Molecular elucidation of drug-induced abnormal assemblies of the hepatitis B virus capsid protein by solid-state NMR.
Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a recent class of anti-HBV antivirals. CAMs disturb proper nucleocapsid assembly, by inducing formation of either aberrant assemblies (CAM-A) or of apparently normal but genome-less empty capsids (CAM-E). Classical structural approaches have revealed the CAM binding sites on the capsid protein (Cp), but conformational information on the CAM-induced off-path aberrant assemblies is lacking. Here we show that solid-state NMR can provide such information, including for wild-type full-length Cp183, and we find that in these assemblies, the asymmetric unit comprises a single Cp molecule rather than the four quasi-equivalent conformers typical for the icosahedral T = 4 symmetry of the normal HBV capsids. Furthermore, while in contrast to truncated Cp149, full-length Cp183 assemblies appear, on the mesoscopic level, unaffected by CAM-A, NMR reveals that on the molecular level, Cp183 assemblies are equally aberrant. Finally, we use a eukaryotic cell-free system to reveal how CAMs modulate capsid-RNA interactions and capsid phosphorylation. Our results establish a structural view on assembly modulation of the HBV capsid, and they provide a rationale for recently observed differences between in-cell versus in vitro capsid assembly modulation.


Effects of xylazine on airway function in ponies with recurrent airway obstruction.
The effect of IV administration of the alpha 2-adrenoceptor agonist xylazine hydrochloride (0.5 mg/kg of body weight) was examined in ponies with recurrent obstructive pulmonary disease, commonly called heaves. Six ponies with the disease (principals) were studied during clinical remission and during an acute attack of airway obstruction precipitated by stabling and feeding of dusty hay. Six control ponies were also studied. In principal ponies with airway obstruction, xylazine administration significantly (P < 0.05) decreased pulmonary resistance and increased dynamic compliance, but did not affect PaO2 or PaCO2. The alpha 2-antagonist yohimbine blocked the pulmonary effects of xylazine. Administration of saline solution was without effect in both groups of ponies at all periods and xylazine did not have effect in controls or in principals in clinical remission.


Differential activation of mouse and human Panx1 channel variants.
Pannexins are ubiquitously expressed in human and mouse tissues. Pannexin 1 (Panx1), the most thoroughly characterized member of this family, forms plasmalemmal membrane channels permeable to relatively large molecules, such as ATP. Although human and mouse Panx1 amino acid sequences are conserved in the presently known regulatory sites involved in trafficking and modulation of the channel, differences are reported in the N- and C-termini of the protein, and the mechanisms of channel activation by different stimuli remain controversial. Here we used a neuroblastoma cell line to study the activation properties of endogenous mPanx1 and exogenously expressed hPanx1. Dye uptake and electrophysiological recordings revealed that in contrast to mouse Panx1, the human ortholog is insensitive to stimulation with high extracellular [K+] but responds similarly to activation of the purinergic P2X7 receptor. The two most frequent Panx1 polymorphisms found in the human population, Q5H (rs1138800) and E390D (rs74549886), exogenously expressed in Panx1-null N2a cells revealed that regarding P2X7 receptor mediated Panx1 activation, the Q5H mutant is a gain of function whereas the E390D mutant is a loss of function variant. Collectively, we demonstrate differences in the activation between human and mouse Panx1 orthologs and suggest that these differences may have translational implications for studies where Panx1 has been shown to have significant impact.


Multivariate analysis of genome-wide data to identify potential pleiotropic genes for type 2 diabetes, obesity and coronary artery disease using MetaCCA.
Although genome-wide association studies (GWAS) have been extensively applied in identifying SNP associated with metabolic diseases, the SNPs identified by this prevailing univariate approach only explain a small percentage of the genetic variance of traits. The extensive previous studies have repeatedly shown type2 diabetes (T2D), obesity and coronary artery disease (CAD) have common genetic mechanisms and the overlapping pathophysiological pathways. The genetic pleiotropy-informed metaCCA method was applied on summary statistics data from three independent meta-GWAS summary statistics to identify shared variants and pleiotropic effect between T2D, obesity and CAD. Furthermore, to refine all genes, we performed gene-based association analyses for these three diseases respectively using VEGAS2. Gene enrichment analysis was applied to explore the potential functional significance of the identified genes. After metaCCA analysis, 833 SNPs reached the Bonferroni corrected threshold (p < 7.99 × 10-7) in the univariate SNP-multivariate phenotype analysis, and 327 genes with a significance threshold (p < 3.73 × 10-6) were identified as potentially pleiotropic genes in the multivariate SNP-multivariate phenotype analysis. By screening the results of gene-based p-values, we identified 22 putative pleiotropic genes which achieved significance threshold in metaCCA analyses and were also associated with at least one disease in the VEGAS2 analyses. The metaCCA method identified novel variants associated with T2D, obesity and CAD by effectively incorporating information from different GWAS datasets. Our analyses may provide insights for some common therapeutic approaches of metabolic diseases based on the pleiotropic genes and common mechanisms identified.


LRRCE: a leucine-rich repeat cysteine capping motif unique to the chordate lineage.
The small leucine-rich repeat proteins and proteoglycans (SLRPs) form an important family of regulatory molecules that participate in many essential functions. They typically control the correct assembly of collagen fibrils, regulate mineral deposition in bone, and modulate the activity of potent cellular growth factors through many signalling cascades. SLRPs belong to the group of extracellular leucine-rich repeat proteins that are flanked at both ends by disulphide-bonded caps that protect the hydrophobic core of the terminal repeats. A capping motif specific to SLRPs has been recently described in the crystal structures of the core proteins of decorin and biglycan. This motif, designated as LRRCE, differs in both sequence and structure from other, more widespread leucine-rich capping motifs. To investigate if the LRRCE motif is a common structural feature found in other leucine-rich repeat proteins, we have defined characteristic sequence patterns and used them in genome-wide searches. The LRRCE motif is a structural element exclusive to the main group of SLRPs. It appears to have evolved during early chordate evolution and is not found in protein sequences from non-chordate genomes. Our search has expanded the family of SLRPs to include new predicted protein sequences, mainly in fishes but with intriguing putative orthologs in mammals. The chromosomal locations of the newly predicted SLRP genes would support the large-scale genome or gene duplications that are thought to have occurred during vertebrate evolution. From this expanded list we describe a new class of SLRP sequences that could be representative of an ancestral SLRP gene. Given its exclusivity the LRRCE motif is a useful annotation tool for the identification and classification of new SLRP sequences in genome databases. The expanded list of members of the SLRP family offers interesting insights into early vertebrate evolution and suggests an early chordate evolutionary origin for the LRRCE capping motif.


