clinical mechanism to predict the thyroid cancer behavior and stratify patients for clinical management.


Microelectrode fabrication by laser direct curing of tiny nanoparticle self-generated from organometallic ink.
In this paper, we present a new laser direct patterning method that selectively cures nanoparticles self-generated from organometallic ink by proper thermal decomposition. This approach has several advantages in the curing rate, resolution and pattern quality compared with the conventional nanoparticle ink based direct laser curing method. It was found that a laser wavelength which is more weakly absorbed by the nanoparticles could produce a more stable and homogeneous curing condition. Finally, arbitrary shaped silver electrodes with narrow width and uniform profile could be achieved on a polymer substrate at a high curing rate of 25 mm/s. This process can be applied for flexible electronics fabrications on heat sensitive polymer substrates.


Employing computer technology to assess visual attention in young children and adolescents with severe mental retardation.
The intent of this investigation was to establish a valid and sensitive computer measurement technique for educational assessment applications. An integral part of the investigation was to establish the similarities and differences in how prior reinforcement histories of individual stimuli affect attention to compound visual cues for young children of normal development versus adolescents with severe mental retardation, both groups having comparable mental age. A series of identical conflict compound discrimination tasks was presented to the two groups. In addition, generalization effects were investigated for both groups by presenting compounds containing some or all novel cues. The similarities and differences in performance for young children of normal development and adolescents with severe mental retardation were analyzed using multiple testing procedures. In addition to assessing stimulus control by presenting stimulus components separately following acquisition of compound discriminations, response topographies of the compound stimuli were recorded with a touch screen attached to a computer monitor screen. This study demonstrated that overselective attention did not occur only for students with severe mental retardation but also for young children of normal development if multiple tests were employed. A difference was found, however, between the two populations in the efficiency with which they shifted attention among elements of complex stimuli depending on prior conditioning histories. Presentation of compounds whose components had conflicting reinforcement histories was found to be a more sensitive assessment technique than presentation of compounds containing some or all novel components for distinguishing between the two groups. The use of multiple testing procedures was critical in preventing false conclusions from altered test performances arising from reinforcement contingencies in effect during the test.


Newly derived children-based food index. An index that may detect childhood overweight and obesity.
A food index (FI) based on a priory knowledge was developed to assess the role of diet on overweight (OW) and obesity (OB) in school-aged children. This included «positive» and «negative» foods based on research evidence and food guidelines, with scores set accordingly. Statistical tests were used to strengthen the sensitivity of the index. The FI was validated using data from the GRECO study. The score ranged from 17 to 53.5 (mean 34.8 ± 5.01) and was inversely associated with body mass index (BMI) (-0.057 ± 0.02; 95% CI -0.098, -0.017) and waist circumference (WC) (-0.08 ± 0.03, 95% CI: -0.137, -0.022). Associations remained significant upon adjusting for age, gender and physical-inactivity (p = 0.02 ad 0.013, respectively). When stratified by gender, the association between FI and WC was not significant for boys (p = 0.08). The association with BMI remained significant for females and males (p = 0.047 and 0.037, respectively). The derived FI seems a valuable tool in detecting OW in children.


Detection of alphaII-spectrin and breakdown products in humans after severe traumatic brain injury.
alphaII-Spectrin is the major structural component of the cortical membrane cytoskeleton. It is a major substrate for the calpain and caspase-3 cysteine proteases there are considerable evidence that alfaII-spectrin is processed by the calpains and caspase-3 to signature cleavage products in vivo after experimental traumatic brain injury (TBI). We sought to determine whether aII-spectrin proteolysis is a potentially reliable biomarker for TBI in humans measuring the levels of spectrin and spectrin breakdown products (SBDPs) in cerebrospinal fluid (CSF) from adults with severe TBI, and studying the relationship between these levels and clinical outcome. This prospective case control study enrolled 8 patients with severe TBI, defined by a Glasgow Coma Score (GCS) of <8, and requiring intraventricular pressure monitoring. Patients without TBI requiring CSF drainage served as controls. Ventricular CSF was drained from each patient at 6, 12, 24, 48, 72, and 96 h following TBI and measured for spectrin and SBDPs. Outcome was assessed using the Glasgow Outcome Score (GOS) 6 months after injury. CSF alphaII-spectrin and calpain and caspase-3 mediated SBDP levels were significantly increased compared to control patients at all time points examined (P<0.001). In patients with a better outcome, CSF spectrin and SBDPs significantly decreased from 6 to 96 h. Patients whose spectrin and SBDP levels remained elevated or failed to decline had a worse outcome (P<0.019). The present work provides the first evidence that protein degradation of alphaII-spectrin is a reliable marker of severe TBI in humans and that both necrotic and apoptotic cell death mechanisms are activated in humans following a severe TBI. Moreover, the temporal profile of degradation may be an important indicator of clinical outcome.


Expression of muscarinic acetylcholine receptors M3 and M5 in osteoporosis.
Cholinergic signaling via muscarinic acetylcholine receptors (mAChR) is known to influence various physiological functions. In bone, M3 mAChR and M5 mAChR were identified on the membrane of osteoblast-like cells. M3 mAChR seems to be particularly relevant for bone physiology, as signaling via this receptor was reported to increase bone formation and decrease bone resorption. Thus, in the present study we investigated the relative mRNA expression of M3 and M5 mAChR in bones of a rat osteoporosis model. Osteoporosis was induced in Sprague-Dawley rats by bilateral ovariectomy and additional feeding of a diet deficient in calcium, vitamins C, D2, D3, and phosphorus, and free of soy and phytoestrogen. After a period of 3, 12, and 14 months, relative mRNA expression of M3 mAChR and M5 mAChR was analyzed in the 11th thoracic vertebra by real-time RT-PCR. Relative mRNA expression of M3 mAChR was significantly reduced in bones of osteoporotic rats compared to sham operated animals that served as controls. Further, M3 mAChR mRNA expression was significantly down-regulated when comparing 14-month osteoporotic rats to 3-month osteoporotic rats. Relative M5 mAChR mRNA was expressed to a lesser extent than M3 mAChR and did not show significant differences in mRNA expression level between the experimental groups. M3 mAChR mRNA expression was reduced upon induction of osteoporosis and progression of disease was associated with further decrease of this receptor, indicating that M3 mAChR is involved in the development and regulation of osteoporosis.


In vivo IL-18 supplementation ameliorates lethal acute lung injury in burn-primed endotoxemic mice: a novel anti-inflammatory role of IL-18.
Previously, we have found that a prior burn insult induces lethal acute lung injury (ALI) and overproduction of proinflammatory cytokines after LPS challenge in mice. The current study was aimed to determine the role of IL-18 in burn-induced LPS hypersensitivity. Except sham group, mice were subjected to a 15% total body surface area full-thickness burn and either untreated or treated with IL-18 alone, IL-18 + anti-IL-10 antibody or IL-18 + isotype immunoglobulin G. LPS was intravenously administered to all mice on the 11th day, and the mice were killed at the indicated time point, or survival was examined. We additionally examined cytokine production by splenic cells in vitro for the elucidation of immunologic mechanisms. Unexpectedly, the liver IL-18 decreased transiently after burn injury, and in vivo IL-18 supplementation improved survival and ameliorated ALI, as well as reducing the lung contents of all cytokines examined, except IL-10. Neutralization of IL-10 cancelled the protective effect of IL-18. In splenic macrophages obtained from burned mice, the production of macrophage inflammatory protein 2 (MIP-2), TNF-alpha, and IL-10 was augmented, whereas in vivo IL-18 supplementation decreased MIP-2 production, but increased IL-10 production. Furthermore, a physiological concentration of IL-18 directly attenuated MIP-2 production by splenic cells in vitro. Burn injury induces LPS hypersensitivity through augmented production of proinflammatory cytokines by systemic macrophages. IL-18 supplementation is protective for LPS-induced lethal ALI through the direct anti-inflammatory effect on macrophages as well as by in vivo acceleration of IL-10 production, and could thus be an effective prophylactic strategy against septic complications in critically ill patients.


