Long-term ethanol consumption promotes hepatic tumorigenesis but impairs normal hepatocyte proliferation in rats.
Chronic and excessive alcohol consumption has been related to an increased risk of several cancers, including that of the liver; however, studies in animal models have yet to conclusively determine whether ethanol acts as a tumor promoter in hepatic tumorigenesis. We examined whether prolonged alcohol consumption could act as a hepatic tumor promoter after initiation by diethylnitrosamine (DEN) in a rat model. Male Sprague-Dawley rats were injected with 20 mg DEN/kg body weight 1 wk before introduction of either an ethanol liquid diet or an isoenergic control liquid diet. Hepatic pathological lesions, hepatocyte proliferation, apoptosis, PPARα and PPARγ, and plasma insulin-like growth factor 1 (IGF-1) levels were assessed after 6 and 10 mo. Mean body and liver weights, plasma IGF-1 concentration, hepatic expressions of proliferating cellular nuclear antigen and Ki-67, and cyclin D1 in ethanol-fed rats were all significantly lower after 10 mo of treatment compared with control rats. In addition, levels of hepatic PPARγ protein, not PPARα, were significantly higher in the ethanol-fed rats after prolonged treatment. Although ethanol feeding also resulted in significantly fewer altered hepatic foci, hepatocellular adenoma was detected in ethanol-fed rats at 10 mo, but not in control rats given the same dose of DEN. Together, these results indicate that chronic, excessive ethanol consumption impairs normal hepatocyte proliferation, which is associated with reduced IGF-1 levels, but promotes hepatic carcinogenesis.


Stability of ruptured intracranial aneurysms treated with detachable coils: is delayed follow-up angiography warranted?
The optimal strategy for monitoring the stability of ruptured intracranial aneurysms following coil embolisation is unclear. The value of delayed follow-up angiography in detecting new recurrences or progression of residual lesions visualised on earlier angiographic studies was determined in the light of the increasing use of non-invasive imaging techniques such as time of flight magnetic resonance angiography (TOF-MRA) for the evaluation of intracranial aneurysm occlusion. Ninety-seven patients with 105 ruptured aneurysms treated with detachable coils in 2005 and 2006 were included. The presence of a residual neck or aneurysm was assessed on catheter angiograms performed at 6 months and 2 years using the Raymond criteria (Class I = completely occluded, class II = small residual neck, class III = aneurysm sac filling). At 6-month follow-up, 32% of class I aneurysms progressed to class II and 6% of these aneurysms required re-treatment. A further 2-year angiogram was obtained in 59 patients with 65 aneurysms. Ninety-six per cent of class I, 100% of the class II and class III aneurysms remained unchanged at 2 years compared to 6 months. In our series, most recurrences were apparent at 6-month follow-up. The vast majority of coiled ruptured aneurysms that were class I or II at 6 months remained stable at 2-year follow-up. In the absence of a residual lesion in the early angiographic study, a further delayed catheter angiogram may not be warranted. The use of non-invasive strategies such as TOF-MRA should be considered.


SLAT/Def6 plays a critical role in the pathogenic process of experimental autoimmune uveitis (EAU).
SWAP 70-like adaptor of T cells (SLAT; aka Def6) is a recently discovered guanine nucleotide exchange factor for Rho guanosine triphosphate (GTP)ases that has been previously shown to play a role in cluster of differentiation(CD)4+ T cell activation, T-helper (Th)1/Th2/Th17 differentiation and development of experimental autoimmune encephalomyelitis. Here, we investigated the role of SLAT/Def6 in the development of experimental autoimmune uveitis (EAU), an animal model for several uveitic conditions in humans. SLAT/Def6 deficient ("KO") mice and C57BL/6 controls were immunized with interphotoreceptor retinoid-binding protein (IRBP), along with pertussis toxin. The development of ocular inflammation was determined by both fundoscopy and histological examination. Lymphoid cells from draining lymph nodes were cultured with IRBP to measure lymphocyte proliferation and release of cytokines. Purified dendritic cells were tested for their capacity to present antigen to responding lymphocytes. In addition, the lymphoid cells were tested for the expression of forkhead box P3 (FoxP3), using conventional methods, and the activity of T-regulatory cells was determined by their capacity to inhibit in vitro proliferative responses. Serum anti -IRBP antibody levels were measured by enzyme-linked immunosorbant assay (ELISA). quantitative polymerase chain reaction (qPCR) was used to determine the transcript levels of cytokines in inflamed eyes. SLAT/Def6 KO mice had significantly reduced EAU compared to controls. Cells isolated from draining lymph nodes of SLAT/Def6 KO mice exhibited impaired proliferation and production of Th1 and Th17 signature cytokines (interferon [IFN]-γ and interleukin [IL]-17, respectively) when compared with cells isolated from control mice. qPCR of inflamed eyes detected similar levels of IFN-γ transcript in control and SLAT/Def6 KO mice, whereas the IL-17 transcript levels in eyes of the SLAT/Def6 KO mice were lower than in eyes of the controls. The SLAT/Def6 KO mice resembled their wild type (WT) controls, however, in the levels of their serum antibody against IRBP, the antigen presenting capacity of their dendritic cells, the proportion of cells expressing Foxp3 and the immunosuppressive activity of their T-regulatory cells. SLAT/Def6 KO mice exhibit reduced capacity to develop ocular inflammation and cellular activity when immunized with IRBP. Our study provides new data showing that SLAT/Def6 plays a major role in the T cell-mediated autoimmune processes that bring about the inflammatory eye disease, EAU.


Morphopathological Effect of Ferrihydrite Nanoparticles in an Experimental Model of Toxic Hemolytic Anemia.
We studied the effect of biogenic ferrihydrite nanoparticles synthesized as a result of the culturing of Klebsiella oxytoca on Wistar rats with experimental toxic hemolytic anemia. The pathology was simulated by single intraperitoneal injection of phenylhydrazine hydrochloride. On day 4, the functional parameters of erythrocytes in rats corresponded to the state of toxic hemolytic anemia. It is shown that ferrihydrite nanoparticles suspension has chronic toxicity and causes morphological changes in organs (mainly in the spleen), which are characterized by accumulation of nanoparticles. Administration of phenylhydrazine induced systemic vascular damage and the formation of extramedullary hematopoietic foci, which indicated a compensatory activation in hematopoiesis in the liver and spleen. Injection of nanoparticles reduced discirculatory and necrotic changes in the kidneys.


Environmentally driven evolution of Rubisco and improved photosynthesis and growth within the C3 genus Limonium (Plumbaginaceae).
Carbon assimilation by most ecosystems requires ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Its kinetic parameters are likely to have evolved in parallel with intracellular CO2 availability, with the result that faster forms of Rubisco occur in species with CO2 -concentrating mechanisms. The Rubisco catalytic properties were determined and evaluated in relation to growth and carbon assimilation capacity in Mediterranean Limonium species, inhabiting severe stress environments. Significant kinetic differences between closely related species depended on two amino acid substitutions at functionally important residues 309 and 328 within the Rubisco large subunit. The Rubisco of species facing the largest CO2 restrictions during drought had relatively high affinity for CO2 (low Michaelis-Menten constant for CO2 Kc) but low maximum rates of carboxylation (kcatc), while the opposite was found for species that maintained higher CO2 concentrations under similar conditions. Rubisco kinetic characteristics were correlated with photosynthetic rate in both well-watered and drought-stressed plants. Moreover, the drought-mediated decrease in plant biomass accumulation was consistently lower in species with higher Rubisco carboxylase catalytic efficiency (kcatc/Kc). The present study is the first demonstration of Rubisco adaptation during species diversification within closely related C3 plants, revealing a direct relationship between Rubisco molecular evolution and the biomass accumulation of closely related species subjected to unfavourable conditions.


Phantom study on three-dimensional target volume delineation by PET/CT-based auto-contouring.
The aim of this study was to determine an appropriate threshold value for delineation of the target volume in PET/CT and to investigate whether we could delineate a target volume by phantom studies. A phantom consisted of six spheres (phi 10-37 mm) filled with 18F solution. Data acquisition was performed PET/CT in non-motion and motion status with high 18F solution and in non-motion status with low 18F solution. In non-motion phantom experiments, we determined two types of threshold value, an absolute SUV (T(SUV)) and a percentage of the maximum SUV (T%). Delineation using threshold values was applied for all spheres and for selected large spheres (a diameter of 22 mm or larger). In motion phantom experiments, data acquisition was performed in a static mode (sPET) and a gated mode (gPET). CT scanning was performed with helical CT (HCT) and 4-dimensional CT (4DCT). The appropriate threshold values were aT% = 27% and aT(SUV) = 2.4 for all spheres, and sT% = 30% and sT(SUV) = 4.3 for selected spheres. For all spheres in sPET/HCT in motion, the delineated volumes were 84%-129% by the aT% and 34%-127% by the aT(SUV). In gPET/4DCT in motion, the delineated volumes were 94-103% by the aT% and 51-131% by the aT(SUV). For low radioactivity spheres, the delineated volumes were all underestimated. A threshold value of T% = 27% was proposed for auto-contouring of lung tumors. Our results also suggested that the respiratory gated data acquisition should be performed in both PET and CT for target volume delineation.


Involvement of the dual-specificity tyrosine phosphorylation-regulated kinase 1A-alternative splicing factor-calcium/calmodulin-dependent protein kinase IIδ signaling pathway in myocardial infarction-induced heart failure of rats.
Alternative splicing factor (ASF)-regulated alternative splicing of calcium/calmodulin-dependent protein kinase IIδ (CaMKIIδ) plays an important role in pathologic cardiac remodeling. ASF can be phosphorylated by dual-specificity tyrosine phosphorylation-regulated kinase 1A (Dyrk1A). This study aimed to investigate the possible involvement of the Dyrk1A-ASF-CaMKIIδ signaling pathway in the progression of myocardial infarction (MI)-induced heart failure (HF). MI in rats was induced by means of left anterior descending coronary artery ligation. Seven weeks after MI, the increase in left ventricular internal diameter at end-diastole (LVIDd), and the decrease in both ejection fraction (EF) and fractional shortening (FS) indicated that MI rats had developed HF. Quantitative real time reverse-transcription polymerase chain reaction indicated the dysregulation of CaMKIIδ alternative splicing, ie, up-regulation of CaMKIIδA and CaMKIIδC and down-regulation of CaMKIIδB in the hearts of HF rats. Electrophoresis and immunostaining revealed that HF activated the phosphorylation of ASF and affected its subcellular localization. Western blot analysis demonstrated a significant elevation in the activity and expression of Dyrk1A in HF rats. Inversely, treatment of MI-induced HF rats with Dyrk1A inhibitor, either harmine or EGCG, improved the symptoms of HF, reversed the molecular changes of Dyrk1A and ASF, and regulated alternative splicing of CaMKIIδ in HF rats. Enhanced activation of Dyrk1A-ASF-CaMKIIδ signaling pathway may underlie the mechanisms of HF after MI, and Dyrk1A inhibition may contribute to inactivation of this pathway and thereby retard the progression of MI-induced HF.