Activation of resorption in fatigue-loaded bone involves both apoptosis and active pro-osteoclastogenic signaling by distinct osteocyte populations.
Osteocyte apoptosis is required to initiate osteoclastic bone resorption following fatigue-induced microdamage in vivo; however, it is unclear whether apoptotic osteocytes also produce the signals that induce osteoclast differentiation. We determined the spatial and temporal patterns of osteocyte apoptosis and expression of pro-osteoclastogenic signaling molecules in vivo. Ulnae from female Sprague-Dawley rats (16-18weeks old) were cyclically loaded to a single fatigue level, and tissues were analyzed 3 and 7days later (prior to the first appearance of osteoclasts). Expression of genes associated with osteoclastogenesis (RANKL, OPG, VEGF) and apoptosis (caspase-3) were assessed by qPCR using RNA isolated from 6mm segments of ulnar mid-diaphysis, with confirmation and spatial localization of gene expression performed by immunohistochemistry. A novel double staining immunohistochemistry method permitted simultaneous localization of apoptotic osteocytes and osteocytes expressing pro-osteoclastogenic signals relative to microdamage sites. Osteocyte staining for caspase-3 and osteoclast regulatory signals exhibited different spatial distributions, with apoptotic (caspase 3-positive) cells highest in the damage region and declining to control levels within several hundred microns of the microdamage focus. Cells expressing RANKL or VEGF peaked between 100 and 300μm from the damage site, then returned to control levels beyond this distance. Conversely, osteocytes in non-fatigued control bones expressed OPG. However, OPG staining was reduced markedly in osteocytes immediately surrounding microdamage. These results demonstrate that while osteocyte apoptosis triggers the bone remodeling response to microdamage, the neighboring non-apoptotic osteocytes are the major source of pro-osteoclastogenic signals. Moreover, both the apoptotic and osteoclast-signaling osteocyte populations are localized in a spatially and temporally restricted pattern consistent with the targeted nature of this remodeling response.


Native kidney BK virus nephropathy associated with chronic lymphocytic leukaemia.
BK virus nephropathy (BKVN) is a well-recognized complication of renal transplantation. Several cases of native kidney BKVN following other solid organ or bone marrow transplants have been reported. We describe a patient with chronic lymphocytic leukaemia who presented with deteriorating renal function with no history of solid organ or bone marrow transplantation. Renal biopsy demonstrated tubular injury characteristic of viral infection, confirmed as BK virus by immunohistochemistry and elevated serum BK viral titres. Treatment with leflunomide reduced serum viral titres and stabilized renal function. This is the first biopsy-proven case of native kidney BKVN in a patient with no previous transplantation history.


Relation between neutrophil-to-lymphocyte ratio and severity of coronary artery stenosis.
This study aimed to investigate the relation between the neutrophil-to-lymphocyte ratio (NLR) and the severity of coronary artery stenosis. A total of 219 patients were included in the study, comprising 51 coronary artery atherosclerosis (CAC) patients, 92 stable angina pectoris (SAP) patients, and 76 acute coronary syndrome (ACS) patients. Based on the results of coronary angiography, all patients were divided into two groups according to the Gensini scores: the low-score group (N = 142) and the high-score group (N = 77). The NLR was computed from the ratio of neutrophils and lymphocytes from the complete blood count. The association between the NLR and severity of coronary artery disease was assessed using correlation analysis and logistic regression. The NLR was higher in ACS patients than in SAP and CAC patients (P < 0.05). In addition, the NLR was higher in the high-score group than in the low-score group (P < 0.05). Correlation analysis showed that the NLR was significantly correlated with the Gensini score. After multivariate analysis, high NLRs were independent predictors of high Gensini scores, together with age and high-density lipoprotein. A cutoff NLR of 2.385 predicted high Gensini scores with a sensitivity and specificity of 64 and 63%, respectively. The study suggests that the NLR is an independent predictor of coronary heart disease that may be useful for predicting the severity of coronary artery stenosis.


Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells.
Pancreatic stellate cells (PSCs) play a key role in desmoplastic stroma, which is a characteristic of pancreatic ductal adenocarcinoma (PDAC), and they also enhance the malignancy of pancreatic cancer cells. Our previous study reported chloroquine's mitigating effects on PSC activation; however, the drug is known to induce adverse effects in clinical practice. The present study aimed to reduce chloroquine doses and develop a useful pre-treatment that targets PSCs using nanoparticles. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as carriers and loaded with indocyanine green (Nano-ICG) or chloroquine (Nano-CQ). Tumor accumulation of Nano-ICG was evaluated using an in vivo imaging system. The effects of chloroquine, Nano-CQ and/or chemotherapy drug gemcitabine were investigated in an orthotopic xenograft mouse model. Nano-ICG selectively accumulated in pancreatic tumors and persisted therein for over 7 days after administration. Additionally, Nano-ICG accumulated in the peritoneal metastasized regions, but not in the liver, kidney and normal pancreatic tissues. Nano-CQ reduced the density of activated PSCs at lower chloroquine doses and significantly restrained tumor progression in combination with gemcitabine. In conclusion, the PLGA nanosystem successfully delivered the drug to pancreatic tumors. Nano-CQ efficiently reduced PSC activation and may be a promising novel pre-treatment strategy for PDAC.


HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway.
It has been previously shown that the HIV-1 envelope glycoprotein 120 (gp120) activates cell signaling by CXCR4, independently of CD4. The present study examines the involvement of different intracellular signaling pathways and their physiopathologic consequences following the CD4-independent interaction between CXCR4 or CCR5 and gp120 in different cell types: primary T cells, CD4(-)/CXCR4(+)/CCR5(+) T cells, or glioma cells. These interactions were compared with those obtained with natural ligands, stromal cell-derived factor 1 alpha (SDF-1alpha) (CXCL12) and macrophage inflammatory protein 1 beta (MIP-1beta) (CCL4) of their respective coreceptors. Thus, both p38 and SAPK/Jun N-terminal kinase mitogen-activated protein kinases (MAPKs) are activated on stimulation of these cells with either T- or M-tropic gp120, as well as with SDF-1alpha or MIP-1beta. In contrast, extracellular signal-related kinase 1 and 2 MAPKs are only activated by MIP-1beta but not by M-tropic gp120. Importantly, T- and M-tropic gp120 are able to induce the secretion of matrix metalloproteinase 9 (MMP-9), an extracellular metalloproteinase present in cerebrospinal fluid of patients with HIV-1 by T cells or glioma cells. Specific inhibition of MAPK p38 activation resulted in a complete abrogation of the induction of the MMP-9 pathogenic factor expression by gp120 or chemokines in both cell types. Because neurodegenerative features in acquired immune deficiency syndrome dementia may involve demyelinization by MMP-9, the specific targeting of p38 could provide a novel means to control HIV-induced cytopathogenic effects and cell homing to viral replication sites. (Blood. 2001;98:541-547)


Enantioselective Synthesis of Medium-Sized-Ring Lactones via Iridium-Catalyzed Z-Retentive Asymmetric Allylic Substitution Reaction.
Medium-sized rings are important structural units, but their synthesis, especially in a highly enantioselective manner, has been a great challenge. Herein we report an enantioselective synthesis of medium-sized-ring lactones by an iridium-catalyzed Z-retentive asymmetric allylic substitution reaction. The reaction features mild conditions and a broad substrate scope. Various eight- to 11-membered-ring lactones can be afforded in moderate to excellent yields (up to 88%) and excellent enantioselectivity (up to 99% ee). The utilization of both Z-allyl precursors and an Ir catalyst is critical for the medium-sized-ring formation.