High maternal body weight and pregnancy outcome.
Evidence of adverse perinatal outcomes among infants of obese pregnant women is confirmed by results of a large Swedish, population-based cohort study. Increasing maternal body weight was associated with perinatal mortality, although it protected against the delivery of a small-for-gestational-age infant.


Cyclin-dependent kinase 5-mediated phosphorylation of chloride intracellular channel 4 promotes oxidative stress-induced neuronal death.
Oxidative stress can cause apoptosis in neurons and may result in neurodegenerative diseases. However, the signaling mechanisms leading to oxidative stress-induced neuronal apoptosis are not fully understood. Oxidative stress stimulates aberrant activation of cyclin-dependent kinase 5 (CDK5), thought to promote neuronal apoptosis by phosphorylating many cell death-related substrates. Here, using protein pulldown methods, immunofluorescence experiments and in vitro kinase assays, we identified chloride intracellular channel 4 (CLIC4), the expression of which increases during neuronal apoptosis, as a CDK5 substrate. We found that activated CDK5 phosphorylated serine 108 in CLIC4, increasing CLIC4 protein stability, and accumulation. Pharmacological inhibition or shRNA-mediated silencing of CDK5 decreased CLIC4 levels in neurons. Moreover, CLIC4 overexpression led to neuronal apoptosis, whereas knockdown or pharmacological inhibition of CLIC4 attenuated H2O2-induced neuronal apoptosis. These results implied that CLIC4, by acting as a substrate of CDK5, mediated neuronal apoptosis induced by aberrant CDK5 activation. Targeting CLIC4 in neurons may therefore provide a therapeutic approach for managing progressive neurodegenerative diseases that arise from neuronal apoptosis.


Anteromedial tibial tubercle transfer without bone graft.
We followed 30 patients for more than 2 years after anteromedial tibial tubercle transfer for persistent patellofemoral pain associated with patellar articular degeneration. Twelve of these patients were followed more than 5 years. We report 93% good and excellent results subjectively and 89% good and excellent results objectively. The quality of improvement was sustained in all 12 of the patients who were evaluated again after more than 5 years from surgery. When examined separately, 75% of those patients with advanced patellar arthrosis achieved a good result; none of these patients achieved an excellent result. Postoperative continuous passive motion has markedly reduced the incidence of stiffness. Serious complications such as compartment syndrome, infection, and skin slough were avoided completely in 51 consecutive cases. Patellofemoral contact pressure studies in five cadaver knees have shown that anteromedial tibial tubercle transfer can provide substantial reduction of patellofemoral contact stress while helping to balance medial and lateral facet pressures. This surgical procedure is mechanically and clinically successful for alleviating intractable pain related to patellar malalignment and articular degeneration. This procedure enables the majority of appropriately selected patients with malalignment and patellar articular degeneration to resume increased levels of activity with substantially diminished pain.


Epitaxial graphene/silicon carbide intercalation: a minireview on graphene modulation and unique 2D materials.
Intercalation of atomic species through epitaxial graphene on silicon carbide began only a few years following its initial report in 2004. The impact of intercalation on the electronic properties of the graphene is well known; however, the intercalant itself can also exhibit intriguing properties not found in nature. This realization has inspired new interest in epitaxial graphene/silicon carbide (EG/SiC) intercalation, where the scope of the technique extends beyond modulation of graphene properties to the creation of new 2D forms of 3D materials. The mission of this minireview is to provide a concise introduction to EG/SiC intercalation and to demonstrate a simplified approach to EG/SiC intercalation. We summarize the primary techniques used to achieve and characterize EG/SiC intercalation, and show that thermal evaporation-based methods can effectively substitute for more complex synthesis techniques, enabling large-scale intercalation of non-refractory metals and compounds including two-dimensional silver (2D-Ag) and gallium nitride (2D-GaNx).


Endoscopic treatment of Barrett's esophagus: From metaplasia to intramucosal carcinoma.
The annual incidence of adenocarcinoma arising from Barrett's esophagus (BE) is approximately 0.5%. Through a process of gradual transformation from low-grade dysplasia to high-grade dysplasia (HGD), adenocarcinoma can develop in the setting of BE. The clinical importance of appropriate identification and treatment of BE in its various stages, from intestinal metaplasia to intramucosal carcinoma (IMC) hinges on the dramatically different prognostic status between early neoplasia and more advanced stages. Once a patient has symptoms of adenocarcinoma, there is usually locally advanced disease with an approximate 5-year survival rate of about 20%. Esophagectomy has been the gold standard treatment for BE with HGD, due to the suspected risk of harboring occult invasive carcinoma, which was traditionally estimated to be as high as 40%. In recent years, the paradigm of BE early neoplasia management has recently evolved, and endoscopic therapies (endoscopic mucosal resection, radiofrequency ablation, and cryotherapy) have entered the clinical forefront as acceptable non-surgical alternatives for HGD and IMC. The goal of endoscopic therapy for HGD or IMC is to ablate all BE epithelium (both dysplastic and non-dysplastic) due to risk of synchronous/metachronous lesion development in the remaining BE segment.


A new look at IgE beyond allergies.
Immunoglobulin E (IgE), though constitutively present at low levels, is most commonly studied in atopic disease where it plays a vital role in mast cell degranulation and in initiating a T helper 2 (Th2) response. With the advent of better detection assays, however, researchers are discovering the importance of IgE in actively contributing to many disease states and pathologies. This review will discuss the latest findings in IgE beyond its role in allergies and recently discovered roles for IgE in its cell-bound form on FcεRI-expressing effector cells like monocytes and dendritic cells. In terms of parasites, we will discuss helminth-induced IgE that appears to protect the worms from immune recognition and a tick-borne illness that elicits an IgE response against red meat. Next, we describe recent findings of how auto-reactive IgE can contribute to the progression of lupus and induce organ damage. Finally, we summarize the emerging roles of IgE in tumor surveillance and antibody-dependent cytotoxicity. We additionally discuss recent or ongoing clinical trials that either target harmful IgE or use the unique characteristics of the isotype.


Amplified spontaneous emission in graded-index polymer optical fibers: theory and experiment.
In this work we analyze experimentally and theoretically the properties of amplified spontaneous emission (ASE) in a rhodamine-6G-doped graded-index polymer optical fiber. A theoretical model based on the laser rate equations describes the ASE features successfully. The dependence of the ASE threshold and efficiency on fiber length is analyzed in detail.


Modulatory effects of bovine seminal plasma on uterine inflammatory processes.
In this study, a simple model to simulate a uterine environment affected by subclinical endometritis was established by culturing isolated primary bovine uterine epithelial cells (pbUEC). Co-incubation of pbUEC and polymorphonuclear (PMN) granulocytes derived from peripheral bovine blood samples, was performed before testing the cell culture supernatant for production of interleukin-8 (IL-8) via ELISA. Cytokine secretion was only detectable after co-incubation of pbUEC with PMN, whereas neither pbUEC nor PMN alone generated IL-8 in relevant chemo attractive doses. Another objective was to examine the influence of bovine seminal plasma (SP) and vesicular gland fluid (VGF) on various functional parameters of PMN including cell viability, production of reactive oxygen species and chemotaxis. Analysis of these effects was conducted by flow cytometry. Viability of PMN was determined by staining the cells with propidium iodide. Seminal plasma was added to suspensions of PMN in increasing increments and resulted in a significant increase of cell membrane damaged PMN when using SP concentrations above 0.2%. The reactive oxygen species production of PMN suspensions, stimulated with phorbol-12-myristate-13-acetate, was significantly decreased by 30% up to 90% when adding 0.06-30‰ of either SP or VGF. The PMN transmigration induced by IL-8 was diminished by 50% when 0.4‰ of either SP or VGF were added. The results of this study indicate a potential regulatory impact of SP and VGF on inflammatory processes in the bovine uterus.