[Clinico-morphological parallels in inflammatory bronchial diseases in people living in radionuclide-contaminated areas].
Overall forty-five children with asthmatic bronchitis (AB) and recurring bronchitis (RB) residing in those territories being affected by radioactive contamination were examined with the aid of pathohistological and histochemical techniques elaborated at the F. G. Ianovskiĭ Institute of Phthisiology and Pulmonology (Ukraine) to study biopsy specimens of the epithelial covering of the gums and bronchial mucosa. AB and RB clinical patterns showed manifest dependence on the degree of the bronchial mucosa tissues reaction to ionizing radiation.


Validity and reliability of the Dutch version of the Camberwell Assessment of Need for the Elderly in community-dwelling people with dementia.
Tailor-made care in dementia requires an individual needs assessment. The Camberwell Assessment of Need for the Elderly (CANE) was developed to assess needs of older people with mental disorders. In this study the validity and reliability of the Dutch version of the CANE were studied among community-dwelling persons with dementia and their informal carers. Interviews were carried out with 236 people with mild to severe dementia and 322 informal carers; 69 informal carers were interviewed twice. Construct and criterion validity and test-retest reliability of the CANE were studied using data for informal carers. Construct validity was also studied for CANE ratings of people with dementia. The construct validity of the CANE was good among people with dementia and informal carers. Criterion validity could be studied for 76.9% of the CANE items, and all significant correlations were convergent. Test-retest reliability of the CANE varied from poor to very good and was best on domains where needs were explicit and problems well defined. Use of the Dutch version of the CANE among community-dwelling people with dementia and their carers is supported by the study results, with the study showing acceptable construct and criterion validity and test-retest reliability of the CANE.


Drusenoid maculopathy in rhesus monkeys (Macaca mulatta): effects of age and gender.
To compare drusenoid maculopathy in monkeys with human age-related macular degeneration, and evaluate the influence of age, gender and caloric restriction. Examination by indirect ophthalmoscopy, slit-lamp biomicroscopy and fundus photography, including in some cases fluorescein angiography, was performed on 61 male and 60 female rhesus macaques of ages 10-39 years. Fifty-four of the monkeys were maintained on a calorically restricted diet (approximately 30% lower than control levels) and 67 on an approximately ad libitum diet for 2-19 years, with all other environmental factors held constant. Maculopathies were graded on a 5-point scale and the effects of age, sex, and diet on prevalence and severity were examined. The retinas of six monkeys with macular drusen, 19-28 years old, were examined histologically. Rhesus monkeys showed a high prevalence (61%) of drusenoid maculopathy. The prevalence and severity of the maculopathy increased with age (p = 0.012). Fully half of all monkeys aged 10-12 years had some detectable degree of drusen. This high prevalence in young adulthood indicates that drusen develop much earlier in rhesus monkeys than in humans, who develop early maculopathy most rapidly at 50-60 years of age, even when correcting for the 3-fold difference in lifespan. No neovascularization or geographic atrophy was found. Females had a higher prevalence and severity than males (p = 0.019). Calorically restricted monkeys had a slightly lower prevalence and severity at 10-12 years than controls, but the difference was not statistically significant. This is an on-going project, and differences between the caloric restricted and ad-lib groups may emerge as the animals age. Some monkeys developed severe maculopathy in their 20s, with others unaffected in their 30s. The histology of drusen resembled those in human retina. Drusenoid maculopathy is common in rhesus monkeys, even in young adult life. Half of the rhesus monkeys examined have drusen at a much younger age than in humans. Severity of maculopathy was greater in female monkeys, a gender difference not consistently found in humans. No differences were detected due to caloric restriction, but a definitive test of this intervention will require a larger sample, longer period of observation, and/or an earlier institution of caloric restriction. Genetic factors are implied because with similar environments, some monkeys are affected at an early age, while older ones are not.


CiTO, the Citation Typing Ontology.
CiTO, the Citation Typing Ontology, is an ontology for describing the nature of reference citations in scientific research articles and other scholarly works, both to other such publications and also to Web information resources, and for publishing these descriptions on the Semantic Web. Citation are described in terms of the factual and rhetorical relationships between citing publication and cited publication, the in-text and global citation frequencies of each cited work, and the nature of the cited work itself, including its publication and peer review status. This paper describes CiTO and illustrates its usefulness both for the annotation of bibliographic reference lists and for the visualization of citation networks. The latest version of CiTO, which this paper describes, is CiTO Version 1.6, published on 19 March 2010. CiTO is written in the Web Ontology Language OWL, uses the namespace http://purl.org/net/cito/, and is available from http://purl.org/net/cito/. This site uses content negotiation to deliver to the user an OWLDoc Web version of the ontology if accessed via a Web browser, or the OWL ontology itself if accessed from an ontology management tool such as Protégé 4 (http://protege.stanford.edu/). Collaborative work is currently under way to harmonize CiTO with other ontologies describing bibliographies and the rhetorical structure of scientific discourse.


Bone marrow T helper cells with a Th1 phenotype induce activation and proliferation of leukemic cells in precursor B acute lymphoblastic leukemia patients.
Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.


Immobilization of iron oxide magnetic nanoparticles for enhancement of vessel wall magnetic resonance imaging--an ex vivo feasibility study.
Emerging data supports a role for negative wall remodeling in the failure of vascular interventions such as vein grafts, yet clinicians/researchers currently lack the ability to temporally/efficiently investigate adventitial surface topography/total vascular wall anatomy in vivo. We established a strategy of immobilizing commercially available iron oxide magnetic nanoparticles (Fe-NPs) onto the surface of human vein conduits to facilitate high-throughput total vascular wall demarcation with magnetic resonance (MR). Binding of activated Fe-NPs to amine groups on the surface of the veins induced a thin layer of negative contrast that differentiated the adventitia from surrounding saline signal in all MR images, enabling delineation of total wall anatomy; this was not possible in simultaneously imaged unlabeled control veins. Under the conditions of this ex vivo experiment, stable covalent binding of Fe-NPs can be achieved (dose-dependent) on human vein surface for MR detection, suggesting a potential strategy for enhancing the ability of MRI to investigate total wall adaptation and remodeling in vein graft failure.


Optimization of photon beam flatness for radiation therapy.
In this work, we investigate the relation between lateral fluence/dose distributions and photon beam uniformity, possibly identifying ways to improve these characteristics. The calculations included treatment head scatter properties associated with three common types of linear accelerators in order to study their impact on the results. For 6 and 18 MV photon beams the lateral fluence distributions were optimized with respect to the resulting calculated flatness, as defined by the International Electrotechnical Commission (IEC), at 10 cm depth in six different field sizes. The limits proposed by IEC for maximum dose ratios ('horns') at the depth of dose maximum have also been accounted for in the optimization procedure. The conclusion was that typical head scatter variations among different types of linear accelerators have a very limited effect on the optimized results, which implies that the existing differences in measured off-axis dose distributions are related to non-equivalent optimization objectives. Finally, a comparison between the theoretically optimized lateral dose distributions and corresponding dose measurements for the three investigated accelerator types was performed. Although the measured data generally fall within the IEC requirements the optimized distributions show better results overall for the evaluated uniformity parameters, indicating that there is room for improved flatness performance in clinical photon beams.


Transarterial chemoembolization (TACE) plus sorafenib versus TACE for intermediate or advanced stage hepatocellular carcinoma: a meta-analysis.
Sorafenib is used in patients with intermediate or advanced stage hepatocellular carcinoma (HCC) before or after of transarterial chemoembolization (TACE). However, the survival outcomes of TACE combined with sorafenib versus TACE alone remain controversial. Thus, we conducted a meta-analysis to evaluate the efficacy and safety of the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC. Pubmed and Embase databases were systematically reviewed for studies published up to November 2013, that compared TACE alone or in combination with sorafenib. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), time to progression (TTP), objective response rate (ORR), and progression free survival (PFS) using random-effects or fixed-effects model, depending on the heterogeneity between the included studies. Six studies published from 2011 to 2013, with a total of 1254 patients, were included in this meta-analysis. The pooled results showed that TACE combined with sorafenib significantly improved OS (HR = 0.65; 95% CI: 0.47-0.89, P = 0.007), TTP (HR = 0.68; 95% CI: 0.52-0.87, P = 0.003), ORR (HR = 1.06; 95% CI: 1.01-1.12, P = 0.021), but did not affect PFS (HR = 0.84; 95% CI: 0.62-1.14, P = 0.267). The incidence of grade III/IV adverse reaction was higher in the TACE plus sorafenib group than in the TACE group. The meta-analysis confirmed that the combination therapy of TACE plus sorafenib in patients with intermediate or advanced stage of HCC, can improve the OS, TTP, and ORR. This combination therapy was also associated with a significantly increased risk of adverse reactions.