[Abdominal pain due to nerve compression].
Persistent abdominal pain in a 15-year-old girl was diagnosed after examination by the GP, the pediatrician, the gynaecologist and finally, the surgeon as rib-tip syndrome. The patient could be treated sufficiently by the injection of local anaesthetics and corticosteroids. In the rib-tip syndrome hypermobility of the lower ribs irritates the intercostal nerves causing pain along the lower edge of the chest. The condition can be established objectively with the aid of fluoroscopy and electrostimulation, electromyography or magnetic stimulation.


HPLC imprinted-stationary phase prepared by precipitation polymerisation for the determination of thiabendazole in fruit.
A molecularly imprinted polymer (MIP) tailored for the HPLC determination of the fungicide thiabendazole (TBZ) has been synthesised in one single preparative step by precipitation polymerisation in an acetonitrile/toluene co-solvent, using TBZ as template molecule, methacrylic acid as functional monomer and divinylbenzene-80 as crosslinker. The imprinted polymer particulates obtained were characterised by scanning electron microscopy and nitrogen sorption porosimetry. These analyses showed clearly that spherical polymer particulates (polymer microspheres) with narrow size distributions (average particle diameter approximately 3.5 microm) and well-developed pore structures had been produced. The imprinted microspheres were packed into a stainless steel HPLC column (50 x 4.6 mm id) and evaluated as an imprinted stationary phase. The imprinting effect was demonstrated clearly, i.e., the column was observed to bind TBZ selectively, and the effect of different chromatographic parameters (e.g., temperature, flow-rate and elution solvents) on TBZ retention/elution studied. Under optimised conditions, the TBZ-imprinted column was used for the HPLC-fluorescence (HPLC-F) determination of TBZ directly from orange (both whole fruit and juice), lemon, grape and strawberry extracts at low concentration levels in less than 15 min, without any need for a clean-up step in the analytical protocol.


Neuropsychological correlates of obsessive characteristics in Tourette syndrome.
The relationship between obsessive-compulsive (OC) characteristics and performance on a test sensitive to frontal lobe function (Wisconsin Card Sorting Test) was examined in a sample of 100 patients between the ages of 6 and 18 years. All patients met DSM-III-R criteria for Tourette syndrome (TS), confirmed by a neurologist or psychiatrist. Performance on the Wisconsin Card Sorting Test was correlated with ratings of OC characteristics, but not with other TS symptoms. This relationship was maintained even when Full-Scale IQ and the total number of Tourette symptoms were controlled. The effect could not be attributed to medication. These findings were interpreted in the context of models of basal ganglia-cortical associations. It was speculated that different symptoms associated with TS may have different neuroanatomic substrates.


Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan.
To evaluate the efficacy of pegylated interferon alpha-2b (peg-IFN alpha-2b) plus ribavirin (RBV) therapy in Japanese patients with chronic hepatitis C (CHC) genotype Ib and a high viral load. One hundred and twenty CHC patients (58.3% male) who received peg-IFN alpha-2b plus RBV therapy for 48 wk were enrolled. Sustained virological response (SVR) and clinical parameters were evaluated. One hundred (83.3%) of 120 patients completed 48 wk of treatment. 53 patients (44.3%) achieved SVR. Early virological response (EVR) and end of treatment response (ETR) rates were 50% and 73.3%, respectively. The clinical parameters (SVR vs non-SVR) associated with SVR, ALT (108.4 IU/L vs 74.5 IU/L, P = 0.063), EVR (76.4% vs 16.4%, P < 0.0001), adherence to peg-IFN (>or= 80% of planned dose) at week 12 (48.1% vs 13.6%, P = 0.00036), adherence to peg-IFN at week 48 (54.7% vs 16.2%, P < 0.0001) and adherence to RBV at week 48 (56.1% vs 32.1%, P = 0.0102) were determined using univariate analysis, and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis. In the older patient group (> 56 years), SVR in females was significantly lower than that in males (17% vs 50%, P = 0.0262). EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR. Peg-IFN alpha-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%. Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFN alpha-2b is important in improving the SVR rate.


Vitamin D and Hyperkinetic Movement Disorders: A Systematic Review.
The importance of vitamin D deficiency in Parkinson's disease, its negative influence on bone health, and even disease pathogenesis has been studied intensively. However, despite its possible severe impact on health and quality of life, there is not a sufficient understanding of its role in other movement disorders. This systematic review aims at providing an overview of the prevalence of vitamin D deficiency, bone metabolism alterations, and fractures in each of the most common hyperkinetic movement disorders (HKMDs). The study search was conducted through PubMed with keywords or Medical Related Subjects (MeSH) of common HKMDs linked with the terms of vitamin D, osteoporosis, injuries, and fractures. Out of 1585 studies screened 40 were included in our review. They show that there is evidence that several HKMDs, including Huntington disease, Restless Legs Syndrome, and tremor, are associated with low vitamin D serum levels in up to 83% and 89% of patients. Reduced bone mineral density associated with vitamin D insufficiency was described in Huntington disease. Our survey suggests that vitamin D deficiency, bone structure changes, and fractures are important but yet under-investigated issues in HKMDs. HKMDs-patients, particularly with a history of previous falls, should have their vitamin D-levels tested and supplemented where appropriate. Contrary to Parkinson's disease, vitamin D deficiency, and bone abnormalities are under-investigated in hyperkinetic movement disorders (HKMDs). Several HKMDs, including essential tremor, RLS, and Huntington disease, are associated with vitamin D deficiency in up to 89%, the latter also with reduced bone mineral density. Testing and where appropriate supplementation is recommended.


Pseudophosphorylated αB-crystallin is a nuclear chaperone imported into the nucleus with help of the SMN complex.
The human small heat shock protein αB-crystallin (HspB5) is a molecular chaperone which is mainly localized in the cytoplasm. A small fraction can also be found in nuclear speckles, of which the localization is mediated by successional phosphorylation at Ser-59 and Ser-45. αB-crystallin does not contain a canonical nuclear localization signal sequence and the mechanism by which αB-crystallin is imported into the nucleus is not known. Here we show that after heat shock pseudophosphorylated αB-crystallin mutant αB-STD, in which all three phosphorylatable serine residues (Ser-19, Ser-45 and Ser-59) were replaced by negatively charged aspartate residues, is released from the nuclear speckles. This allows αB-crystallin to chaperone proteins in the nucleoplasm, as shown by the ability of αB-STD to restore nuclear firefly luciferase activity after a heat shock. With the help of a yeast two-hybrid screen we found that αB-crystallin can interact with the C-terminal part of Gemin3 and confirmed this interaction by co-immunoprecipitation. Gemin3 is a component of the SMN complex, which is involved in the assembly and nuclear import of U-snRNPs. Knockdown of Gemin3 in an in situ nuclear import assay strongly reduced the accumulation of αB-STD in nuclear speckles. Furthermore, depletion of SMN inhibited nuclear import of fluorescently labeled recombinant αB-STD in an in vitro nuclear import assay, which could be restored by the addition of purified SMN complex. These results show that the SMN-complex facilitates the accumulation of hyperphosphorylated αB-crystallin in nuclear speckles, thereby creating a chaperone depot enabling a rapid chaperone function in the nucleus in response to stress.