COG133 Attenuates the Early Brain Injury Induced by Blood-Brain Barrier Disruption in Experimental Subarachnoid Hemorrhage.
Subarachnoid hemorrhage (SAH) is a kind of severe hemorrhagic stroke, and early brain injury acted as one of the main causes of death and delayed neurological deficit in patients with subarachnoid hemorrhage. In this process, the function and structural integrity of the blood-brain barrier play an important role. In this study, we have observed whether the apolipoprotein E (apoE) mimetic peptide, COG133, can alleviate early brain injury after subarachnoid hemorrhage. For this purpose, an experimental subarachnoid hemorrhage model was constructed in mice and treated by intravenous injection of COG133 at a dosage of 1 mg/kg. Then, the function and integrity of the blood-brain barrier were detected, and the pyroptosis level of the neuron was determined. The results showed that COG133 could protect blood-brain barrier function and structure integrity, reduce early brain injury, and ameliorate neurological function after subarachnoid hemorrhage. In terms of molecular mechanism, COG133 inhibits blood-brain barrier destruction through the proinflammatory CypA-NF-κB-MMP9 pathway and reduces neuronal pyroptosis by inhibiting NLRP3 inflammasome activation. In conclusion, this study demonstrated that apoE-mimetic peptide, COG133, can play a neuroprotective role by protecting blood-brain barrier function and inhibiting brain cell pyroptosis to reduce early brain injury after subarachnoid hemorrhage.


Increased cerebral oxidative damage and decreased antioxidant defenses in ovariectomized and sham-operated rats supplemented with vitamin A.
Previous studies have linked oxidative stress with aging and aging-related processes, including menopause. Abnormalities in the redox state similar to those observed in menopausal women can be modeled experimentally with rat ovariectomy. The aim of the present study was to investigate the effects of vitamin A (retinol palmitate) supplementation (500 or 1,500 IU kg(-1) day(-1) for 30 days) on behavioral parameters and brain redox profile in ovariectomized (OVX) and sham-operated rats. Ovariectomy caused pronounced uterine atrophy and decreased locomotor/exploratory activity. Moreover, we found increased hypothalamic and frontal cortex superoxide dismutase/catalase (SOD/CAT) ratio and decreased hippocampal thiol content, accompanied by increased frontal cortex lipid oxidative damage (TBARS) in OVX rats. Vitamin A at 1,500 IUkg(-1) day(-1) decreased exploratory behavior and decreased total hippocampal thiol content in sham-operated rats, increased hippocampal SOD/CAT ratio and decreased total antioxidant potential in the hippocampus of both sham and OVX groups, and increased cortical TBARS levels in OVX rats. Thus, vitamin A may induce a pro-oxidant state in discrete brain regions of sham-operated and OVX rats. These results suggest some caution regarding the use of high doses of vitamin A supplementation during menopause.


The interplay of socio-economic status represented by paternal educational level, white matter structure and reading.
A child's school achievement is influenced by environmental factors. The environmental factors, when represented by socio-economic status (SES) of the family, have been demonstrated to be related to the reading skills of a child. The neural correlates of the relation between SES and reading have been less thoroughly investigated. The present study expands current research by exploring the relation between SES, quantified by paternal educational level, reading of the offspring and the structure of white matter pathways in the left hemisphere as derived from DTI-based tractography analyses. Therefore, three dorsal white matter pathways, i.e. the long, anterior and posterior segments of the arcuate fasciculus (AF), and three ventral white matter pathways, i.e. the inferior fronto-occipital fasciculus (IFOF), the inferior longitudinal fasciculus (ILF) and the uncinate fasciculus (UF), were manually dissected in the left hemisphere of 34 adolescents with a wide range of reading skills. The results demonstrated a relation between word reading, SES quantified by paternal educational level, and fractional anisotropy (FA) within the left dorsal AF segment and the left ventral UF. Thus, the present study proposes a relationship between paternal educational level and a specific white matter pathway that is important for reading, aiming to guide future research that can determine processes underlying this relationship.


Evaluation of Meniscal Tissue after Meniscal Repair Using Ultrahigh Field MRI.
The study evaluates the meniscal tissue after primary meniscal suturing using 7-Tesla (T) magnetic resonance imaging with T2* mapping at 6 and 12 months after surgery to investigate the differences between repaired meniscal tissue and healthy meniscal tissue in the medial and lateral compartment. This prospective study included 11 patients (9m/2f) with a mean age of 30.6 years (standard deviation 9.0). Patients with a meniscal tear that was treated arthroscopically with meniscus suturing, using an all-inside technique, were included. All patients and seven healthy volunteers were imaged on a 7-T whole-body system. T2* mapping of the meniscus was applied on sagittal slices. Regions-of-interest were defined manually in the red and white zone of each medial and lateral meniscus to measure T2*-values. In the medial posterior and medial anterior horn similar T2*-values were measured in the red and white zone at 6- and 12-month follow-up. Compared with the control group higher T2*-values were found in the repaired medial meniscus. After 12-months T2*-values decreased to normal values in the anterior horn and remained elevated in the posterior horn. In the red zone of the lateral posterior horn a significant decrease in the T2*-values (from 8.2 milliseconds to 5.9 milliseconds) (p = 0.04), indicates successful repair; a tendency toward a decrease in the white zone between the 6 and 12 months follow-up was observed. In the red zone of the lateral anterior horn the T2*-values decreased significantly during follow-up and in the white zone of the lateral anterior horn T2*-values were comparable. In comparison to the control group higher T2*-values were measured at 6-months; however, the T2*-values showed comparable values in the repaired lateral meniscus after 12 months. The T2* mapping results of the current study indicated a better healing response of the red zone of the lateral posterior horn compared with the medial posterior horn.


The Six Sigma initiative at Mount Sinai Medical Center.
Lean Six Sigma, in various forms, has been used widely in many Fortune 500 companies. Motorola, General Electric, Sony, American Express, and Bechtel all use Six Sigma to improve quality and performance. While the impact of this methodology has been documented extensively by the press in manufacturing and transactional settings, less evidence is available regarding its utility in health care environments. Mount Sinai Medical Center initiated a Six Sigma program in 2000 to determine its applicability and value in a large academic medical center. This article discusses Mount Sinai Medical Center's experience adapting this methodology to improve both patient care and business processes and outcomes. We present an overview of Six Sigma, and offer examples of projects undertaken using this data-driven approach to performance improvement. Lastly, the article provides insights and lessons learned regarding this organization-wide experience.


Community Partners in Care: Leveraging Community Diversity to Improve Depression Care for Underserved Populations.
Research suggests that the quality and outcomes of depression treatment for adults can be substantially improved through "collaborative care" programs. However, there is a lack of resources required to implement such programs in vulnerable communities. Our paper examines the planning phase of the Community Partners in Care (CPIC) initiative, which addresses this problem through a unique approach in which academic institutions partner directly with a wide range of community-based and service organizations in all phases of the project fielded in two underserved communities in Los Angeles. CPIC offers a unique opportunity to understand how diverse organizations can work together to address community depression care needs and to analyze the potential strengths and tradeoffs of coordinating among such varied entities. This article focuses on intra-group dynamics that surround the process of participatory research and reports results of the first wave of process evaluation of the planning phase of the CPIC initiative. Our analysis explores two main themes: Community-Partnered Participatory Research and benefits and challenges of collaboration in diverse groups.