Unilateral laryngeal and hypoglossal paralysis (Tapia's syndrome) following rhinoplasty in general anaesthesia: case report and review of the literature.
Extracranial involvement of the recurrent laryngeal nerve and the hypoglossal nerve is known as Tapia's syndrome. Ipsilateral paralysis of the vocal cord and tongue is present. Lesion of these nerves may be a rare complication of airway management. Herein, a case of Tapia's Syndrome complicating transoral intubation during general anaesthesia in a rhinoplasty operation, together with a review of pertinent literature to evaluate the incidence and the possible pathogenic mechanism of the lesion. There are recent reports in the literature on mono or bilateral paralysis of the XII or laryngeal recurrent nerve after use of laryngeal mask with a pathogenic mechanism of compression. Furthermore, there are reports, following oro-tracheal intubation, of recurrent laryngeal paralysis, likely legacies to the compression of the anterior branch of inferior laryngeal nerve by the cuff of the oro-tracheal tube against the postero-medial part of the thyroid cartilage. Hypoglossal nerve damage could be caused by a stretching of the nerve against the greater horn of the hyoid bone by a laryngeal mask or oro-tracheal tube or compression of the posterior part of the laryngoscope or oro-tracheal tube. In our case, the lesion probably occurred as the result of a two-fold compressive mechanism: on one hand, compression by the cuff of the endo-tracheal tube due to excessive throat pack in the oro-pharynx; on the other hand a prolonged stretching mechanism of these nerves may have occurred due to excessive anterior and lateral flexion of the head. From the data reported in the literature, as in our case, complete recovery of function is generally achieved within the first six months. This progressive recovery of function suggests nerve damage of a neuro-praxic type, which is typical of compression injury. In conclusion, the response of this rare complication confirms the importance not only of the position of the head and patient on the operating table but also the meticulous and correct performance of the routine manoeuvres of airway management.


An analysis of the relationship between proximal and distal motor control.
The purpose of this investigation was to test the ontogenetic principle that the development of proximal postural stability precedes, and is necessary for, the development of distal fine motor control. The Posture and Fine Motor Assessment of Infants (Case-Smith, 1987) was used to examine the relationship between proximal and distal motor function in 60 normal infants. Low positive partial correlations were found between components of posture and fine motor control. Although all partial correlations, except those between the head component of postural control and the fine motor scores, were significant, they were not strong enough to support the validity of the proximal-distal principle. They appear instead to reflect a functional rather than an ontogenetic relationship. These findings have implications for treatment and further research.


The DAILY (Daily Automated Intensive Log for Youth) trial: a wireless, portable system to improve adherence and glycemic control in youth with diabetes.
Blood glucose (BG) monitoring (BGM) is an important component of diabetes management. New wireless technologies may facilitate BGM and help to optimize glycemic control. We evaluated an integrated wireless approach with and without a motivational game in youth with diabetes. Forty youth, 8-18 years old, each received a handheld device fitted with a wireless modem and diabetes data management software, plus a wireless-enabled BG monitor. Half were randomized to receive the new technologies along with an integrated motivational game in which the participants would guess a BG level following collection of three earlier readings (Game Group). BG data, insulin doses, and carbohydrate intake were displayed graphically prior to the glucose estimation. The other group received the new technologies alone (Control Group). Both groups were instructed to perform BGM four times daily and transmit their data to a central server via the wireless modem. Feasibility of implementation and outcomes were ascertained after 4 weeks. Ninety-three percent of participants successfully transmitted their data wirelessly to the server. The Game Group transmitted significantly more glucose values than the Control Group (P < 0.001). The Game Group also had significantly less hyperglycemia (glucose >/=13.9 mmol/L or >/=250 mg/dL) than the Control Group (P < 0.001). Youth in the Game Group displayed a significant increase in diabetes knowledge over the 4-week trial (P < 0.005). Finally, there was a trend for more youth in the Game Group to maintain hemoglobin A1C values </=8% (P = 0.06). Thus a pediatric population with diabetes can successfully implement new technologies to facilitate BGM. Use of a motivational game appears to increase the frequency of monitoring, reduce the frequency of hyperglycemia, and improve diabetes knowledge, and may help to optimize glycemic control.


Primary alloreactive cytotoxic T-lymphocytes are not commonly restricted by self-HLA class I antigens.
To assess the role of HLA Class I molecules in the indirect presentation of alloantigen, we have investigated the fine specificity and MHC restriction of in vitro primary alloreactive cytotoxic T-lymphocytes (CTL), using limiting dilution analysis of CTL precursor frequencies in HLA-mismatched responder-stimulator pairs. By employing split-well analysis of limiting dilution (LD) microcultures and third-party target cells bearing a stimulatory HLA Class I antigen alone or in combination with a single responder HLA antigen, we demonstrate that self-Class I restriction of HLA-A- or HLA-B-specific CTL precursors is not a common feature of the primary in vitro alloresponse. Higher frequencies of alloantigen-specific CTL precursors in the presence of self-HLA antigens were only detected in 5 of 31 limiting dilution assays established from seven different responder-stimulator pairs. In two cases, the higher precursor frequencies could be explained on the basis of Class II-restricted presentation of Class I-derived antigenic peptide and are supported by flow cytometric analysis of HLA antigen expression on target cells. The remaining 3 assays of this type were suggestive of Class I restriction but revealed only marginally higher frequency estimates. All other LD assays revealed lower CTL precursor frequency estimates in the presence of self-HLA Class I antigens. A higher antigen-specific CTLp frequency was not detected when targets shared three HLA Class I antigens with the responder, demonstrating that we had not biased the responses by selecting single HLA antigen-sharing targets in the other assays. Analysis of reactivity against PHA blast targets at the single cell per well level demonstrated that CTL reactive only with the original stimulator comprised the majority of lytic reactions. Heteroclitic CTL (i.e., CTL that recognize single HLA targets only and not the original stimulator) formed only a small fraction of total reactivity. Our results confirm the role of Class II antigens in the indirect presentation of alloantigen in vitro but suggest that HLA Class I antigens play a limited role in this phenomenon.


Analysis of sections of implanted macroporous calcium phosphate bone substitutes by proton-induced X-emission method and energy-dispersive spectrometry.
The osseointegration of porous calcium phosphate ceramics once implanted evolves in several stages. The mechanism of integration of such material usually is evaluated by histologic analysis. The trace elements present in bone can be detected in the ceramic and help to provide a semiquantitative evaluation of osseointegration. Two different methods of microanalysis, energy-dispersive spectrometry (EDS) and proton induced x-emission (PIXE) were used in this study to determine the appearance of trace elements (Zn, Sr, and Fe) present in bone at the implantation site containing the ceramic. Porous HA-ceramic cylinders were implanted in the cortical bone of sheep femurs for periods ranging from 2 to 36 weeks. Thick sections of the implant-containing bone were made at the end of the implantation period. A scanning line with proton or electron impacts 0.5 mm apart was plotted from the edges of the cortical bone across the implanted ceramic and the resulting x-ray spectra were determined. Following EDS analysis, the sections were surface-stained, observed under a light microscope, and the pore volume occupied by bone tissue was measured. The spectra obtained by PIXE method showed two regions for each element characterising either the bone tissue or the ceramic. Zinc and strontium present in the bone tissue, but absent from the ceramic, appeared 8 and 12 weeks after implantation, respectively. The concentration of iron present in the implant decreased with time. EDS showed no significant level of either element in the bone or the ceramic. Histologic observation revealed that immature bone invaded the pores of the outer layer of the ceramic as early as 2 weeks after implantation. The ceramics were totally osseointegrated 20 weeks after implantation, although ceramic degradation continued for longer. In this experiment, the PIXE method was apparently sufficiently sensitive for monitoring the amount of trace element appearing in bone-implanted material.


Reiki: a supportive therapy in nursing practice and self-care for nurses.
Reiki is a complementary, energy-based healing modality. It has ancient roots, but is uniquely suited to modern nursing practice. Reiki training offers a precise technique for tapping into healing energy, or ki, and transmitting it through touch. Reiki treatments are gently balancing and provide energy that supports the well-being of the recipient in a holistic and individualistic way. Relaxation, pain relief, physical healing, reduced emotional distress, and a deepened awareness of spiritual connection are among the benefits attributed to Reiki in anecdotes, case studies, and exploratory research, as summarized in this review of literature. Reiki is easily adaptable to nursing practice in a variety of settings, and can provide support for the practitioners of Reiki themselves, as well as benefiting those they treat with Reiki.


Coordinated changes in contractility, energetics, and isomyosins after aortic stenosis.
To investigate possible alterations of myocardial performance in young rats, cardiac hypertrophy was induced by stenosis of the ascending aorta (AS) in three groups of 25-day-old rats that were compared with three groups of sham-operated controls (C). The cardiac overload duration was 8-10 days, 1 mo, and 2 mo in groups 1, 2, and 3, respectively. Mechanics and energetics were studied in left ventricular papillary muscles, and determination of the V1 and V3 isomyosin pattern was achieved in the same papillary muscle. The majority of quantitative changes concerning the cardiac growth process, contractility, and isomyosin shifts occurred within 8-10 days of stenosis. At this point, the degree of left ventricular hypertrophy relative to C was 53 +/- 6%, whereas maximum unloaded shortening velocity (Vmax) decreased significantly (2.8 +/- 0.1 in C vs. 1.9 +/- 0.1 Lmax/s in AS), peak power output (Emax) decreased (1.8 +/- 0.3 in C vs. 0.6 +/- 0.1 in AS), and the curvature of Hill's hyperbola increased (1.3 +/- 0.4 in C vs. 2.0 +/- 0.7 in AS); moreover, the percent V1 isomyosin decreased significantly (98 +/- 1 in C vs. 51 +/- 3% in AS) and the percent V3 isomyosin increased significantly (2 +/- 1 in C vs. 26 +/- 2% in AS). Beyond 8-10 days of AS, additional changes in cardiac hypertrophy and in mechanical and biochemical parameters were less marked.(ABSTRACT TRUNCATED AT 250 WORDS)


Position statement on classification of basal cell carcinomas. Part 2: EADO proposal for new operational staging system adapted to basal cell carcinomas.
No simple staging system has emerged for basal cell carcinomas (BCCs), since they do not follow the TNM process, and practitioners failed to agree on simple clinical or pathological criteria as a basis for a classification. Operational classification of BCCs is required for decision-making, trials and guidelines. Unsupervised clustering of real cases of difficult-to-treat BCCs (DTT-BCCs; part 1) has demonstrated that experts could blindly agree on a five groups classification of DTT-BCCs based on five patterns of clinical situations. Using this five patterns to generate an operational and comprehensive classification of BCCs. Testing practitioner's agreement, when using the five patterns classification to ensure that it is robust enough to be used in the practice. Generating the first version of a staging system of BCCs based on pattern recognition. Sixty-two physicians, including 48 practitioners and the 14 experts who participated in the generation of the five different patterns of DTT-BCCs, agreed on 90% of cases when classifying 199 DTT-BCCs cases using the five patterns classification (part 1) attesting that this classification is understandable and usable in practice. In order to cover the whole field of BCCs, these five groups of DTT-BCCs were added a group representing the huge number of easy-to-treat BCCs, for which sub-classification has little interest, and a group of very rare metastatic cases, resulting in a four-stage and seven-substage staging system of BCCs. A practical classification adapted to the specificities of BCCs is proposed. It is the first tumour classification based on pattern recognition of clinical situations, which proves to be consistent and usable. This EADO staging system version 1 will be improved step by step and tested as a decision tool and a prognostic instrument.