LGBTQI + Migrants: A Systematic Review and Conceptual Framework of Health, Safety and Wellbeing during Migration.
The health and safety of LGBTQI+ migrants or migrants who are of diverse sexual orientation, gender identity or expression (SOGIE) remains an under-studied area, particularly for the period during transit from their place of origin to destination. This systematic review aims to describe the literature on the health risks and consequences among SOGIE migrants during transit and examine their access and use of services. Six peer-reviewed databases and websites of nine large migration organisations were searched to identify the literature on forced migrants and sexual and gender minorities. Twenty English-language studies from 2000-2021 were included and analysed drawing on a conceptual framework. Studies emerged from six regions and the majority of research participants identified as gay men. In general, quality appraisal demonstrated studies as either medium or high quality. Findings suggested five common themes associated with SOGIE health and well-being, including: daily exposure to discrimination, harassment and violence; coping, social support and resilience; access to services; mental health; and physical and sexual health. Depression, anxiety and post-traumatic stress disorder (PTSD) were prevalent amongst SOGIE migrants, particularly when associated with detention or camp environments, and were exacerbated by social isolation. Barriers to accessing healthcare were identified and specific sexual health services were often found lacking, especially for trans persons. Unsurprisingly, during transit, SOGIE migrants are very likely to experience the double marginalisation of their migrant or minority status and their gender identity. Results indicate that services for SOGIE migrants need to tailor service access and support approaches to respond to the particular health and protection needs of SOGIE individuals in each setting.


Giant multicystic malignant pheochromocytoma.
Pheochromocytoma is a rare tumor originating from the embryonic neural crest and secreting high levels of catecholamines. The average tumor size is approximately 7 cm, and the average weight is approximately 200 g in the previous publications. Sometimes these tumors may be bigger. In this report, a case of multicystic malignant pheochromocytoma with a huge size is presented, which is seldom reported in the past. A 37-year-old male patient was referred to our hospital for etiological investigation of his recently diagnosed hypertension. Contrast-enhanced computed tomography (CT) examination was performed for further evaluation of the lesion and surrounding tissues. The lesion was 18×8×13 cm in size. It had lobulated margins, large cystic components, and peripheral and septal contrast enhancement. The levels of metanephrine, normetanephrine, adrenaline, noradrenaline, vanilmandelic acid, and dopamine were significantly elevated. The patient was prepared for surgery. In the pathological evaluation, the mass weighed 1018 g and was 18×8×13 cm in size. He was diagnosed with malignant pheochromocytoma. After eight months, a CT examination showed a recurrent mass, liver metastasis, and distant metastasis. The patient received chemotherapy and radiotherapy. Multicystic malignant pheochromocytoma may reach huge sizes without causing any symptoms.


Technologists, radiologists and the next hundred years.
During the past century, radiology has produced phenomenal research, developed sound systems of education for radiologic technologists and radiologists and established a tradition of excellence in patient care. Such advances have, in many cases, occurred only through cooperative efforts between radiologic technologists and radiologists. But health care reform looms ahead, and with it will come many uncertainties. This article examines some of the changes radiologists and radiologic technologists may experience during this period of change, including shifts in research methods, educational systems and clinical practice patterns. The author believes that as the next 100 years of our profession unfold, radiologic technologists and radiologists must work together to ensure radiology's continued growth and to protect the quality of its educational systems and its high standard of patient care.


Annulative π-extension of BODIPYs made easy via gold(i)-catalyzed cycloisomerization.
Here we report gold(i)-catalyzed cycloisomerization as a new powerful synthetic tool for the preparation of π-extended BODIPY derivatives. The catalytic system PPhF 3AuCl/AgSbF6 enables the synthesis of [b]-[2,1]naphtho-fused-BODIPYs (2a-2c) under mild conditions, in excellent yields and short reaction times. The reaction is totally regioselective to the 6-endo-dig product and for the α-position of the BODIPY, which is both the kinetically and thermodynamically favored pathway, as supported by the free energy profile calculated by means of Density Functional Theory (DFT). Moreover, this methodology also allows the synthesis of two new families of [b]-aryl-fused-BODIPYs, namely, [3,4]phenanthro- (2e and 2f) and [1,2]naphtho-fused (2g) BODIPYs. Their molecular and electronic structures were established by NMR and UV-vis spectroscopies as well as single-crystal X-ray diffraction analysis. As can be noted from the X-ray structures, 2a, 2e and 2g present interesting structural differences at both the molecular and packing level. Interestingly, despite being isomers, the UV/vis spectra of 2a and 2g revealed significant differences in their electronic structures. The origin of this finding was studied by Time-Dependent DFT calculations. Calculated DFT Nuclear Independent Chemical Shift (NICS(0)) values also supported the different electronic structures of 2a and 2g.


An experimental study of small-joint compression arthrodesis.
Arthrodesis of the interphalangeal and metacarpophalangeal joints is a technically demanding procedure with significant failure rates. A method of compression arthrodesis that was developed by one of the authors (RWB) using a compression clamp and crossed Kirschner wires is reported. This technique has been used without complication in the successful arthrodesis of 125 consecutive interphalangeal and metacarpophalangeal fusions by two of the authors (RWB and JAIG). An in vivo model of small-joint arthrodesis was then developed using the rabbit humeroulnar joint to compare this method of compression clamp arthrodesis with the tension band technique. Biomechanical testing at both 2 and 8 weeks postoperatively showed compression clamp arthrodesis to compare favorably with the tension band technique.