Understanding iron homeostasis through genetic analysis of hemochromatosis and related disorders.
Genetic analysis of hemochromatosis has led to the discovery of a number of genes whose mutations disrupt iron homeostasis and lead to iron overload. The introduction of molecular tests into clinical practice has provided a tool for early diagnosis of these conditions. It has become clear that hemochromatosis includes a spectrum of disorders that range from simple biochemical abnormalities to chronic asymptomatic tissue damage in midlife to serious life-threatening diseases in young subjects. Molecular studies have identified the systemic loop that controls iron homeostasis and is centered on the hepcidin-ferroportin interaction. The complexity of this regulatory pathway accounts for the genetic heterogeneity of hemochromatosis and related disorders and raises the possibility that genes encoding components of the pathway may be modifiers of the main genotype. Molecular diagnosis has improved the classification of the genetic conditions leading to iron overload and identified novel entities, characterized by both iron loading and variable degrees of anemia. Despite the progress in the diagnosis, classification, and mechanisms of iron overload disorders, the treatment of affected patients continues to rely on regular phlebotomy. Understanding the molecular circuitry of iron control may lead to the identification of potential therapeutic targets for novel treatment strategies to be used in association with or as an alternative to phlebotomy.


Auditory stimulation enhances thalamic somatosensory high-frequency oscillations in healthy humans: a neurophysiological marker of cross-sensory sensitization?
Electrical stimulation of upper limb nerves evokes a train of high-frequency wavelets (high-frequency oscillations, HFOs) on the human scalp. These HFOs are related to the influence of arousal-promoting structures on somatosensory input processing, and are generated in the primary somatosensory cortex (post-synaptic HFOs) and the terminal tracts of thalamocortical radiations (pre-synaptic HFOs). We previously reported that HFOs do not undergo habituation to repeated stimulations; here, we verified whether HFOs could be modulated by external sensitizing stimuli. We recorded somatosensory evoked potentials (SSEPs) in 15 healthy volunteers before and after sensitization training with an auditory stimulus. Pre-synaptic HFO amplitudes, reflecting somatosensory thalamic/thalamocortical activity, significantly increased after the sensitizing acoustic stimulation, whereas both the low-frequency N20 SSEP component and post-synaptic HFOs were unaffected. Cross-talk between subcortical arousal-related structures is a probable mechanism for the pre-synaptic HFO effect observed in this study. We propose that part of the ascending somatosensory input encoded in HFOs is specifically able to convey sensitized inputs. This preferential involvement in sensitization mechanisms suggests that HFOs play a critical role in the detection of potentially relevant stimuli, and act at very early stages of somatosensory input processing.


RAS inhibitors decrease apoptosis of acinar cells and increase elimination of pancreatic stellate cells after in the course of experimental chronic pancreatitis induced by dibutyltin dichloride.
Chronic pancreatitis (CP) is a progressive disease, in which the exocrine function of the gland is gradually lost and fibrosis develops due to repeated episodes of acute pancreatitis. The aim of the study was to investigate the effects of RAS inhibitors on the apoptosis of acinar cells and pancreatic stellate cells (PSCs) elimination in experimental CP induced by dibutyltin dichloride (DBTC). CP was induced by administration of DBTC to the femoral vein. Simultaneously captopril, losartan, enalapril and lisinopril were administered intraperitoneally. The rats were decapitated after 60 days and tissue of pancreas was collected. In rats treated by DBTC the features of inflammatory infiltration, ductal lumen dilatation, fibrosis were found. Strong reactivity with caspase2(L) and clusterin-beta antibodies was observed in areas of fibrosis. In animals treated with RAS inhibitors inflammatory changes and fibrosis were less severe. In groups of rats treated with DBTC and RAS inhibitors immunoreactivity of caspase(2L) and clusterin-beta was weak. Positive immunostaining against smooth muscle actine and desmin was observed in the elongated cells (PSC-s). This reaction was weak in groups of rat treated with DBTC and RAS inhibitors. Treatment of CP rats with RAS inhibitors alleviate apoptosis of pancreatic acinar cells and induces PSCs elimination.


Personality Disorder Symptoms and Suicidality: Low Desire and High Plans for Suicide in Military Inpatients and Outpatients.
This study characterizes the personality disorder (PD) symptoms of patients who endorse a perplexing combination of low desire and high plans for suicide. Five PD (antisocial, narcissistic, borderline, dependent, avoidant) symptoms were examined at the junction of two suicide risk factors: (a) suicidal desire/ideation and (b) resolved plans/preparations. Participants (N = 250) were recruited from U.S. Army Medical Center affiliated sites, including two outpatient clinics, an inpatient facility, and an emergency room. Self-report measures of PD and suicide symptoms were administered. The interaction of desire and plans was entered into multiple regression equations predicting PD symptoms. Patients endorsing low desire and high plans for suicide reported significantly more antisocial and narcissistic symptoms and fewer borderline, avoidant, and dependent PD symptoms. These findings support the existence of patients who endorse suicide plans in the absence of strong suicidal desire and suggest that they display antisocial and narcissistic personality characteristics. Future directions and clinical implications are discussed.


Anti-Inflammatory Effect of Technologically Processed Antibodies to the Molecules of the Major Histocompatibility Complex in a Model of Acute Inflammation In Vivo.
The anti-inflammatory effect of technologically processed antibodies (TPA) to immune targets (MHC I and MHC II) was assessed in the carrageenan-induced rat paw edema model. The parameters "increase in edema" and "suppression of edema" significantly decreased (p<0.05) against the background of treatment with TPA and the reference drug indomethacin compared to the placebo group. The tested TPA produced an anti-inflammatory effect.


The multi-allelic APRR2 gene is associated with fruit pigment accumulation in melon and watermelon.
Color and pigment contents are important aspects of fruit quality and consumer acceptance of cucurbit crops. Here, we describe the independent mapping and cloning of a common causative APRR2 gene regulating pigment accumulation in melon and watermelon. We initially show that the APRR2 transcription factor is causative for the qualitative difference between dark and light green rind in both crops. Further analyses establish the link between sequence or expression level variations in the CmAPRR2 gene and pigment content in the rind and flesh of mature melon fruits. A genome-wide association study (GWAS) of young fruit rind color in a panel composed of 177 diverse melon accessions did not result in any significant association, leading to an earlier assumption that multiple genes are involved in shaping the overall phenotypic variation in this trait. Through resequencing of 25 representative accessions and allelism tests between light rind accessions, we show that multiple independent single nucleotide polymorphisms in the CmAPRR2 gene are causative of the light rind phenotype. The multi-haplotypic nature of this gene explains the lack of detection power obtained through genotyping by sequencing-based GWAS and confirms the pivotal role of this gene in shaping fruit color variation in melon. This study demonstrates the power of combining bi- and multi-allelic designs with deep sequencing, to resolve lack of power due to high haplotypic diversity and low allele frequencies. Due to its central role and broad effect on pigment accumulation in fruits, the APRR2 gene is an attractive target for carotenoid bio-fortification of cucurbit crops.


Cancer-associated thrombosis: What about microRNAs targeting the tissue factor coagulation pathway?
Cancer patients are often diagnosed with venous thromboembolism (VTE), a cardiovascular disease that substantially decreases their quality of life and survival rate. Haemostasis in these patients is deregulated, which is reflected in the common presentation of a blood hypercoagulation state. Despite the inconsistent results, existing evidence suggests that the expression of microRNAs (miRNAs) is deregulated in the context of venous thrombogenesis in the general population. However, few miRNAs are known to be linked to cancer-associated VTE due to the lack of studies with oncological patients. Parallelly, coagulation factor III, also known as tissue factor (TF), tissue factor pathway inhibitor 1 (TFPI1) and tissue factor pathway inhibitor 2 (TFPI2) have been proposed to have a central role in cancer-associated VTE and tumour progression. However, contrary to what was expected, the role of miRNAs targeting the TF coagulation pathway (or extrinsic coagulation pathway) is poorly explored in cancer-induced thrombogenesis. In this review, in addition to miRNAs implicated in VTE, TF and TFPI1/2-targeting miRNAs were revised. Future studies should clarify the implications of these non-coding RNAs in tumour coagulome.