Malignant tumours mimicking periapical lesions: A report of three cases and literature review.
Apical periodontitis shows radiographic signs such as widening of the periodontal ligament and periapical radiolucency, which differ in extent depending on the stage of the lesion. However, other lesions can be associated with or coincidental to the apical region, representing developmental lesions and benign or malignant tumours. This article describes three cases of malignant tumours, a central mucoepidermoid carcinoma (CMEC), a chondroblast osteosarcoma and an osteosarcoma of the jaw (OSJ) that presented as periapical lesions. Endodontists must be aware of unsuccessful treatment, persistent pain, signs of paraesthesia, a rapid growth rate and delayed response to therapy associated with atypical features. Complementary examinations, such as biopsy and computed tomography, can allow the early diagnosis of malignant tumours, leading to a better prognosis and thus increased survival rates and improvement in quality of life.


Identification of a neurologic scale that optimizes EMS detection of older adult traumatic brain injury patients who require transport to a trauma center.
We sought to identify a scale or components of a scale that optimize detection of older adult traumatic brain injury (TBI) patients who require transport to a trauma center, regardless of mechanism. We assembled a consensus panel consisting of nine experts in geriatric emergency medicine, prehospital medicine, trauma surgery, geriatric medicine, and TBI, as well as prehospital providers, to evaluate the existing scales used to identify TBI. We reviewed the relevant literature and solicited group feedback to create a list of candidate scales and criteria for evaluation. Using the nominal group technique, scales were evaluated by the expert panel through an iterative process until consensus was achieved. We identified 15 scales for evaluation. The panel's criteria for rating the scales included ease of administration, prehospital familiarity with scale components, feasibility of use with older adults, time to administer, and strength of evidence for their performance in the prehospital setting. After review and discussion of aggregated ratings, the panel identified the Simplified Motor Scale, GCS-Motor Component, and AVPU (alert, voice, pain, unresponsive) as the strongest scales, but determined that none meet all EMS provider and patient needs due to poor usability and lack of supportive evidence. The panel proposed that a dichotomized decision scheme that includes domains of the top-rated scales -level of alertness (alert vs. not alert) and motor function (obeys commands vs. does not obey) -may be more effective in identifying older adult TBI patients who require transport to a trauma center in the prehospital setting. Existing scales to identify TBI are inadequate to detect older adult TBI patients who require transport to a trauma center. A new algorithm, derived from elements of previously established scales, has the potential to guide prehospital providers in improving the triage of older adult TBI patients, but needs further evaluation prior to use.


Vertebral plasma cellular osteomyelitis.
Plasma cellular osteomyelitis is a chronic recurrent, unifocal or multifocal inflammatory disorder, which has an unknown aetiology. The infectious focus or foci may occur in different sites of the skeleton. This unusual clinical entity has been reported in over 200 cases in the relevant literature, but the involvement of the spine with plasma cellular osteomyelitis has not been reported before. Because of the rarity of this disease and the possible difficulty in differentiating plasma cell osteomyelitis, both clinically and histopathologically from the other similar afflictions of the spine, we describe our case.


The effects of noise and palatal appliances on the speech of five-year-old children.
Forty children of age five were divided into two groups according to articulation skill. Each child named pictures while wearing a palatal dental appliance in quiet and in the presence of an intense noise. Articulation errors and vocal intensity were measured in all conditions. Errors increased when appliances were placed and when noise was presented, but there was no interaction between the effects of appliances and noise on articulation. Intensity increased when noise was presented and decreased when appliances were placed. There was no interaction between the effects of appliances and noise on intensity. Children in the High and Low Articulation Skills groups did not differ in response to appliances or noise. The articulation results are very similar to results described earlier in an adult group. The children's vocal intensity changes were almost twice as large as those reported for the adult group. There may be a complex interaction between speech measure, type of feedback manipulation, and stage of development.


Pathway-specific reporter genes to study stem cell biology.
Little is known on the phenotypic characteristics of stem cells (SCs) after they are transplanted to the myocardium, in part due to lack of noninvasive platforms to study SCs directly in the living subject. Reporter gene imaging has played a valuable role in the noninvasive assessment of cell fate in vivo. In this study, we validated a pathway-specific reporter gene that can be used to noninvasively image the phenotype of SCs transplanted to the myocardium. Rat mesenchymal SCs (MSCs) were studied for phenotypic evidence of myogenic characteristics under in vitro conditions. After markers of myogenic characteristics were identified, we constructed a reporter gene sensor, comprising the firefly luciferase (Fluc) reporter gene driven by the troponin T (TnT) promoter (cardio MSCs had threefold expression in polymerase chain reaction compared to control MSCs) using a two-step signal amplification strategy. MSCs transfected with TnT-Fluc were studied and validated under in vitro conditions, showing a strong signal after MSCs acquired myogenic characteristics. Lastly, we observed that cardio MSCs had higher expression of the reporter sensor compared to control cells (0.005 ± 0.0005 vs 0.0025 ± 0.0008 Tnt-Fluc/ubiquitin-Fluc, P < .05), and that this novel sensor can detect the change in the phenotype of MSCs directly in the living subject. Pathway-specific reporter gene imaging allows assessment of changes in the phenotype of MSCs after delivery to the ischemic myocardium, providing important information on the phenotype of these cells. Imaging sensors like the one described here are critical to better understanding of the changes that SCs undergo after transplantation.


Mental health case management in Canada: job description analyses.
The purpose of this study was to examine case managers' (CM) job position descriptions through content analysis. There were 29 case manager job position descriptions examined. The job descriptions could be grouped into four categories: (1) what the individuals should bring to the position, (2) what they did as CM, (3) to whom they were accountable, and (4) what was valued. Themes included focus on client as individual, focus on the external/system, or outer-directed work, and the articulation point between the individual and broader system. The CM works directly and indirectly in the system and community through education, organizing, planning, and networking, as well as through provision of direct care to the individual client. The expectations of the positions are extensive.


Does Explicit Polarizability Improve Simulations of Phase Behavior of Ionic Liquids?
Molecular dynamics simulations are performed for a test set of 20 aprotic ionic liquids to investigate whether including an explicit polarizability model in the force field leads to higher accuracy and reliability of the calculated phase behavior properties, especially the enthalpy of fusion. A classical nonpolarizable all-atom optimized potentials for liquid simulations (OPLS) force-field model developed by Canongia Lopes and Pádua (CL&P) serves as a reference level of theory. Polarizability is included either in the form of Drude oscillators, resulting in the CL&P-D models, or in the framework of the atomic multipole optimized energetics for biomolecular application (AMOEBA) force field with polarizable atomic sites. Benchmarking of the calculated fusion enthalpy values against the experimental data reveals that overall the nonpolarizable CL&P model and polarizable CL&P-D models perform similarly with average deviations of about 30%. However, fusion enthalpies from the CL&P-D models exhibit a stronger correlation with their experimental counterparts. The least successful predictions are interestingly obtained from AMOEBA (deviation ca. 60%), which may indicate that a reparametrization of this force-field model is needed to achieve improved predictions of the fusion enthalpy. In general, all FF models tend to underestimate the fusion enthalpies. In addition, quantum chemical calculations are used to compute the electronic cohesive energies of the crystalline phases of the ionic liquids and of the interaction energies within the ion pair. Significant positive correlations are found between the fusion enthalpy and the cohesive energies. The character of the present anions predetermines the magnitude of individual mechanistic components of the interaction energy and related enthalpic and cohesive properties.


Crystal structures of human 3-hydroxyanthranilate 3,4-dioxygenase with native and non-native metals bound in the active site.
3-Hydroxyanthranilate 3,4-dioxygenase (3HAO) is an enzyme in the microglial branch of the kynurenine pathway of tryptophan degradation. 3HAO is a non-heme iron-containing, ring-cleaving extradiol dioxygenase that catalyzes the addition of both atoms of O2 to the kynurenine pathway metabolite 3-hydroxyanthranilic acid (3-HANA) to form quinolinic acid (QUIN). QUIN is a highly potent excitotoxin that has been implicated in a number of neurodegenerative conditions, making 3HAO a target for pharmacological downregulation. Here, the first crystal structure of human 3HAO with the native iron bound in its active site is presented, together with an additional structure with zinc (a known inhibitor of human 3HAO) bound in the active site. The metal-binding environment is examined both structurally and via inductively coupled plasma mass spectrometry (ICP-MS), X-ray fluorescence spectroscopy (XRF) and electron paramagnetic resonance spectroscopy (EPR). The studies identified Met35 as the source of potential new interactions with substrates and inhibitors, which may prove useful in future therapeutic efforts.