Effects of Oxygen Supply During Training on Subjects With COPD Who Are Normoxemic at Rest and During Exercise: A Blinded Randomized Controlled Trial.
It is well established that physical training enhances functionality and quality of life in patients with COPD. However, little data exist concerning the effects of the usefulness of oxygen supply during exercise training for > 3 months in patients with COPD who are normoxemic at rest and during exercise. We hypothesized that oxygen supply during training sessions enables higher training intensity and thus optimizes training results in patients with COPD. In this blinded randomized controlled study, we carried out a 24-week training program with progressively increasing loads involving large muscle groups. In addition, we compared the influences of oxygen supplementation. Thirty-six subjects with moderate-to-severe COPD who were not dependent on long-term oxygen therapy trained under supervision for 24 weeks (3 times/week at 30 min/session). Subjects were randomized into 2 groups: oxygen supply via nasal cannula at a flow of 4 L/min and compressed air at the same flow throughout the training program. Lung function tests at rest (inspiratory vital capacity, FEV1, Tiffeneau index), cycle spiroergometry (peak ventilation, peak oxygen uptake, peak respiratory exchange rate, submaximal and peak lactic acid concentrations), 6-min walk tests, and quality-of-life assessments (Medical Outcomes Study 36-Item Short Form questionnaire) were conducted before and after 12 and 24 weeks. Independent of oxygen supplementation, statistically significant improvements occurred in quality of life, maximal tolerated load during cycling, peak oxygen uptake, and 6-min walk test after 12 weeks of training. Notably, there were no further improvements from 12 to 24 weeks despite progressively increased training loads. Endurance training 3 times/week resulted in significant improvements in quality of life and exercise capacity in subjects with moderate-to-severe COPD within the initial 12 weeks, followed by a stable period over the following 12 weeks with no further benefits of supplemental oxygen.


Almanac 2012--adult cardiac surgery: the national society journals present selected research that has driven recent advances in clinical cardiology.
This review covers the important publications in adult cardiac surgery in the last few years, including the current evidence base for surgical revascularisation and the use of off-pump surgery, bilateral internal mammary arteries and endoscopic vein harvesting. The changes in conventional aortic valve surgery are described alongside the outcomes of clinical trials and registries for transcatheter aortic valve implantation, and the introduction of less invasive and novel approaches of conventional aortic valve replacement surgery. Surgery for mitral valve disease is also considered, with particular reference to surgery for asymptomatic degenerative mitral regurgitation.


PROP taster status, food preferences and consumption of high-calorie snacks and sweet beverages among 6-year-old ethnically diverse children.
A healthy diet is important for optimal growth and development in children. Food preferences are a main determinant of children's intake. The aim of this study was to examine the associations of 6-n-propylthiouracil (PROP) taster status (taste sensitivity to PROP) with children's food preferences and consumption of high-calorie snacks and sweet beverages among ethnically diverse children. We analysed data from 5585 6-year-old children enrolled in the Generation R Study, a birth cohort study in Rotterdam, the Netherlands. PROP taster status was evaluated using a suprathreshold screening solution. Food preferences of the children were assessed by a two-stage protocol using photographs of eight food items (candy, chocolate, mayonnaise, whipped cream, soup, potato chips, carrot and bread), yielding both hedonic ratings (1-3) and rank order scores (1-8). Univariate and multivariable linear and logistic regression analyses were performed, using tasters as the reference group. Non-tasters had a slightly higher preference for carrots (β: -0.07; 95% CI: -0.13, -0.02 and β: -0.15; 95% CI: -0.27, -0.02 for hedonic ratings and rank order scores, respectively) and bread (hedonic ratings; β: -0.06; 95% CI: -0.11, -0.01) compared with tasters. No differences were found in children's preference for sweet, fat or salty food items. Furthermore, there were no associations of PROP taster status with the consumption of high-calorie snacks ≥ 2 times/day (aOR: 1.06; 95% CI: 0.91,1.24) or sweet beverages ≥ 3 glasses/day (aOR: 1.06; 95% CI: 0.92,1.23). Other factors relating to the family food environment may be more important for young children's food preferences and consumption of high-calorie snacks and sweet beverages than their innate taste sensitivity.


Conflicts of interest in vaccine safety research.
Conflicts of interest (COIs) cloud vaccine safety research. Sponsors of research have competing interests that may impede the objective study of vaccine side effects. Vaccine manufacturers, health officials, and medical journals may have financial and bureaucratic reasons for not wanting to acknowledge the risks of vaccines. Conversely, some advocacy groups may have legislative and financial reasons to sponsor research that finds risks in vaccines. Using the vaccine-autism debate as an illustration, this article details the conflicts of interest each of these groups faces, outlines the current state of vaccine safety research, and suggests remedies to address COIs. Minimizing COIs in vaccine safety research could reduce research bias and restore greater trust in the vaccine program.


Beneficial effects of diltiazem in coronary artery disease.
The effects of the new calcium channel blocking agent diltiazem were evaluated in 11 patients with stable angina pectoris and confirmed obstructive coronary artery disease at rest and during rapid atrial pacing. Symptomatic, metabolic, coronary, and systemic haemodynamic indices were monitored at rest and during pacing induced ischaemia. At rest, after the administration of intravenous diltiazem, potent vasodilator effects were observed with a significant fall in mean blood pressure and an increase in cardiac index. Importantly, however, the systemic vasodilator effect of diltiazem was associated with no significant increase in heart rate. During pacing there was similar decrease in mean blood pressure after diltiazem, and mean pacing time to angina increased significantly. Three patients did not develop angina on repeat pacing. Coupled with an improved pacing time to angina there was a significant improvement in myocardial lactate extraction during pacing, changing from lactate production to lactate extraction after diltiazem. This study confirms the antianginal effects of diltiazem and suggests that this agent may have advantages in the management of angina pectoris. The results suggest that diltiazem may exert its beneficial effect not only by reducing afterload reduction but also by a direct metabolic effect on the myocardium.


Activating CD94:NKG2C and inhibitory CD94:NKG2A receptors are expressed by distinct subsets of committed CD8+ TCR alphabeta lymphocytes.
A subset of CD8(+) T cells express the natural killer cell receptors CD94:NKG2A or CD94:NKG2C. We found that although many CD8(+) T cells transcribe CD94 and NKG2C, expression of a functional CD94:NKG2C receptor is restricted to highly differentiated effector cells. CD94:NKG2A is expressed by a different subset consisting of CCR7(+) memory cells and CCR7(-) effector cells. Since NKG2A can only be induced on naive CD8(+) T cells while CD94(-) memory cells are refractory, it is likely that commitment to the CD94:NKG2A(+) subset occurs during the first encounter with antigen. CCR7(+)CD94:NKG2A(+) T cells recirculate through lymph nodes where upon activation, they produce large quantities of IFN-gamma. These cells occur as a separate CD94:NKG2A(+) T cell lineage with a distinct TCR repertoire that differs from that of the other CD8(+)CD94(-) T cells activated in situ.


[Additive effect of repeated impulse air waves on the activity of rat and human hepatic enzymes].
Impulse air waves (IAW) applied in non-destructive and weakly destructive intensities reduced the activity of lysosomal and microsomal enzymes as well as the activity of adenylate cyclase in the liver of laboratory rats. Five times repeated single application of IAW in intensities causing no noticeable biochemical (and morphological) changes led to shifts in the activity of rat hepatic enzymes. IAW which failed to produce a biological effect in humans when applied separately, inhibited noticeably antipyrine biotransformation in volunteers when applied repeatedly 80 times. It is concluded that the action of repeated subthreshold IAW is additive in character.