Trajectories of social resource use among informal lung cancer caregivers.
Social support is a key component in maintaining cancer caregiver well-being, and many resources exist to facilitate caregivers' use of social support (eg, cancer support groups). This study sought to determine how informal cancer caregivers use social resources over the course of caregiving. The data are from the Comprehensive Health Enhancement Support System study of informal caregivers (n = 202) of patients with recently diagnosed lung cancer. Caregivers self-reported their sociodemographic and caregiving characteristics and social resource use over 6 months. Generalized additive models were used to assess social resource use over time, and generalized estimating equation logistic regression models were used to assess the correlates of social resource use. Nearly two-thirds of caregivers reported any social resource use. The most prevalent social resources were faith-based groups (38%) and social clubs (30%). Only 1 in 4 caregivers participated in a formal resource such as counseling (11%) or a cancer support group (6%). Social resource use was lowest immediately after the diagnosis and increased over time. Formal resource use exhibited a nonlinear association with time such that formal resource use peaked approximately 9 to 10 months after the cancer diagnosis. Caregivers were more likely to report social resource use if the patient also reported social engagement. This study has found that many cancer caregivers do not use social resources, although social resource use increases over time after the cancer diagnosis. Because of the association between social engagement and well-being, this information may inform future research and interventions to improve outcomes for cancer caregivers and their families.


Anti-Tumor and Anti-Metastasis Effects of Berbamine-Loaded Lipid Nanoparticles on Pancreatic Cancer.
The aim of the study was to investigate the therapeutic potential of Berbamine-loaded lipid nanoparticles (BBM-NPs) in pancreatic cancer. Dopamine polymerization-polylactide-TPGS nanoparticles were synthesized to prepare BBM-NPs, and the change in particle size of BBM-NPs was measured. Cell Counting Kit-8 (CCK8) assay, plate cloning experiment, and apoptosis analysis were performed to evaluate the cytotoxicity of BBM-NPs against the pancreatic cancer cells (PANC-1 and AsPC-1). Migration and invasion abilities of the tumor cells were determined by Transwell and wound healing assays. The intracellular level of ROS and expression of tumor progression-related proteins were measured using ROS-kit and western blot assay. Besides, an in vivo study was performed in the Balb/c nude mice to analyze the function of BBM-NPs in tumor growth. The in vitro studies showed that BBM-NPs with stable particle size and sustained drug release effectively inhibited the viability, proliferation, migration, and invasion of pancreatic cancer cells, while promoting cell apoptosis. Moreover, the in vivo experiments revealed that compared to Free BBM, BBM-NPs exhibited a stronger inhibitory effect on the growth of xenograft tumors derived from PANC-1 cells in mice. In addition, increased expressions of ROS, Bax, Cleaved Caspase-3, and γ-H2AX, as well as decreased expressions of MMP2, MMP9 and Bcl-2 were identified in both Free BBM and BBM-NPs groups, while BBM-NPs exhibited a stronger effect on protein expression than Free BBM. In summary, BBM-loaded lipid nanoparticles enhanced the therapeutic effects of BBM on pancreatic cancer, providing a promising strategy for targeted cancer therapy.


Capitation funding in Australia: imperatives and impediments.
Health service funding mechanisms are pivotal in the pursuit of health system objectives, as they provide strong financial incentives for actors in the system to achieve policy goals. Underpinning funding mechanisms is a set of key economic principles, or objectives, that should guide their design and use: efficiency, equity, and accountability. The Australian health system has historically performed relatively poorly in relation to these objectives, with evidence of inefficiencies, inequities, and poor accountability in many areas of health services. The primary cause of these shortcomings may lie in the complex set of funding and delivery arrangements at the State and Federal levels of government. Potentially significant improvements in the performance of the health system would be available from the integration of the funding and delivery of services within a single tier of government, coupled with the development of a national weighted capitation approach to funding. To develop a national capitation funding model a number of unique factors require consideration, including the current fragmentation of services, the role of the private sector, the needs of indigenous populations, and the effects of rurality. The data available to develop a capitation model is of a level of detail and quality not readily found elsewhere. If policy statements promoting efficiency, accountability, and particularly equity are to be actively pursued, a national capitation model based on robust methods should become a cornerstone of Australian health system reform.


Condition dependence of male and female genital structures in the seed beetle Callosobruchus maculatus (Coleoptera: Bruchidae).
Theory predicts that costly secondary sexual traits will evolve heightened condition dependence, and many studies have reported strong condition dependence of signal and weapon traits in a variety of species. However, although genital structures often play key roles in intersexual interactions and appear to be subject to sexual or sexually antagonistic selection, few studies have examined the condition dependence of genital structures, especially in both sexes simultaneously. We investigated the responses of male and female genital structures to manipulation of larval diet quality (new versus once-used mung beans) in the bruchid seed beetle Callosobruchus maculatus. We quantified effects on mean relative size and static allometry of the male aedeagus, aedeagal spines, flap and paramere and the female reproductive tract and bursal spines. None of the male traits showed a significant effect of diet quality. In females, we found that longer bursal spines (relative to body size) were expressed on low-quality diet. Although the function of bursal spines is poorly understood, we suggest that greater bursal spine length in low-condition females may represent a sexually antagonistic adaptation. Overall, we found no evidence that genital traits in C. maculatus are expressed to a greater extent when nutrients are more abundant. This suggests that, even though some genital traits appear to function as secondary sexual traits, genital traits do not exhibit heightened condition dependence in this species. We discuss possible reasons for this finding.


Expression of insulin-like growth factor 1 and its receptor in preovulatory follicles and in the corpus luteum in the bitch.
In the bitch, ovarian follicular and corpus luteum (CL) development and function are regulated by gonadotropins as well as local factors, the role of which is especially important during the early CL phase of relative gonadotrophic independence. We assumed that insulin-like growth factor 1 (IGF1) has a paracrine/autocrine regulatory role in ovarian follicular and luteal function in the dog. To address our hypothesis, we studied gene and protein expression of IGF1 and its receptor (IGF1R) in preovulatory follicles and in the CL of pregnant and non-pregnant dogs, and following antigestagen (aglepristone, progesterone receptor blocker) treatment in mid-gestation. Ovaries in the follicular phase were collected from five bitches. CL were collected on pregnancy Days 8-12 (pre-implantation), 18-25 (post-implantation), 35-40 (mid-gestation), at prepartum luteolysis, and 24 h and 72 h after aglepristone treatment in mid-gestation (n = 3-5 per group). From non-pregnant bitches, CL were collected on Days 5, 15, 25, 35, 45, 65 after ovulation (n = 4-5 per group). Semi-quantitative real-time (TaqMan) PCR and immunohistochemistry were applied. IGF1 immunostaining in preovulatory follicles seemed stronger in theca interna than granulosa cells. IGF1R signals appeared more intense in granulosa cells at the apical part of mural folds. In pregnant dogs, luteal IGF1 mRNA expression decreased significantly from pre-implantation to prepartum luteolysis, while IGF1R expression increased at prepartum luteolysis. Aglepristone treatment in mid-gestation had no effect on IGF1 and IGF1R mRNA levels. In non-pregnant bitches, highest IGF1 mRNA concentrations were found in the early CL and decreased by Days 45 and 65, while IGF1R expression did not change. In the CL of pregnant bitches, signals for IGF1 and IGF1R in luteal cells were strongest at pre- and post-implantation and weakest at prepartum luteolysis. IGF1 and IGF1R immunostaining was also detected in macrophages and in blood vessels. In conclusion, IGF1 may have a paracrine or autocrine role in granulosa and theca interna cells in preovulatory follicles. As IGF1 was highest represented in early luteal stages in pregnant and non-pregnant bitches, this may support a role for IGF1 in steroid synthesis, angiogenesis and cell proliferation as well as in immune function in the early canine CL. The unaffected mRNA levels after aglepristone treatment may support that IGF1 is not directly regulated by local progesterone in an auto- or paracrine manner.