False recall is reduced by damage to the ventromedial prefrontal cortex: implications for understanding the neural correlates of schematic memory.
Schematic memory, or contextual knowledge derived from experience (Bartlett, 1932), benefits memory function by enhancing retention and speeding learning of related information (Bransford and Johnson, 1972; Tse et al., 2007). However, schematic memory can also promote memory errors, producing false memories. One demonstration is the "false memory effect" of the Deese-Roediger-McDermott (DRM) paradigm (Roediger and McDermott, 1995): studying words that fit a common schema (e.g., cold, blizzard, winter) often produces memory for a nonstudied word (e.g., snow). We propose that frontal lobe regions that contribute to complex decision-making processes by weighting various alternatives, such as ventromedial prefrontal cortex (vmPFC), may also contribute to memory processes by weighting the influence of schematic knowledge. We investigated the role of human vmPFC in false memory by combining a neuropsychological approach with the DRM task. Patients with vmPFC lesions (n = 7) and healthy comparison participants (n = 14) studied word lists that excluded a common associate (the critical item). Recall and recognition tests revealed expected high levels of false recall and recognition of critical items by healthy participants. In contrast, vmPFC patients showed consistently reduced false recall, with significantly fewer intrusions of critical items. False recognition was also marginally reduced among vmPFC patients. Our findings suggest that vmPFC increases the influence of schematically congruent memories, a contribution that may be related to the role of the vmPFC in decision making. These novel neuropsychological results highlight a role for the vmPFC as part of a memory network including the medial temporal lobes and hippocampus (Andrews-Hanna et al., 2010).


A short report on a preliminary interventional study to evaluate play-mediated interaction skills in caregivers of children with autism spectrum disorder from Sri Lanka.
Most children with autism spectrum disorder live in low- and middle-income countries. Most of them do not have access to timely and culturally acceptable interventions. Research from high-income countries and low- and middle-income countries, such as Sri Lanka, show that parent-mediated intervention programmes improve functional outcomes, highlighting the importance of parents as partners. We undertook a preliminary study to evaluate how play-based parent coaching will enhance the parent interaction skills to promote social-emotional, cognitive and language skills in children with autism spectrum disorder aged 2-4 years. We evaluated how parents acquire interaction skills to engage with children using a caregiver skills assessment checklist adapted from freely accessible resources. Before and after training, all parent-child dyads participated in a 10-min video-recorded play session with a set of toys of their choice. Over the course of 2 weeks, all parents spent 2 h/day playing and interacting with the child to harness the desired skills. The results showed that the parental training had a positive effect on all 30 caregivers in gaining skills, with a significant improvement in all three domains with the highest impact on skills for social-emotional development. Overall, parents reported high levels of satisfaction on the training. The significant improvement in parent interaction skills was promising. However, further studies to look at the sustainability of the skills and the impact on children's overall development need to be looked into using larger and more generalised studies.


Effects of Vibration Training in Interstitial Lung Diseases: A Randomized Controlled Trial.
Numerous studies have reported positive effects of exercise training in patients with interstitial lung disease (ILD) on physical capacity and quality of life. However, evidence is rare on the effects of specific forms of training and further pathophysiological mechanisms in these patients. In this multicenter study we aimed to explore the clinical effects of whole-body vibration training (WBVT) in patients with ILD on various outcome measures, including proinflammatory cytokines and myostatin. We randomly assigned 26 patients with different forms of multidisciplinary confirmed fibrotic ILDs either to the WBVT group (n = 11; 55% male, 61 ± 14 years old, forced vital capacity 83.2 ± 29.3% predicted, 6-min walking distance [6MWD] 478 ± 79 m) performing 3 months of a standardized training (3 times per week), or to a control training group (CTG, n = 15; 60% male, 63 ± 9 years old, FVC 74.6 ± 20.5% predicted, 6MWD 455 ± 85 m) performing sham WBV training. Training in the two groups was performed on a GalileoTM vibration plate (6-20 vs. 5 Hz). The functional assessments before and after the intervention period included pulmonary function, 6MWD test, chair rise test, ultrasonographic measurement of quadriceps muscle thickness (cross-sectional area), quality of life questionnaires, and serum samples. We observed a significant increase in 6MWD (∆Training = 30 m [12-67], p = 0.024) and a decrease of myostatin (∆Training = -465 pg/mL [-713 to -166], p = 0.008) in the WBVT group. In contrast, no significant differences were observed in the CTG. The present study demonstrates that WBVT is able to significantly increase 6MWD and decrease myostatin in patients with fibrotic ILDs. Therefore, WBVT seems to be a beneficial and feasible training modality in ILD patients. Clinical Trial Registry: German Clinical Trials Registry (DRKS00012930).


Tarsal pseudo-coalition--a positional artifact.
Pseudo-coalition of the talocalcaneal joint is a positional artifact which is created by either slight abduction or inversion of the foot on the lateral radiograph. This apparent bony bridge is due to overlap of normal structures on opposite sides of the hindfoot. It may be distinguished from a true coalition by the following features: 1) it disappears in a truly lateral radiograph, 2) there is no associated talar spur, and 3) there are no clinical findings of spastic flat foot. In addition, the true medial talocalcaneal bridge requires special views for its demonstration and cannot be seen in a lateral radiograph.


Molecular tweezers targeting transthyretin amyloidosis.
Transthyretin (TTR) amyloidoses comprise a wide spectrum of acquired and hereditary diseases triggered by extracellular deposition of toxic TTR aggregates in various organs. Despite recent advances regarding the elucidation of the molecular mechanisms underlying TTR misfolding and pathogenic self-assembly, there is still no effective therapy for treatment of these fatal disorders. Recently, the "molecular tweezers", CLR01, has been reported to inhibit self-assembly and toxicity of different amyloidogenic proteins in vitro, including TTR, by interfering with hydrophobic and electrostatic interactions known to play an important role in the aggregation process. In addition, CLR01 showed therapeutic effects in animal models of Alzheimer's disease and Parkinson's disease. Here, we assessed the ability of CLR01 to modulate TTR misfolding and aggregation in cell culture and in an animal model. In cell culture assays we found that CLR01 inhibited TTR oligomerization in the conditioned medium and alleviated TTR-induced neurotoxicity by redirecting TTR aggregation into the formation of innocuous assemblies. To determine whether CLR01 was effective in vivo, we tested the compound in mice expressing TTR V30M, a model of familial amyloidotic polyneuropathy, which recapitulates the main pathological features of the human disease. Immunohistochemical and Western blot analyses showed a significant decrease in TTR burden in the gastrointestinal tract and the peripheral nervous system in mice treated with CLR01, with a concomitant reduction in aggregate-induced endoplasmic reticulum stress response, protein oxidation, and apoptosis. Taken together, our preclinical data suggest that CLR01 is a promising lead compound for development of innovative, disease-modifying therapy for TTR amyloidosis.


CRYPTOCHROME is a blue-light sensor that regulates neuronal firing rate.
Light-responsive neural activity in central brain neurons is generally conveyed through opsin-based signaling from external photoreceptors. Large lateral ventral arousal neurons (lLNvs) in Drosophila melanogaster increase action potential firing within seconds in response to light in the absence of all opsin-based photoreceptors. Light-evoked changes in membrane resting potential occur in about 100 milliseconds. The light response is selective for blue wavelengths corresponding to the spectral sensitivity of CRYPTOCHROME (CRY). cry-null lines are light-unresponsive, but restored CRY expression in the lLNv rescues responsiveness. Furthermore, expression of CRY in neurons that are normally unresponsive to light confers responsiveness. The CRY-mediated light response requires a flavin redox-based mechanism and depends on potassium channel conductance, but is independent of the classical circadian CRY-TIMELESS interaction.


Potential electrophysiologic mechanisms responsible for dysrhythmias associated with reperfusion of ischemic myocardium.
Dysrhythmia associated with reperfusion may not only play a critical role in sudden cardiac death, but also, the presence of dysrhythmia during intracoronary administration of thrombolytic agents may reflect heterogeneity of recovery of excitability and, hence, salvage of ischemic myocardium. The electrophysiologic basis for these dysrhythmias appears to be heterogeneity of electrical recovery resulting in reentry or enhanced ventricular automaticity. Although the precise mechanisms are unknown, rapid changes in K+, PCO2 and intracellular Ca++ appear to play major roles. In addition, alterations in the regional concentration or tissue compartment localization of amphiphilic lipid metabolites such as lysophosphoglycerides and long-chain acyl carnitines may affect not only the development of dysrhythmia during reperfusion, but also the salvage of ischemic myocardium. Recent experimental evidence in several species also suggests a prominent role of alpha 1-adrenergic stimulation in the evolution of dysrhythmia associated with reperfusion.


Evaluating and Improving Vitek MS for Identification of Clinically Relevant Species of Trichosporon and the Closely Related Genera Cutaneotrichosporon and Apiotrichum.
Trichosporon species are relevant etiologic agents of hospital-acquired infections. High mortality rates are attributed to Trichosporon deep-seated infections in immunocompromised individuals, making fast and accurate species identification relevant for hastening the discovery of best-targeted therapy. Recently, Trichosporon taxonomy has been reassessed, and three genera have been proposed for the pathogenic species: Trichosporon, Cutaneotrichosporon, and Apiotrichum Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) has replaced old phenotypic methods for microorganism identification in clinical laboratories, but spectral profile databases have to be evaluated and improved for optimal species identification performance. Vitek MS (bioMérieux) is one of the commercially available MALDI-TOF MS platforms for pathogen identification, and its spectral profile databases remain poorly evaluated for Trichosporon, Cutaneotrichosporon, and Apiotrichum species identification. We herein evaluated and improved Vitek MS for the identification of the main clinical relevant species of Trichosporon, Cutaneotrichosporon, and Apiotrichum using a large set of strains and isolates belonging to different yeast collections in Brazil and France.


Phosphatases as small-molecule targets: inhibiting the endogenous inhibitors of kinases.
Inositols and their phosphorylated derivatives, phosphoinositides, play an important role in diverse cellular functions. They have been recognized as second messengers and are accurately controlled by phosphatases and kinases, such as phosphoinositide 3-kinase and the phosphatidylinositol 3-phosphatase PTEN (phosphatase and tensin homologue deleted on chromosome 10). Specific inhibitors targeting phosphoinositide 3-kinase and protein phosphatases have been described and characterized, but no small-molecule tools for phosphoinositide phosphatases are currently available. The present mini-review gives an overview of representative phosphatase inhibitors and summarizes the work that has been done recently on molecules that inhibit PTEN.