The Effect of Emotional Dissonance and Mental Load on Need for Recovery and Work Engagement among Italian Fixed-Term Researchers.
Although many studies have been conducted to evaluate the risk and protective factors on psychological health among academic staff, little attention has been paid to fixed-term researchers, the weakest figures in the academic context. By using the Job Demands-Resources model as theoretical framework, we investigated: (1) the role of some job demands (workload, mental load, and emotional dissonance) in predicting the need for recovery; (2) the role of some job resources (independence, career opportunities, and work-life balance) in predicting work engagement; and (3) the moderating role of the contract type (more or less precarious). We focused in particular on emotional dissonance (the discrepancy between emotions that need to be displayed and what is really felt), assuming its unique role in predicting fatigue. Results of structural equation modeling analysis generally supported our hypotheses and highlighted a so far undiscovered path between mental load and work engagement. Specifically, mental load leads to fatigue only indirectly through workload and emotional dissonance, while significantly predicting the absorption and the dedication of fixed-term Italian researchers. The latter relationship was also moderated by the contract type, so that mental load predicts dedication especially among researchers in the most precarious condition.


Conformation of MgATP bound to 5-phospho-alpha-D-ribose 1-diphosphate synthetase by two-dimensional transferred nuclear Overhauser effect spectroscopy.
The conformation of MgATP bound at the active site of Salmonella typhimurium 5-phospho-alpha-D-ribose 1-diphosphate synthetase (PRibPP synthetase) has been investigated by two-dimensional transferred-NOE spectroscopy (TRNOESY). Inter-proton NOEs of the ligand were measured in the presence of the protein at several mixing times in the range of 40-300 ms at 500 MHz and 10 degrees C. Measurements were made at low ligand concentrations (approximately 1 mM) in order to avoid weak non-specific ligand-protein interactions and to ensure that the NOE arises from the ligand bound at the active site. The inter-proton distances were determined from the experimentally observed NOE buildup curves by comparing them with theoretical simulations obtained by using the complete relaxation matrix. These distances were used as constraints in molecular modeling and energy minimization calculations to deduce the structure of the bound ligand. PRibPP synthetase is known to appreciably aggregate so that it exists in multiple oligomeric forms in solution. The structure was determined under the assumption that the ligand assumes the same conformation on each subunit of every oligomer regardless of its size. On the basis of the rotational correlation time deduced for the enzyme-nucleotide complexes, it is estimated that the average oligomer of PRibPP synthetase, in the sample used for the TRNOESY measurements, consists of about 30 subunits, whereas the smallest active form of the protein is a pentamer. The conformation of enzyme-bound MgATP is described by a glycosidic torsion angle chi = 50 +/- 5 degrees and phase angle of pseudorotation P = 114.9 degrees corresponding to a 1T degree sugar pucker. It is noteworthy that the value of the glycosidic torsion angle obtained in this pyrophosphoryl transfer enzyme complex agrees well with those obtained previously for MgATP complexes of creatine kinase, pyruvate kinase (active and ancillary sites), and arginine kinase. The sugar pucker, on the other hand, differs from one enzyme complex to another.


Disparities of obesity and non-communicable disease burden between the Tibetan Plateau and developed megacities in China.
Non-communicable diseases (NCDs) including risk factors, e.g., obesity, are the major causes of preventable deaths in China, yet NCD disparities in China remain under-studied. This study aimed to compare the determinants and burden of NCDs within four selected provinces in mainland China: the least developed Qinghai-Tibet Plateau group (PG, Tibetan Autonomous Region [TAR] and Qinghai Province) and most developed megacity group (MCG, Shanghai, and Beijing). Studies, reports, and other official sources with comparable data for NCD burden and related determinants for the four provinces were searched. Geographic, demographic, socioeconomic, and dietary characteristics and selected health indicators (e.g., life expectancy) were extracted from the China Statistical Yearbook and China Health Statistics Yearbook. Data on NCD burdens were extracted from the National Chronic Disease and Risk Factor Surveillance Study and other nationally representative studies. The overall NCD mortality rates and prevalence of metabolic risk factors including obesity, hypertension, and diabetes in mainland China have increased in the past 20 years, and this trend is expected to continue. The PG had the highest level of standardized mortality rates (SMRs) on NCDs (711.6-896.1/100,000, 6th/6-level); the MCG had the lowest (290.6-389.6/100,000, 1st/6-level) in mainland China. The gaps in SMRs were particularly high with regard to chronic respiratory diseases (PG 6th/6-level, MCG 1st/6-level) and cardiovascular diseases (6th/6 and 4th/6 in TAR and Qinghai; 1st/6-level and 2nd/6-level in Shanghai and Beijing). In contrast, the prevalence rates of obesity, hypertension, and diabetes were generally higher or comparable in MCG compared to PG. Diabetes prevalence was particularly high in MCG (5th/5-level, 13.36-14.35%) and low in PG (1st/5-level, 6.20-10.39%). However, awareness, treatment, and control of hypertension were poor in PG. Additionally, PG had much lower and severely inadequate intakes of vegetables, fruits, and dairy products, with additional indicators of lower socioeconomic status (education, income, etc.,) compared with MCG. Evidence showed large disparities in NCD burden in China's provinces. Socioeconomic disparity and dietary determinants are probably the reasons. Integrated policies and actions are needed.


Splanchnic clearance of plasma vasopressin in the dog: evidence for prehepatic extraction.
It is generally considered that the liver is primarily responsible for the extraction of vasopressin from the circulating blood by the splanchnic viscera. To investigate this matter further, measurements were made in the anesthetized dog of the concentrations of vasopressin in arterial, portal venous, and hepatic venous plasma, and of total splanchnic plasma flow and hepatic arterial plasma flow. The total splanchnic vasopressin extraction ratio was 12.9 +/- 1.0%. However, the concentration of vasopressin in portal venous plasma was consistently lower than in arterial plasma, and there was a substantial prehepatic extraction of vasopressin, averaging 10.5 +/- 0.8%. A quantitative evaluation of the contribution of the "prehepatic" viscera, i.e., viscera with venous drainage into the portal vein, is provided by the relevant clearances of vasopressin. The prehepatic and total splanchnic vasopressin clearances were 1.58 +/- 0.20 and 3.04 +/- 0.31 ml X min-1 X kg-1, respectively. Thus, the splanchnic viscera other than the liver were responsible for approximately half of the splanchnic clearance of vasopressin; the remainder could be attributed to the liver. Immunoreactive vasopressin was not found in the bile. In splenectomized dogs, in which venous blood was collected from the superior mesenteric vein, the vasopressin extraction ratio was 14.6 +/- 2.3%, suggesting that the prehepatic clearance of vasopressin occurs largely in the mesenteric bed. A more specific localization of the prehepatic clearance sites has not as yet been made.