Assessment of regional systolic and diastolic dysfunction in familial hypertrophic cardiomyopathy using MR tagging.
Diastolic and systolic left ventricular (LV) dysfunction often significantly contribute to disabling symptoms in familial hypertrophic cardiomyopathy (FHC). This study compares regional LV function (midwall circumferential strain) during systole and diastole in eight FHC patients and six normal volunteers (NVs) using MR tagging. A prospectively-gated fast gradient-echo sequence with an echo-train readout was modified to support complementary spatial modulation of magnetization (CSPAMM) tagging and full cardiac cycle data acquisition using the cardiac phase to order reconstruction (CAPTOR), thus providing tag persistence and data acquisition during the entire cardiac cycle. Total systolic strains in FHC patients were significantly reduced in septal and inferior regions (both P < 0.01). Early-diastolic strain rates were reduced in all regions of the FHC group (all P < 0.03). The combination of CSPAMM and CAPTOR allows regional indices of myocardial function to be quantified throughout the cardiac cycle. This technique reveals regional differences in systolic and diastolic impairment in FHC patients.


Comparative analysis of nutritional guidelines for vitamin D.
Vitamin D is essential for calcium and bone homeostasis. Humans are largely dependent on UVB-radiation-induced photosynthesis of vitamin D, as few foods contain vitamin D. However, the same radiation that produces vitamin D is also carcinogenic, albeit with a long lag time, and causes DNA damage. In view of the increasing life expectancy, avoiding excessive sun exposure is prudent. Several groups of people have a shortfall between their requirements for vitamin D and their combined endogenous synthesis and intake from natural foods, and therefore need vitamin D supplementation. Governments and scientific societies are regularly updating their recommendations for intake of vitamin D, especially for groups that should (infants) or prefer to (especially elderly individuals) avoid direct sunlight. An overview of such guidelines is presented in this Review. A fairly large consensus exists that all infants should receive 400 international units (IU) (10 μg) daily during their first year of life and that elderly individuals should have access to vitamin D supplementation (at recommended dosages varying from 400 IU to 800 IU daily in most governmental guidelines but at higher dosages in other guidelines). All guidelines unanimously agree that serum levels of 25-hydroxyvitamin D (25OHD) <25 nmol/l (10 ng/ml) should be avoided at all ages. Children and adults who have limited sun exposure should receive vitamin D supplementation, but the recommended doses vary widely (from 200 IU to 2,000 IU daily), in line with disagreement regarding the minimal desirable serum concentration of 25OHD (which varies from 25 nmol/l to >100 nmol/l).


Heterojunction PbS nanocrystal solar cells with oxide charge-transport layers.
Oxides are commonly employed as electron-transport layers in optoelectronic devices based on semiconductor nanocrystals, but are relatively rare as hole-transport layers. We report studies of NiO hole-transport layers in PbS nanocrystal photovoltaic structures. Transient fluorescence experiments are used to verify the relevant energy levels for hole transfer. On the basis of these results, planar heterojunction devices with ZnO as the photoanode and NiO as the photocathode were fabricated and characterized. Solution-processed devices were used to systematically study the dependence on nanocrystal size and achieve conversion efficiency as high as 2.5%. Optical modeling indicates that optimum performance should be obtained with thinner oxide layers than can be produced reliably by solution casting. Room-temperature sputtering allows deposition of oxide layers as thin as 10 nm, which enables optimization of device performance with respect to the thickness of the charge-transport layers. The best devices achieve an open-circuit voltage of 0.72 V and efficiency of 5.3% while eliminating most organic material from the structure and being compatible with tandem structures.


A small circular TAR RNA decoy specifically inhibits Tat-activated HIV-1 transcription.
Linear TAR RNA has previously been used as a decoy to inhibit HIV-1 transcription in vitro and HIV-1 replication in vivo. A 48 nucleotide circular RNA containing the stem, bulge and loop of the HIV-1 TAR element was synthesized using the self-splicing activity of a group I permuted intron-exon and was tested for its ability to function as a TAR decoy in vitro. This small circular TAR molecule was exceptionally stable in HeLa nuclear extracts, whereas a similar linear TAR molecule was rapidly degraded. The TAR circle bound specifically to Tfr38, a peptide containing the TAR-binding region of Tat. The ability of Tat to trans-activate transcription from the HIV-1 promoter in vitro was efficiently inhibited by circular TAR RNA but not by TAR circles that contained either bulge or loop mutations. TAR circles did not inhibit transactivation exclusively by binding to Tat since this inhibition was not reversed by adding excess Tat to the transcription reaction. Together, these data suggest that TAR circles act as decoys that inhibit transactivation by binding to Tat and at least one cellular factor. These data also demonstrate the utility of small circular RNA molecules as tools for biochemical studies.


Couples coping with sensory loss: A dyadic study of the roles of self- and perceived partner acceptance.
Hearing-, vision-, and dual-sensory loss have been linked to relational and psychological distress among adults with sensory loss (AWSLs) and their spouses. Regardless, research on factors associated with couples' adjustment is lacking. This study examined the stability and strength of associations between self-acceptance of sensory loss, perceived partner acceptance of sensory loss, and relationship satisfaction and psychological distress among AWSLs and their spouses over time. A total of 122 AWSLs and their spouses completed an online survey at two time points over a 6-month period. A multigroup (i.e., time 1 and time 2) actor-partner interdependence model assessed the stability and strength of actor and partner effects of self-acceptance and perceived partner acceptance on each partner's relationship satisfaction and psychological distress over time. No moderation by time was identified, indicating stability in associations over the 6-month period. Overall, both actor and partner effects were evident. Specifically, self-acceptance among AWSLs was inversely associated with own psychological distress and the relationship satisfaction of spouses. Self-acceptance by spouses was inversely associated with the psychological distress of AWSLs and spouses. Perception of spouse acceptance by AWSLs was positively associated with own and spouse relationship satisfaction. Interventions targeting acceptance that incorporate a family systems perspective may be beneficial in alleviating psychological and relational distress among couples coping with sensory loss. Statement of contribution What is already known on this subject? The experience of hearing and/or vision loss has been linked to heightened distress both psychologically and within intimate relationships. Prior research has demonstrated a link between an individual's ability to accept their sensory loss and healthier well-being. What does this study add? This is the first dyadic study of sensory loss acceptance and its link to relationship satisfaction and distress. Acceptance operates interpersonally protecting against distress for those with sensory loss and their spouses. Perceiving that one's spouse accepts the sensory loss is important for both partner's relationship satisfaction.


6-hydroxy-3-succinoylpyridine hydroxylase catalyzes a central step of nicotine degradation in Agrobacterium tumefaciens S33.
Nicotine is a main alkaloid in tobacco and is also the primary toxic compound in tobacco wastes. It can be degraded by bacteria via either pyridine pathway or pyrrolidine pathway. Previously, a fused pathway of the pyridine pathway and the pyrrolidine pathway was proposed for nicotine degradation by Agrobacterium tumefaciens S33, in which 6-hydroxy-3-succinoylpyridine (HSP) is a key intermediate connecting the two pathways. We report here the purification and properties of an NADH-dependent HSP hydroxylase from A. tumefaciens S33. The 90-kDa homodimeric flavoprotein catalyzed the oxidative decarboxylation of HSP to 2,5-dihydroxypyridine (2,5-DHP) in the presence of NADH and FAD at pH 8.0 at a specific rate of about 18.8 ± 1.85 µmol min-1 mg protein-1. Its gene was identified by searching the N-terminal amino acid residues of the purified protein against the genome draft of the bacterium. It encodes a protein composed of 391 amino acids with 62% identity to HSP hydroxylase (HspB) from Pseudomonas putida S16, which degrades nicotine via the pyrrolidine pathway. Considering the application potential of 2,5-DHP in agriculture and medicine, we developed a route to transform HSP into 2,5-DHP with recombinant HSP hydroxylase and an NADH-regenerating system (formate, NAD+ and formate dehydrogenase), via which around 0.53 ± 0.03 mM 2,5-DHP was produced from 0.76 ± 0.01 mM HSP with a molar conversion as 69.7%. This study presents the biochemical properties of the key enzyme HSP hydroxylase which is involved in the fused nicotine degradation pathway of the pyridine and pyrrolidine pathways and a new green route to biochemically synthesize functionalized 2,5-DHP.