Recyclable three-dimensional Ag nanoparticle-decorated TiO2 nanorod arrays for surface-enhanced Raman scattering.
Multifunctional Ag nanoparticle-decorated TiO2 nanorod arrays were prepared by two simple processes. TiO2 nanorod arrays were first fabricated by the hydrothermal route and then Ag nanoparticles were decorated on the nanorods by the chemical reduction impregnation method. Three-dimensional Ag/TiO2 arrays were used as an active substrate for surface-enhanced Raman scattering (SERS). The results show that the detection limit for rhodamine 6G (R6G) was as low as 10(-7)M and the Raman enhancement factor was as large as 10(5). After calibrating the Raman peak intensities of R6G, it could be quantitatively detected. More importantly, the photocatalytic activity of TiO2 provides a self-cleaning capability to the SERS substrate, which can be recycled and used to degrade many Ag surface adsorbates such as R6G, methyl orange, Congo red, and methylene blue after exposure to visible light. The absorbed small molecules can all be rapidly and completely removed from the SERS substrate, which has been successfully reused four times without a decrease in accuracy or sensitivity. Our results reveal that the unique recyclable property not only paves a new way to solve the single-use problem of traditional SERS substrates but also provides more SERS platforms for multiple detections of other organic molecular species.


Astrocytic transporters in Alzheimer's disease.
Astrocytes play a fundamental role in maintaining the health and function of the central nervous system. Increasing evidence indicates that astrocytes undergo both cellular and molecular changes at an early stage in neurological diseases, including Alzheimer's disease (AD). These changes may reflect a change from a neuroprotective to a neurotoxic phenotype. Given the lack of current disease-modifying therapies for AD, astrocytes have become an interesting and viable target for therapeutic intervention. The astrocyte transport system covers a diverse array of proteins involved in metabolic support, neurotransmission and synaptic architecture. Therefore, specific targeting of individual transporter families has the potential to suppress neurodegeneration, a characteristic hallmark of AD. A small number of the 400 transporter superfamilies are expressed in astrocytes, with evidence highlighting a fraction of these are implicated in AD. Here, we review the current evidence for six astrocytic transporter subfamilies involved in AD, as reported in both animal and human studies. This review confirms that astrocytes are indeed a viable target, highlights the complexities of studying astrocytes and provides future directives to exploit the potential of astrocytes in tackling AD.


Adrenocortical function and plasma norepinephrine in normal human subjects.
Abnormal adrenocortical regulation has been reported in patients with endogenous depression, including excessive cortisol production with loss of circadian periodicity and decreased suppression by dexamethasone. The inhibitory effect of the neurotransmitter norepinephrine (NE) on the hypothalamic-pituitary adrenal (HPA) axis through the regulation of corticotropin-releasing factor has been suggested by animal in vitro studies. In this study of six normal human subjects we have examined the relationship of basal cortisol activity and its sensitivity to dexamethasone suppression, measured by 24-hr urinary free cortisol, with basal noradrenergic activity, diurnal variation, and response to postural stimulation, measured by plasma NE. Base-line cortisol and the degree of dexamethasone suppression were significantly inversely correlated with all base-line measures of NE response to stimulation. NE response to stimulation on the morning after dexamethasone was also inversely correlated with the degree of cortisol suppression. The increase in the morning NE response to stimulation after dexamethasone was inversely correlated with both base-line and suppressed cortisol levels. There is significant diurnal variation in stimulated NE activity after dexamethasone. There results are consistent with an inhibitory role for NE in the regulation of HPA system and a reciprocal effect for cortisol on noradrenergic activity. The implication of this relationship for the understanding of adrenocortical regulation in depression is discussed.


Long-term outcomes of sutureless and rapid-deployment aortic valve replacement: a systematic review and meta-analysis.
Sutureless and rapid-deployment aortic valve replacement (SURD-AVR) has become a prominent area of research as the medical community evaluate its place amongst other aortic valve interventions. The main advantages of SURD-AVR established to date are the reduced cross-clamp and cardiopulmonary bypass (CPB) times, as well as facilitating minimally invasive surgery in high-risk surgical patients. This current systematic review and meta-analysis, to our knowledge, is the first focusing on long-term outcomes regarding safety, efficacy and durability of SURD-AVR from available current literature. A literature search via six electronic databases was performed from their inception to November 2019. Inclusion criteria for this systematic review included survival and postoperative echocardiographic outcomes greater than five years in patients who underwent SURD-AVR with either Perceval or Intuity valves. Studies were identified and data extracted by two independent reviewers. Long-term survival outcomes were aggregated using digitized Kaplan-Meier curves where available. After applying predefined inclusion and exclusion criteria, four studies were identified for review. All four studies were observational and in total reported data for 1,998 patients. Almost half (42.4%) of patients underwent SURD-AVR via full sternotomy, with almost one third (30.1%) also undergoing concomitant cardiac procedures. Aggregate overall survival rates at 1-, 2-, 3-, and 5-year follow-up were 94.9%, 91.2%, 89.0%, and 84.2%, respectively. Incidence of strokes (4.8%), severe paravalvular leaks (PVLs) (1.5%) and permanent pacemaker (PPM) insertion (8.2%) at up to 5-year follow-up were acceptable. At 5-year follow-up hemodynamic outcomes were also acceptable for mean pressure gradient (MPG) (range, 8.8-13.6 mmHg), peak pressure gradient (PPG) (range, 18.9-21.1 mmHg) and effective orifice area (EOA) (range, 1.5-1.8 cm2). Evaluation of the evidence reporting long-term outcomes of SURD-AVR suggests that it is a safe procedure for AVR with low rates of complications. Long-term outcomes presented in this review show that not only does SURD-AVR have acceptable survival rates, but also good hemodynamic performance at 5-year follow-up.


Development and characterization of a novel mAb against bilitranslocase - a new biomarker of renal carcinoma.
Bilitranslocase (TC 2.A.65.1.1) is a bilirubin-specific membrane transporter, found on absorptive (stomach and intestine) and excretory (kidney and liver) epithelia and in vascular endothelium. Polyclonal antibodies have been raised in rabbits in the past, using a synthetic peptide corresponding to AA65-77 of rat liver bilitranslocase, as an antigen. Affinity-purified antibodies from immune sera have been found to inhibit various membrane transport functions, including the bilirubin uptake into human hepatocytes and the uptake of some flavonoids into human vascular endothelial cells. It was described by means of immunohistochemistry using polyclonal antibodies that bilitranslocase expression is severely down-regulated in clear cell renal carcinoma. The aim of our work was development and characterization of high-affinity, specific mAbs against bilitranslocase, which can be used as a potential diagnostic tool in renal cell carcinoma as well as in a wide variety of biological assays on different human tissues. Mice were immunized with a multi-antigen peptide corresponding to segment 65-75 of predicted primary structure of the bilitranslocase protein. By a sequence of cloning, immune- and functional tests, we aimed at obtaining a specific monoclonal antibody which recognizes a 37 kDa membrane protein, and influences the transport activity of bilitranslocase. On the basis of previous results, specific IgM monoclonal antibodies were produced in BALB/c mice, in order to further improve and extend the immunological approach to the study of bilitranslocase in renal cancer cells as well as to develop its potential diagnostics use. In this article we show an immunological approach, based on newly developed monoclonal antibodies, to a detailed biochemical and functional characterization of a protein whose gene and protein structure is still unknown. We were able to demonstrate our novel mAb as a tumor marker candidate of renal cell carcinoma, which may prove useful in the diagnostic procedures.


Overexpression of GmGASA32 promoted soybean height by interacting with GmCDC25.
GmGASA is the GASA gibberellin regulated cysteine-rich protein family. The expression of GmGASA is up-regulated by gibberellin, which is the longest plant hormone in plants playing vital roles in plant development. However, very few reports explaining the direct regulation of downstream genes by GASA gene are available. In the current study, the GmGASA32, a member of the GASA family affecting soybean height was identified. In the early stage, preliminary verification of the response of GmGASA32 to gibberellin through phenotypic experiment was done. The promoter activity analysis confirmed that GmGASA32 was induced by gibberellin. Subcellular localization showed that GmGASA32-GFP fusion protein enriched in the nucleus after gibberellin treatment. In order to confirm the function of GmGASA32 in the nucleus, we confirmed that the GASA domain in the C terminal of GmGASA32 can interact with GmCDC25 (cell cycle-associated protein) through the bimolecular fluorescence complementation (BiFC) assay.


MAIT cells are licensed through granzyme exchange to kill bacterially sensitized targets.
Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population restricted by the non-polymorphic, major histocompatibility complex class I-related protein 1, MR1. MAIT cells are activated by a broad range of bacteria through detection of riboflavin metabolites bound by MR1, but their direct cytolytic capacity upon recognition of cognate target cells remains unclear. We show that resting human MAIT cells are uniquely characterized by a lack of granzyme (Gr) B and low perforin expression, key granule proteins required for efficient cytotoxic activity, but high levels of expression of GrA and GrK. Bacterial activation of MAIT cells rapidly induced GrB and perforin, licensing these cells to kill their cognate target cells. Using a novel flow cytometry-based killing assay, we show that licensed MAIT cells, but not ex vivo MAIT cells from the same donors, can efficiently kill Escherichia coli-exposed B-cell lines in an MR1- and degranulation-dependent manner. Finally, we show that MAIT cells are highly proliferative in response to antigenic and cytokine stimulation, maintaining high expression of GrB, perforin, and GrA, but reduced expression of GrK following antigenic proliferation. The tightly regulated cytolytic capacity of MAIT cells may have an important role in the control of intracellular bacterial infections, such as Mycobacterium tuberculosis.


A brain-specific isoform of apoptosis-inducing factor 2 attenuates ischemia-induced oxidative stress in HT22 cells.
Apoptosis-inducing factor (AIF) is a family of conserved mitochondrial flavoproteins that have both vital and lethal functions in cells. The function and regulation of AIF-1, the original described and most abundant isoform, has been extensively studied, whereas three other AIF isoforms have not been further characterized. Here, we investigated the role of AIF-2, a brain-specific isoform of AIF, in an in vitro ischemia model in neuronal HT22 cells. We showed that AIF-2 was constitutively expressed in HT22 cells, and the oxygen and glucose deprivation (OGD) did not alter AIF-2 expression. Downregulation of AIF-2 with specific siRNA aggravated OGD-induced lactate dehydrogenase (LDH) release, apoptosis and loss of cell viability, whereas overexpression of AIF-2 through lentivirus transfection exerted the opposite effects. In OGD-treated cells, AIF-2 overexpression promoted the endogenous antioxidant enzyme activities, preserved mitochondrial membrane potential (MMP), inhibited cytochrome c release, and thereby prevented reactive oxygen species (ROS) generation and lipid peroxidation. In addition, AIF-2 significantly prevented the OGD-induced AIF-1 translocation from cytoplasm to the nuclei. In view of these considerations, AIF-2 might represent an ideal strategy to avoid AIF-1 associated neurotoxicity, and could be tested against brain ischemia in animal models.