Alternative wavefunction ansatz for including explicit electron-proton correlation in the nuclear-electronic orbital approach.
The nuclear-electronic orbital (NEO) approach treats specified nuclei quantum mechanically on the same level as the electrons with molecular orbital techniques. The explicitly correlated Hartree-Fock (NEO-XCHF) approach was developed to incorporate electron-nucleus dynamical correlation directly into the variational optimization of the nuclear-electronic wavefunction. In the original version of this approach, the Hartree-Fock wavefunction is multiplied by (1+Ĝ), where Ĝ is a geminal operator expressed as a sum of Gaussian type geminal functions that depend on the electron-proton distance. Herein, a new wavefunction ansatz is proposed to avoid the computation of five- and six-particle integrals and to simplify the computation of the lower dimensional integrals involving the geminal functions. In the new ansatz, denoted NEO-XCHF2, the Hartree-Fock wavefunction is multiplied by √(1+Ĝ) rather than (1+Ĝ). Although the NEO-XCHF2 ansatz eliminates the integrals that are quadratic in the geminal functions, it introduces terms in the kinetic energy integrals with no known analytical solution. A truncated expansion scheme is devised to approximate these problematic terms. An alternative hybrid approach, in which the kinetic energy terms are calculated with the original NEO-XCHF ansatz and the potential energy terms are calculated with the NEO-XCHF2 ansatz, is also implemented. Applications to a series of model systems with up to four electrons provide validation for the NEO-XCHF2 approach and the treatments of the kinetic energy terms.


PVBA-UiO-66 using a flexible PVBA with multi-coordination groups as mixed ligands and their super adsorption towards methylene blue.
A series of poly-vinyl benzoic acid (PVBA) and UiO-66 materials (PVBA-UiO-66) were prepared by a mixed-linker approach. Using a flexible PVBA with multi-coordination groups as mixed ligands, mesopores and uncoordinated benzoic groups were introduced into the UiO-66 crystal structures, thus leading to a special structure and functionality. The structure of the PVBA-UiO-66 was characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and nitrogen gas adsorption measurements. The adsorption property toward methylene blue (MB) of PVBA-UiO-66 was studied. The adsorption of MB by UiO-66 and PVBA (43%)-UiO-66 fit the Langmuir model and Freundlich model well. The result showed that PVBA (43%)-UiO-66 has super adsorption capacity as high as 909 mg g-1 for MB owing to the mesopores and the uncomplexed carboxyl groups which were caused by the long PVBA involved in coordination. The adsorption kinetics of MB onto PVBA (43%)-UiO-66 can be well fitted to the pseudo-second-order model. The process of adsorption MB onto PVBA-UiO-66 is spontaneous and thermodynamically favorable at 303, 313 and 323 K.


Sickle cell disease and the "difficult patient" conundrum.
The convergence of sickle cell disease's unique political, historical, cultural, medical, and psychological dimensions begets an especially distressing plight for sufferers of the disease. Too often, this convergence results in sickle cell patients being classified as "difficult." As Autumn Fiester recently argued, traditional understanding of the "difficult" patient warrants reevaluation. By acknowledging the nuanced dimensions of sickle cell disease, we identify barriers to care particular to the disease, which further substantiate the need to redefine orthodox notions of the "difficult" patient. We support development of mechanisms in both health care provider education and third-party consultation support by the Ethics Consultation Service, or by other appropriately designated specialists, to respect the manifold dimensions of sickle cell disease as a necessary step toward the enhancement of clinical care for sickle cell patients.


Publication bias may exist among prognostic accuracy studies of middle cerebral artery Doppler ultrasound.
The objective of this study was to assess if there is evidence of publication bias in prognostic accuracy studies of middle cerebral artery (MCA) or cerebroplacental ratio (CPR) for adverse perinatal outcome. We queried PubMed, EMBASE, the Cochrane Library, and ClinicalTrials.gov and searched abstract books of five perinatal conferences (1989-2017). We included prognostic accuracy studies on MCA and/or CPR. Highest reported accuracy estimates, sample size, study design, and conclusion positivity were extracted and compared. We included 127 full-text articles and 51 conference abstracts, 29 of which had not been reported as full-text article. In conference abstracts not reported in full, median negative predictive value was significantly lower compared to full-text articles (0.79 [interquartile range 0.67-0.97] vs. 0.95 [0.89-0.99]; P < 0.001). No significant difference was identified for positive predictive value (0.62 vs. 0.59; P = 0.827), sensitivity (0.67 vs. 0.71; P = 0.159), and specificity (0.86 vs. 0.86; P = 0.632). Study design differed significantly as well (P = 0.030), with fewer prospective studies in conference abstracts not reported in full compared to full-text articles (28% vs. 54%). We found no significant differences in sample size or conclusion positivity. Possibly, a publication bias in previously published meta-analyses of MCA and CPR has led to overly generous estimates of prognostic performance.


Abusive help-- helping abuse: the psychodynamic impact of severe personality disorder on caring institutions.
Personality-disordered patients have invariably suffered abuse at the hands of carers when young, and they tend to repeat an abusive relationship when they encounter care in later life. The provision of care in psychiatric, forensic, penal and other institutions may degenerate into a form of unconscious abuse perpetrated against those in care. This is almost always unrecognized and the experience of carers is often to mismanage their own frustrated inability to understand what is happening to them, their charges and the institution.


Metachronous double primary cancer of epithelial and mesenchymal origins: A case report of a rare clinical phenomenon.
Metachronous double primary cancers from the same origin have previously been reported in several studies; however, the occurrence of double primary cancers from different tissue origins has not been reported earlier. We analyzed 10 patients with requirement surgical treatment. After over 6 months of the surgery, histopathological examination confirmed the presence of at least two neoplastic lesions with distinct histopathology at different locations. These patients underwent surgery and the hematoxylin and eosin staining was performed according to standard protocol in all cases. Since the occurrence of multiple primary cancers is an extremely rare event, it is difficult to find a large sample size of patients with double primary cancers at one study center. All patients included in this study received surgical therapy twice and had a final tissue histopathologic diagnosis. Based on our findings, it is concluded that a prolonged follow-up examination for cancer patients should be taken into consideration to provide early detection of secondary tumors and improve overall life expectancy of these patients. Furthermore, clinicians should be well aware of the possibility of cancer patients developing a second primary cancer of a different tissue origin.


Effects of undergoing multiplex genetic susceptibility testing on parent attitudes towards testing their children.
Parents may pursue common disease risk information about themselves via multiplex genetic susceptibility testing (MGST) for their children. To prospectively assess whether parents who received MGST disclosed their test results to their child, intended to change the child's health habits, or have the child tested. Eighty parents who opted for free MGST completed an online survey about a child in their household before undergoing MGST and a follow-up telephone survey 3 months after receiving results. Few parents (21 %) disclosed results to the child. Undergoing MGST was unrelated to intentions to change the child's health habits but did increase parental willingness to test the child. Greater willingness to test a child was associated with positive attitudes toward pediatric genetic testing and intentions to change the child's health habits. The experience of receiving MGST had little impact on parents' perceptions or behaviors related to their minor child.