The Effect of Cognitive Remediation Therapy on Social Skills in Institutionalized Elderly Patients with Schizophrenia.
There are limited scientific investigations on cognitive remediation in elderly patients with schizophrenia. The present study was aimed to examine the efficacy of cognitive remediation therapy on social skills in institutionalized elderly patients with schizophrenia. The study employed a randomized clinical trial. A total of 60 institutionalized elderly patients with schizophrenia from Razi Psychiatric Hospital, Tehran were selected and randomly allocated into two equal groups (control and intervention). The intervention group attended to cognitive remediation therapy for 8 weeks. The Evaluation of Living Skills Scale for psychiatric patients was used for data collection. The Chi Square, independent and paired t-tests using SPSS, version 22, were employed to analyze the data. The mean age of 60 elderly patients participated in the study was 65.25 ± 4.19 years. No significant differences were found between two groups at baseline. However, independent t-tests showed significant differences between the intervention and the control group in social skills after implementation of intervention. Additionally, the results of paired t-tests revealed significant improvements in intervention group on communication skills (t=5.50, p<0.001), behavioral problems with others (t=5.44, p<0.001), and self-care (t=4.70, p<0.001). No significant differences were observed from pretest to post test in control group. The results of the present study may support the efficacy of cognitive remediation therapy on social skills of elderly patients with schizophrenia.


Perturbation of Thymocyte Development Underlies the PRRS Pandemic: A Testable Hypothesis.
Porcine reproductive and respiratory syndrome virus (PRRSV) causes immune dysregulation during the Critical Window of Immunological Development. We hypothesize that thymocyte development is altered by infected thymic antigen presenting cells (TAPCs) in the fetal/neonatal thymus that interact with double-positive thymocytes causing an acute deficiency of T cells that produces "holes" in the T cell repertoire allowing for poor recognition of PRRSV and other neonatal pathogens. The deficiency may be the result of random elimination of PRRSV-specific T cells or the generation of T cells that accept PRRSV epitopes as self-antigens. Loss of helper T cells for virus neutralizing (VN) epitopes can result in the failure of selection for B cells in lymph node germinal centers capable of producing high affinity VN antibodies. Generation of cytotoxic and regulatory T cells may also be impaired. Similar to infections with LDV, LCMV, MCMV, HIV-1 and trypanosomes, the host responds to the deficiency of pathogen-specific T cells and perhaps regulatory T cells, by "last ditch" polyclonal B cell activation. In colostrum-deprived PRRSV-infected isolator piglets, this results in hypergammaglobulinemia, which we believe to be a "red herring" that detracts attention from the thymic atrophy story, but leads to our second independent hypothesis. Since hypergammaglobulinemia has not been reported in PRRSV-infected conventionally-reared piglets, we hypothesize that this is due to the down-regulatory effect of passive maternal IgG and cytokines in porcine colostrum, especially TGFβ which stimulates development of regulatory T cells (Tregs).


Atypical visual field asymmetries in redundancy masking.
Redundancy masking is the reduction of the perceived number of items in repeating patterns. It shares a number of characteristics with crowding, the impairment of target identification in visual clutter. Crowding strongly depends on the location of the target in the visual field. For example, it is stronger in the upper compared to the lower visual field and is usually weakest on the horizontal meridian. This pattern of visual field asymmetries is common in spatial vision, as revealed by tasks measuring, for example, spatial resolution and contrast sensitivity. Here, to characterize redundancy masking and reveal its similarities to and differences from other spatial tasks, we investigated whether redundancy masking shows the same typical visual field asymmetries. Observers were presented with three to six radially arranged lines at 10° eccentricity at one of eight locations around fixation and were asked to report the number of lines. We found asymmetries that differed pronouncedly from those found in crowding. Redundancy masking did not differ between upper and lower visual fields. Importantly, redundancy masking was stronger on the horizontal meridian than on the vertical meridian, the opposite of what is usually found in crowding. These results show that redundancy masking diverges from crowding in regard to visual field asymmetries, suggesting different underlying mechanisms of redundancy masking and crowding. We suggest that the observed atypical visual field asymmetries in redundancy masking are due to the superior extraction of regularity and a more pronounced compression of visual space on the horizontal compared to the vertical meridian.


Predicting properties of new ionic liquids: density functional theory and experimental studies of tetra-alkylammonium salts of (thio)carboxylate anions, RCO2⁻, RCOS⁻ and RCS2⁻.
Density functional theory calculations of alkyl-carboxylate anions and their sulfur substituted variants are presented here as an aid for the development of new ionic liquids. Electron transfer both within the anion, and between the anion and cation of an ion pair, are described using natural bond order analysis, using tetraethylammonium as a common cation. The overall stabilising effect of this electron transfer is quantified for the series of anions, and is found to correlate with clear trends in ion-pair binding energy. These and other electronic properties determine which compounds are synthesised, and experimental results validate the computational results. In combination with tetraethylammonium, a carboxylate with an unsaturated alkyl chain produces an ionic liquid at room temperature. However, computations suggest that sulfur substituted anions will produce a lower melting point and perhaps more fluid ionic liquid, but one which would be less stable against oxidation.


Dynamin: functional design of a membrane fission catalyst.
Dynamin, best studied for its role in clathrin-mediated endocytosis, is the prototypical member of a family of multidomain GTPases involved in fission and remodeling of multiple organelles. Recent studies have shown that dynamin alone can catalyze fission of membrane tubules and vesicle formation from planar lipid templates. Thus, dynamin appears to be a self-sufficient fission machine. Here we review the biochemical activities and structural features of dynamin required for fission activity. As all changes in membrane topology require energetically unfavorable rearrangements of the lipid bilayer, we discuss the interplay between dynamin and its lipid substrates that are critical to defining a nonleaky pathway to membrane fission. We propose a two-stage model for dynamin-catalyzed fission. In stage one, dynamin's mechanochemical activities induce localized curvature stress and position its lipid-interacting pleckstrin homology domains to create a catalytic center that, in stage two, guides lipid remodeling through hemifission intermediates to drive membrane fission.


Evidence for physiological regulation of myometrial gap junction permeability.
We have investigated whether direct intercellular communication between uterine smooth muscle cells of delivering rats is influenced by intracellular adenosine 3',5'-cyclic monophosphate concentration ([cAMPi]) and agents relevant to the hormonal control of pregnancy and parturition. The rate of diffusion of phosphorylated 2-[3H]deoxy-D-glucose (2-DG) in strips of longitudinal myometrium from rats in labor, indicated by the apparent diffusion coefficient for this molecule, was observed to be significantly reduced in tissues with elevated [cAMPi] (after treatment with dibutyryl cAMP, 8-bromo cAMP, forskolin, and theophylline) in the absence of any change in the area of gap junctions (GJs). Similarly, several agonists that elevate [cAMPi] in this tissue (e.g., isoproterenol, relaxin, carbacyclin, prostaglandin E2) also reduced 2-DG diffusion. These data suggest that the permeability of GJs in uterine smooth muscle may be regulated by [cAMPi] and physiologically relevant agonists. Control of GJ permeability may be important for the physiological regulation of intercellular communication and the extent of synchronous contractile activity in the uterine wall during pregnancy and parturition.