Incorporating a gender lens into nutrition and health-related policies in Fiji: analysis of policies and stakeholder perspectives.
Gender equality, zero hunger and healthy lives and well-being for all, are three of the Sustainable Development Goals (SDGs) that underpin Fiji's National Development Plan. Work towards each of these goals contributes to the reduction of non-communicable diseases (NCDs). There are gender differences in NCD burden in Fiji. It is, however, unclear whether a gender lens could be more effectively included in nutrition and health-related policies. This study consisted of three components: (i) a policy content analysis of gender inclusion in nutrition and health-related policies (n = 11); (ii) policy analysis using the WHO Gender Analysis tool to identify opportunities for strengthening future policy; and (iii) informant interviews (n = 18), to understand perceptions of the prospects for gender considerations in future policies. Gender equality was a goal in seven policies (64%); however, most focused on women of reproductive age. One of the policies was ranked as gender responsive. Main themes from key informant interviews were: 1) a needs-based approach for the focus on specific population groups in policies; 2) gender-related roles and responsibilities around nutrition and health; 3) what is considered "equitable" when it comes to gender, nutrition, and health; 4) current considerations of gender in policies and ideas for further gender inclusion; and 5) barriers and enablers to the inclusion of gender considerations in policies. Informants acknowledged gender differences in the burden of nutrition-related NCDs, yet most did not identify a need for stronger inclusion of gender considerations within policies. There is considerable scope for greater inclusion of gender in nutrition and health-related policies in Fiji. This could be done by: 1) framing gender considerations in ways that are actionable and inclusive of a range of gender identities; 2) undertaking advocacy through actor networks to highlight the need for gender-responsive nutrition and health-related policies for key stakeholder groups; 3) ensuring that data collected to monitor policy implementation is disaggregated by sex and genders; and 4) promoting equitable participation in nutrition related issues in communities and governance processes. Action on these four areas are likely critical enablers to more gender equitable NCD reduction in Fiji.


Endothelin-1 gene polymorphisms influence cerebrospinal fluid endothelin-1 levels following aneurysmal subarachnoid hemorrhage.
Aneurysmal subarachnoid hemorrhage is a type of stroke with high morbidity and mortality. Increased endothelin-1 (ET-1) levels have been associated with increased risk of cerebral vasospasm, which is associated with increased morbidity. The purpose of this study was to investigate the relationships between ET-1 genotypes and ET-1 protein levels in cerebrospinal fluid (CSF) measured 72 hr before angiographic vasospasm measurement in subjects at high risk of cerebral vasospasm. Specifically, this study evaluated the differences between variant positive and variant negative groups of nine different ET-1 single-nucleotide polymorphisms (SNPs) in relationship with the ET-1 protein exposure rate. The CSF ET-1 protein levels were quantified using enzyme-linked immunosorbent assay. One functional SNP and eight ET-1 tagging SNPs were selected because they represent genetic variability in the entire ET-1 gene. The variant negative group of SNP rs2070699 was associated with a significantly higher ET-1 exposure rate than the variant positive group (p = 0.004), while the variant positive group of the rs5370 group showed a trend toward association with a higher ET-1 exposure rate (p = 0.051). Other SNPs were not informative. This is the first study to show differences in ET-1 exposure rate 72 hr before angiography in relation to ET-1 genotypes. These exploratory findings need to be replicated in a larger study; if replicated, these differences in genotypes may be a way to inform clinicians of those patients at a higher risk of increased ET-1 protein levels, which may lead to a higher risk of angiographic vasospasm.


Sugar hydrazide imides: a new family of glycosidase inhibitors.
The preparation of a novel type of iminosugar including a hydrazide imide moiety is described. The sugar hydrazide imides (3S,4S,5R,6R)-1-amino-3,4,5-trihydroxy-6-(hydroxymethyl)-2-iminopiperidine acetate and (3S,4S,5R,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)-2-imino-1-(methylamino)piperidine acetate presented here behave as inhibitors of α/β-glucosidases in the low micromolar concentration range. The former inhibitor displays a pH-dependent inhibition of β-glucosidase. The N-methylated counterpart behaves as an anomer-selective competitive micromolar inhibitor of α-glucosidase.


Prevention of bladder cancer incidence and recurrence: tobacco use.
To summarize the current knowledge about smoking carcinogenesis in bladder cancer (BCa), individual susceptibility and impact of smoking on incidence and outcomes of nonmuscle invasive BCa (NMIBC) and muscle-invasive BCa (MIBC). To assess the impact of smoking cessation on oncological outcomes. Smoking pattern, intensity, and duration are responsible for an increased risk of developing BCa and for worse tumor features at presentation. Tobacco consumption is associated with a higher risk of recurrence in NMIBC and with an impaired intravesical therapy efficacy. To date, the impact of smoking on oncological outcomes after radical surgery remains unclear. Smoking cessation decreases the risk of BCa and may also allow benefits on treatment outcomes. Nonetheless, the magnitude of the effect remains unclear and prospective series with the specific aim of weighing smoking cessation on outcomes are needed. Because even a 5-min counseling in the urology setting may be sufficient to significantly enhance smoking cessation rates, adequate knowledge of links between tobacco and BCa, from its molecular pathophysiology and its harms to benefits of cessation is paramount for urologists and for everyday clinical practice.


De novo ZIC2 frameshift variant associated with frontonasal dysplasia in a Limousin calf.
Bovine frontonasal dysplasias like arhinencephaly, synophthalmia, cyclopia and anophthalmia are sporadic congenital facial malformations. In this study, computed tomography, necropsy, histopathological examinations and whole genome sequencing on an Illumina NextSeq500 were performed to characterize a stillborn Limousin calf with frontonasal dysplasia. In order to identify private genetic and structural variants, we screened whole genome sequencing data of the affected calf and unaffected relatives including parents, a maternal and paternal halfsibling. The stillborn calf exhibited severe craniofacial malformations. Nose and maxilla were absent, mandibles were upwardly curved and a median cleft palate was evident. Eyes, optic nerve and orbital cavities were not developed and the rudimentary orbita showed hypotelorism. A defect centrally in the front skull covered with a membrane extended into the intracranial cavity. Aprosencephaly affected telencephalic and diencephalic structures and cerebellum. In addition, a shortened tail was seen. Filtering whole genome sequencing data revealed a private frameshift variant within the candidate gene ZIC2 in the affected calf. This variant was heterozygous mutant in this case and homozygous wild type in parents, half-siblings and controls. We found a novel ZIC2 frameshift mutation in an aprosencephalic Limousin calf. The origin of this variant is most likely due to a de novo mutation in the germline of one parent or during very early embryonic development. To the authors' best knowledge, this is the first identified mutation in cattle associated with bovine frontonasal dysplasia.


Argentatin C Analogues with Potential Antinociceptive Activity and Other Triterpenoid Constituents from the Aerial Parts of Parthenium incanum.
Four new triterpenes, 25-dehydroxy-25-methoxyargentatin C (1), 20S-hydroxyargentatin C (2), 20S-hydroxyisoargentatin C (3), and 24-epi-argentatin C (4), together with 10 known triterpenes (5-14) were isolated from the aerial parts of Parthenium incanum. The structures of 1-4 were elucidated by detailed analysis of their spectroscopic data, and the known compounds 5-14 were identified by comparison of their spectroscopic data with those reported. Since argentatin C (11) was found to exhibit antinociceptive activity by decreasing the excitability of rat and macaque dorsal root ganglia (DRG) neurons, 11 and its new analogues 1-4 were evaluated for their ability to decrease the excitability of rat DRG neurons. Of the argentatin C analogues tested, 25-dehydroxy-25-methoxyargentatin C (1) and 24-epi-argentatin C (4) decreased neuronal excitability in a manner comparable to 11. Preliminary structure-activity relationships for the action potential-reducing effects of argentatin C (11) and its analogues 1-4, and their predicted binding sites in pain-relevant voltage-gated sodium and calcium channels (VGSCs and VGCCs) in DRG neurons are presented.


Phase change instability in the mantle.
In the presence of a temperature gradient, phase changes of the type believed to exist in the upper mantle, in which the less dense phase lies above the dense phase, may be unstable. Approximate calculations show such phase change instabilities are possible for both the 400-kilometer olivine-spinel phase transition and also for partial melting at shallower depths. The resulting flow patterns may provide a driving mechanism for the new global tectonics.


Hierarchical Bayesian models of transcriptional and translational regulation processes with delays.
Simultaneous recordings of gene network dynamics across large populations have revealed that cell characteristics vary considerably even in clonal lines. Inferring the variability of parameters that determine gene dynamics is key to understanding cellular behavior. However, this is complicated by the fact that the outcomes and effects of many reactions are not observable directly. Unobserved reactions can be replaced with time delays to reduce model dimensionality and simplify inference. However, the resulting models are non-Markovian, and require the development of new inference techniques. We propose a non-Markovian, hierarchical Bayesian inference framework for quantifying the variability of cellular processes within and across cells in a population. We illustrate our approach using a delayed birth-death process. In general, a distributed delay model, rather than a popular fixed delay model, is needed for inference, even if only mean reaction delays are of interest. Using in silico and experimental data we show that the proposed hierarchical framework is robust and leads to improved estimates compared to its non-hierarchical counterpart. We apply our method to data obtained using time-lapse microscopy and infer the parameters that describe the dynamics of protein production at the single cell and population level. The mean delays in protein production are larger than previously reported, have a coefficient of variation of around 0.2 across the population, and are not strongly correlated with protein production or growth rates. Accompanying code in Python is available at https://github.com/mvcortez/Bayesian-Inference. firstname.lastname@example.com or firstname.lastname@example.com or firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


Ethics, Abortion Access, and Emergency Care Post-Dobbs: The Gray Areas.
Clinical management of emergency pregnancy care, such as ectopic pregnancy or heavy bleeding with pregnancy of unknown location, includes upholding legal and ethical standards. For health care providers unwilling to provide evidence-based life-saving abortion care due to personal beliefs, clear guidance dictates disclosure of these limitations to the patient and colleagues, followed by immediate referral for appropriate care. However, this decision-making pathway may not be engaged due to a variety of factors: providers' beliefs preclude adherence to referral responsibilities, political discourse confuses patients as to their options and rights, and a constantly changing state and national legal landscape leads providers to question their ability to practice to their full scope of clinical care. Although this disruption of evidence-based standard of care existed pre-Dobbs, the moral disorder is now heightened. This Clinical Rounds highlights a patient vignette describing the risks of abortion restrictions for patients and providers alike, particularly when an individual provider's concerns for violating institutional guidelines sets a precedent for nursing response and forecloses on collaborative input or ethics consultation. The history of physician-only abortion exceptionalism and exclusion of nurses and midwives despite a significant history of nurses and midwives in abortion care grounds an argument for focusing on the impact of unethical and substandard care on the interprofessional care team leading to moral distress and negative patient outcomes. Patient-centered models of care, such as frameworks common in nursing and midwifery, offer opportunities to consider how all providers practicing to their full scope in interprofessional and collaborative ways, such as in emergency rooms and labor departments, might mitigate obstructions to abortion care that risk pregnant people's lives.