[The diagnostic value of epicutaneous tests in intolerance for dentures made of stainless steel].
A total of 19 patients with stainless denture intolerance were examined. In addition to the routine stomatological examination, the authors determined pH of mixed saliva, measured the steady-state potentials of dentures, and performed epicutaneous tests with samples made of stainless steel, chromium and nickel. In all the patients, the epicutaneous tests with chromium and/or nickel were positive, those with stainless steel were negative. Abnormal reactions can be accounted for by the influence of an electroplating factor in 8 patients and by an allergic factor in 6. It is impossible to explain the pathogenesis of intolerance in 3 patients. Replacement of the dentures by those made of other material resulted in full recovery. Terminological aspects are also dealt with in the present paper.


Molecular mechanisms for enhanced DNA vaccine immunogenicity.
In the two decades since their initial discovery, DNA vaccines technologies have come a long way. Unfortunately, when applied to human subjects inadequate immunogenicity is still the biggest challenge for practical DNA vaccine use. Many different strategies have been tested in preclinical models to address this problem, including novel plasmid vectors and codon optimization to enhance antigen expression, new gene transfection systems or electroporation to increase delivery efficiency, protein or live virus vector boosting regimens to maximise immune stimulation, and formulation of DNA vaccines with traditional or molecular adjuvants. Better understanding of the mechanisms of action of DNA vaccines has also enabled better use of the intrinsic host response to DNA to improve vaccine immunogenicity. This review summarizes recent advances in DNA vaccine technologies and related intracellular events and how these might impact on future directions of DNA vaccine development.


The endoscopist and malignant and non-malignant biliary obstruction.
Patients with biliary strictures often represent a diagnostic and therapeutic challenge, due to the site and complexity of biliary obstruction and wide differential diagnosis. Multidisciplinary decision making is required to reach an accurate and timely diagnosis and to plan optimal care. Developments in endoscopic ultrasound and peroral cholangioscopy have advanced the diagnostic yield of biliary endoscopy, and novel optical imaging techniques are emerging. Endoscopic approaches to biliary drainage are preferred in most scenarios, and recent advances in therapeutic endoscopic ultrasound allow drainage where the previous alternatives were only percutaneous or surgical. Here we review recent advances in endoscopic practice for the diagnosis and management of biliary strictures. This article is part of a Special Issue entitled: Cholangiocytes in Health and Diseaseedited by Jesus Banales, Marco Marzioni and Peter Jansen.


Contemporary paradigms for research related to women's mental health.
Mental health problems are serious health concerns that affect women across diverse settings internationally. Knowledge of this population historically has been informed by research using a positivist approach. This article is a critical examination of contemporary paradigms for research related to women's mental health. We begin the article with an introduction to women's mental health, followed by an overview of the postpositivist, critical theory, and constructivist paradigms. We then present a critical examination of the benefits and limitations of these paradigms in relation to the study of women's mental health. We conclude with implications for research and practice.


Barriers to optimizing vitamin D3 intake for the elderly.
Available data on metabolic utilization of vitamin D3 indicate a total daily requirement of approximately 4000 international units (iu) (100 microg) or twice the current tolerable upper intake level (UL). In young individuals, most of this comes from the skin. However, cutaneous vitamin D3 synthesis declines with age, creating a need for increasing oral intake to maintain optimal serum 25-hydroxyvitamin D [25(OH)D] concentrations. Estimates of the population distribution of serum 25(OH)D values, coupled with available dose-response data, indicate that it would require input of an additional 2600 iu/d (65 microg/d) of oral vitamin D3 to ensure that 97.5% of older women have 25(OH)D values at or above desirable levels. The age-related decline in cutaneous input, taken together with the UL, creates a substantial barrier to the deployment of public health strategies to optimize vitamin D status in the elderly.


Developmental effects of dietary nucleotides in second-generation weaned rats.
The aim of the present study was to evaluate dietary effects of dietary nucleotides (NTs) on developmental parameters in second-generation Sprague-Dawley rats. Experimental design was set up as six groups, including one control and five nucleotide administered groups, doses ranged from 0.01% to 1.28% nucleotides. First-generation (F0) rats were divided into two terms: (1) fed for 90-day study; (2) mated for offspring (F1). After weaning, each group of second-generation F1 rats was fed the control diet. Evaluating parameters were weight gain and food utilization ratios of rats, hematological and biochemical parameters, and organ pathology. The results showed that there was a greater weight gain and food utilization ratio in weaned rats (F0 and F1). Furthermore, weight gain and food utilization ratios were increased in the first 2 weeks of F1 male and the first week of F1 female rats. There were no significant changes in blood indicators of NT groups with the exception of decrease in aspartate aminotransferase and serum uric acid levels. Overall, it was demonstrated that NT supplements could promote the early growth and development at a 0.01% dose. Although NTs may have cumulative reproductive effects, they were safe even at a high-dose supplementation. Additionally, NT supplementation could promote restoration and optimize liver function.


Activation of mitogen-activated protein kinase in estrogen receptor alpha-positive breast cancer cells in vitro induces an in vivo molecular phenotype of estrogen receptor alpha-negative human breast tumors.
Breast cancer presents as either estrogen receptor alpha (ERalpha) positive or negative, with ERalpha+ tumors responding to antiestrogen therapy and having a better prognosis. By themselves, mRNA expression signatures of estrogen regulation in ERalpha+ breast cancer cells do not account for the vast molecular differences observed between ERalpha+ and ERalpha- cancers. In ERalpha- tumors, overexpression of epidermal growth factor receptor (EGFR) or c-erbB-2, leading to increased growth factor signaling, is observed such that mitogen-activated protein (MAP) kinase (MAPK) is significantly hyperactivated compared with ERalpha+ breast cancer. In ERalpha+/progesterone receptor-positive, estrogen-dependent MCF-7 breast cancer cells, we stably overexpressed EGFR or constitutively active erbB-2, Raf, or MAP/extracellular signal-regulated kinase kinase, resulting in cell lines exhibiting hyperactivation of MAPK, estrogen-independent growth, and the reversible down-regulation of ERalpha expression. By global mRNA profiling, we found a "MAPK signature" of approximately 400 genes consistently up-regulated or down-regulated in each of the MAPK+ cell lines. In several independent profile data sets of human breast tumors, the in vitro MAPK signature was able to accurately distinguish ER+ from ER- tumors. In addition, our in vitro mRNA profile data revealed distinct mRNA signatures specific to either erbB-2 or EGFR activation. A subset of breast tumor profiles was found to share extensive similarities with either the erbB-2-specific or the EGFR-specific signatures. Our results confirm that increased MAPK activation causes loss of ERalpha expression and suggest that hyperactivation of MAPK plays a role in the generation of the ERalpha- phenotype in breast cancer. These MAPK+ cell lines are excellent models for investigating the underlying mechanisms behind the ERalpha- phenotype.


Middle tertiary volcanism during ridge-trench interactions in Western california.
Bimodal volcanism in the Santa Maria Province of west-central California occurred when segments of the East Pacific Rise interacted with a subduction zone along the California margin during the Early Miocene (about 17 million years ago). Isotopic compositions of neodymium and strontium as well as trace-element data indicate that these volcanic rocks were derived from a depleted-mantle (mid-ocean ridge basalt) source. After ridge-trench interactions, the depleted-mantle reservoir was juxtaposed beneath the continental margin and was erupted to form basalts. It also assimilated and partially melted local Jurassic-Cretaceous sedimentary and metasedimentary basement rocks to form rhyolites and dacites.


Variation in metabolism of biochemical test substrates by Klebsiella species: an epidemiological tool.
The variation in metabolism of biochemical test substrates by klebsiella isolates has been demonstrated. It is suggested that this variation is likely to result in false-negative reactions in biochemical tests incubated for short periods. The observations made may explain the reported difficulties in obtaining reproducible results in biotyping Klebsiella strains. Preliminary work suggests that differences in substrate metabolism will provide a means of increasing the sensitivity of methods for the biochemical typing of Klebsiella spp.