Morphological differences in parr of Atlantic salmon Salmo salar from three regions in Norway.
Morphological characters were compared in parr (total length 33-166 mm) of Atlantic salmon Salmo salar sampled from eight wild populations in three regions, three in northern, two in the middle and three in southern Norway, covering a distance of 1700 km (from 70° N to 58° N). On the basis of morphological characters 94·6% of the individuals were correctly classified into the three regions. Discrimination between populations within these three regions also had a high degree of correct classification (89·0-95·8%). Principle component analysis identified largest differences to be in head characters, notably eye diameter and jawbone, with the smallest diameter and head size among the northernmost populations. Fish from the southern rivers had a deeper body form whereas fish from the middle region had larger heads and pectoral fins. This illustrates that S. salar already in the early parr stage has morphological traits, which can be used in discrimination between regions and populations and that these differences are discernible in spite of the volume of escaped farmed fish spawning in Norwegian rivers during the past 30 years.


Profile of Nagasaki Islands Study (NaIS): A Population-Based Prospective Cohort Study on Multi-disease.
In an aging society, it is important to visualize the conditions of people living with diseases or disabilities, such as frailty and sarcopenia, and determine the environmental and genetic factors underlying such conditions. Atherosclerosis and arterial stiffness are key conditions between these factors and noncommunicable diseases. In 2014, we launched a population-based prospective open-cohort study, the Nagasaki Islands Study (NaIS), which was conducted in Goto City, located in the remote islands of Nagasaki Prefecture, Japan, mostly involving middle-aged and older residents. We conducted our own health checkups along with the annual standardized checkups organized by the municipality; recruited study participants; and started to follow-up with them for vital status (death), migration, and occurrence of diseases such as myocardial infarction, stroke, fracture, and human T-cell leukemia virus type 1 (HTLV-1) -associated uveitis. Our checkups were conducted as baseline surveys in different areas of Goto City during the fiscal years 2014-2016, secondary surveys during 2017-2019, and tertiary surveys since 2021, consisting of medical interviews, physical examinations, blood and urine tests, body composition measurements, osteoporosis screening, arterial stiffness measurements, carotid ultrasonography, and dental examination. A total of 4,957 residents participated in either the baseline or secondary surveys and were followed-up; and 3,594 and 3,364 residents (aged 27-96 and 28-98 years) participated in the baseline and secondary surveys, respectively. In conclusion, the NaIS has been undertaken to reveal the influence of aging and risk factors of noncommunicable diseases and disabilities, with an aim to contribute towards better healthcare in the future.


Point-of-care ultrasound compared with conventional radiographic evaluation in children with suspected distal forearm fractures in the Netherlands: a diagnostic accuracy study.
Distal forearm fractures are common in children. The reference standard to diagnose these fractures is by conventional radiography, which exposes these patients to harmful radiation. Ultrasound (US) seems to be a good alternative. However, emergency physicians (EPs) in the Netherlands have limited experience in using US for diagnosing fractures in children. The primary objective was to determine the accuracy of US, performed by a Dutch EP, compared with conventional radiography, in diagnosing distal forearm fractures in children. As a secondary objective, differences in pain scores during the performance of both US and plain radiography were determined. Children, aged between 0 and 14 years old, suspected of having a distal forearm fracture were enrolled at the Emergency Department. US and radiographic findings were compared. Statistics for accuracy were calculated. Pain scores were recorded during US and radiography and compared as well. All participating operators received an hour-long pretrial training. 100 patients were enrolled. The mean age was 9.5 years (SD, 3.6), and 50% were women. Overall diagnostic accuracy was 92% (95% CI 85%-96%). The sensitivity, specificity, positive and negative predictive values, positive and negative likelihood ratios for US were 95% (95% CI 87% to 99%), 86% (95% CI 71% to 95%), 92% (95% CI 83% to 97%), 91% (95% CI 76% to 98%), 6.86 (95% CI 3.04 to 15.51) and 0.05 (95% CI 0.02 to 0.17), respectively. The pain scores during US and radiographic imaging were 3.3 and 4.6, respectively (p<0.01). In this study, we showed that US is an accurate method for diagnosing distal forearm fractures in children. The main advantages are that it is radiation-free and rapidly practicable, and that patients experience it as less painful than radiography. Moreover, this study has proven that with minimal experience in US, good diagnostic accuracy can be achieved after brief training.


Management of urolithiasis in pregnancy.
Urolithiasis is the most common cause of nonobstetric abdominal pain, resulting in 1.7 admissions per 1000 deliveries. Urolithiasis most commonly occurs in the second and third trimesters, with an incidence between 1:125 and 1:2000. Acute urinary system obstructions are challenging to manage in obstetric patients because they contribute to physiological and anatomical changes that result in pathological outcomes. The restricted use of computed tomography in diagnosing and managing urolithiasis is particularly challenging. In addition, a prompt diagnosis is required because the presence of renal calculi during pregnancy increases the risk of fulminating sepsis and preterm delivery. Affected pregnancies are conservatively managed; however, 1 in 4 requires surgical intervention. Indications for surgical interventions are complex and range from nephrostomy insertion to empirical stent placement or ureteroscopy. Therefore, a multidisciplinary approach is required to optimize patient care. The diagnosis and management of urolithiasis in pregnancy are complex. We reviewed the role, safety, advantages and disadvantages of diagnostic tests and treatment used to manage acute urinary obstructions in pregnancy.


Randomizing world trade. II. A weighted network analysis.
Based on the misleading expectation that weighted network properties always offer a more complete description than purely topological ones, current economic models of the International Trade Network (ITN) generally aim at explaining local weighted properties, not local binary ones. Here we complement our analysis of the binary projections of the ITN by considering its weighted representations. We show that, unlike the binary case, all possible weighted representations of the ITN (directed and undirected, aggregated and disaggregated) cannot be traced back to local country-specific properties, which are therefore of limited informativeness. Our two papers show that traditional macroeconomic approaches systematically fail to capture the key properties of the ITN. In the binary case, they do not focus on the degree sequence and hence cannot characterize or replicate higher-order properties. In the weighted case, they generally focus on the strength sequence, but the knowledge of the latter is not enough in order to understand or reproduce indirect effects.


A probabilistic pathway score (PROPS) for classification with applications to inflammatory bowel disease.
Gene-based supervised machine learning classification models have been widely used to differentiate disease states, predict disease progression and determine effective treatment options. However, many of these classifiers are sensitive to noise and frequently do not replicate in external validation sets. For complex, heterogeneous diseases, these classifiers are further limited by being unable to capture varying combinations of genes that lead to the same phenotype. Pathway-based classification can overcome these challenges by using robust, aggregate features to represent biological mechanisms. In this work, we developed a novel pathway-based approach, PRObabilistic Pathway Score, which uses genes to calculate individualized pathway scores for classification. Unlike previous individualized pathway-based classification methods that use gene sets, we incorporate gene interactions using probabilistic graphical models to more accurately represent the underlying biology and achieve better performance. We apply our method to differentiate two similar complex diseases, ulcerative colitis (UC) and Crohn's disease (CD), which are the two main types of inflammatory bowel disease (IBD). Using five IBD datasets, we compare our method against four gene-based and four alternative pathway-based classifiers in distinguishing CD from UC. We demonstrate superior classification performance and provide biological insight into the top pathways separating CD from UC. PROPS is available as a R package, which can be downloaded at http://simtk.org/home/props or on Bioconductor. firstname.lastname@example.com. Supplementary data are available at Bioinformatics online.


[Endoscopic endonasal transsphenoidal approach for growth hormone-producing pituitary adenomas. Preliminary results].
An endoscopic endonasal transsphenoidal approach is reported as less invasive, allowing an earlier discharge. Published series have never focused on its use in acromegalic patients. To assess the effectiveness of an endoscopic endonasal transsphenoidal approach in the management of growth hormone-secreting adenomas. Nineteen consecutively operated patients were assessed with a prospective follow-up of one year. Sex ratio was 0.7/1 and gross total removal was obtained in 16 cases (84%), subtotal in three (16%). The only complication was a cerebrospinal fluid leak requiring spinal drainage. The median in-hospital stay was 2.5 days. Sixteen patients experienced clinical improvement (84%) and no changes were observed in three (16%). Residual tumor was seen in two cases (11%). Growth hormone levels < 2 ng/dl were seen in 17 cases (89%) and only two patients (11%) had a level >2 ng/dl. Insulin-like growth factor-1 levels were normalized in 16 cases (84%) and remained elevated in three patients (16%). One patient presented an isolated elevated level of insulin-like growth factor-1. Patients with residual tumor and elevated growth hormone and insulin-like growth factor-1 levels underwent complementary radiosurgery. The endoscopic endonasal transsphenoidal approach seems to be useful in acromegaly, with a high rate of clinical and biochemical cure among other benefits.