The role of anxious distress in immune dysregulation in patients with major depressive disorder.
Although depression with anxious distress appears to be a clinically relevant subtype of major depressive disorder (MDD), whether it involves specific pathophysiology remains unclear. Inflammation has been implicated, but not comprehensively studied. We examined within a large MDD sample whether anxious distress and related anxiety features are associated with differential basal inflammation and innate cytokine production capacity. Data are from 1078 MDD patients from the Netherlands Study of Depression and Anxiety. In addition to the DSM-5 anxious distress specifier, we studied various dimensional anxiety scales (e.g. Inventory of Depressive Symptomatology anxiety arousal subscale [IDS-AA], Beck Anxiety Inventory [BAI], Mood and Anxiety Symptoms Questionnaire Anxious Arousal scale [MASQ-AA]). The specifier was constructed using five self-report items from the IDS and BAI. Basal inflammatory markers included C-reactive protein (CRP), interleukin (IL)-6 and tumor necrosis factor (TNF)-α. Innate production capacity was assessed by 13 lipopolysaccharide (LPS)-stimulated inflammatory markers. Basal and LPS-stimulated inflammation index scores were created. Basal inflammation was not associated with anxious distress (prevalence = 54.3%) in MDD patients, except for a modest positive association for BAI score. However, anxious distress was associated with higher LPS-stimulated levels (interferon-γ, IL-6, monocyte chemotactic protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, matrix metalloproteinase (MMP)-2, TNF-α, LPS-stimulated index). Other anxiety indicators (anxious distress specifier score, BAI, MASQ-AA) were also associated with increased innate production capacity. Within a large MDD sample, the anxious distress specifier was associated with increased innate cytokine production capacity but not with basal inflammation. Results from dimensional anxiety indicators largely confirm these results. These findings provide new insight into the pathophysiology of anxious depression.


Metapangenomics reveals depth-dependent shifts in metabolic potential for the ubiquitous marine bacterial SAR324 lineage.
Oceanic microbiomes play a pivotal role in the global carbon cycle and are central to the transformation and recycling of carbon and energy in the ocean's interior. SAR324 is a ubiquitous but poorly understood uncultivated clade of Deltaproteobacteria that inhabits the entire water column, from ocean surface waters to its deep interior. Although some progress has been made in elucidating potential metabolic traits of SAR324 in the dark ocean, very little is known about the ecology and the metabolic capabilities of this group in the euphotic and twilight zones. To investigate the comparative genomics, ecology, and physiological potential of the SAR324 clade, we examined the distribution and variability of key genomic features and metabolic pathways in this group from surface waters to the abyss in the North Pacific Subtropical Gyre, one of the largest biomes on Earth. We leveraged a pangenomic ecological approach, combining spatio-temporally resolved single-amplified genome, metagenomic, and metatranscriptomic datasets. The data revealed substantial genomic diversity throughout the SAR324 clade, with distinct depth and temporal distributions that clearly differentiated ecotypes. Phylogenomic subclade delineation, environmental distributions, genomic feature similarities, and metabolic capacities revealed strong congruence. The four SAR324 ecotypes delineated in this study revealed striking divergence from one another with respect to their habitat-specific metabolic potentials. The ecotypes living in the dark or twilight oceans shared genomic features and metabolic capabilities consistent with a sulfur-based chemolithoautotrophic lifestyle. In contrast, those inhabiting the sunlit ocean displayed higher plasticity energy-related metabolic pathways, supporting a presumptive photoheterotrophic lifestyle. In epipelagic SAR324 ecotypes, we observed the presence of two types of proton-pumping rhodopsins, as well as genomic, transcriptomic, and ecological evidence for active photoheterotrophy, based on xanthorhodopsin-like light-harvesting proteins. Combining pangenomic and both metagenomic and metatranscriptomic profiling revealed a striking divergence in the vertical distribution, genomic composition, metabolic potential, and predicted lifestyle strategies of geographically co-located members of the SAR324 bacterial clade. The results highlight the utility of metapangenomic approaches employed across environmental gradients, to decipher the properties and variation in function and ecological traits of specific phylogenetic clades within complex microbiomes. Video abstract.


Impact of delayed radiotherapy on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy.
To evaluate the effect of the surgery-radiotherapy interval (SRI) on local control in node-negative breast cancer patients treated with breast-conserving surgery and adjuvant radiotherapy without chemotherapy. From February 1992 to January 2002, 171 patients with node-negative breast cancer underwent breast-conserving surgery and adjuvant radiotherapy without chemotherapy. The whole breast was irradiated up to 50.4 Gy in 28 fractions followed by a 10-Gy boost to the tumor bed. Forty-four patients received tamoxifen in addition to radiotherapy. Patients were divided into 2 groups according to the length of SRI: <6 weeks (128 patients) versus ≥6 weeks (43 patients). The median follow-up period was 87 months (range, 22-167). The 8-year local control rates of patients with SRI <6 weeks and ≥6 weeks were 94.5% and 92.7%, respectively (P = 0.1140). When age, tumor size, resection margin status, combination with hormonal therapy, and SRI were incorporated into the Cox proportional hazards model, SRI <6 weeks and age at diagnosis ≥40 years were associated with increased local control (P = 0.0343 and 0.0264, respectively). In the subgroup analysis, SRI <6 weeks was correlated with a higher local control rate for patients aged <40 years (P = 0.0142). Among older patients, however, there was no statistical difference in local control according to SRI (P = 0.6655). Treatment interval had no impact on overall and distant metastasis-free survival. Early radiotherapy within 6 weeks of breast-conserving surgery is associated with increased local control in patients with node-negative breast cancer not undergoing chemotherapy.


Dissociating vision and visual attention in the human pulvinar.
The pulvinar region of the thalamus has repeatedly been linked with the control of attention. However, the functions of the pulvinar remain poorly characterized, both in human and in nonhuman primates. In a functional MRI study, we examined the relative contributions to activity in the human posterior pulvinar made by visual drive (the presence of an unattended visual stimulus) and attention (covert spatial attention to the stimulus). In an event-related design, large optic flow stimuli were presented to the left and/or right of a central fixation point. When unattended, the stimuli robustly activated two regions of the pulvinar, one medial and one dorsal with respect to the lateral geniculate. The activity in both regions shows a strong contralateral bias, suggesting retinotopic organization. Primate physiology suggests that the two regions could be two portions of the same double map of the visual field. In our paradigm, attending to the stimulus enhanced the response by about 20%. Thus attention is not necessary to activate the human pulvinar and the degree of attentional enhancement matches, but does not exceed, that seen in the cortical regions with which the posterior pulvinar connects.


Assessments and Interventions to Address Challenging Behavior in Individuals with Intellectual Disability and Autism Spectrum Disorder in Japan: A Consolidated Review.
Intellectual disability and autism spectrum disorder are neurodevelopmental disorders that emerge during the developmental period. A significant barrier that impedes the social adaptation of individuals with these disorders is the exhibition of problem behaviors, such as self-injurious, stereotyped, and aggressive/destructive behaviors. In recent years, these problem behaviors have been collectively referred to as "challenging behavior," in accordance with the contention that they result from an interaction between the individual and his or her social environment. Evidence-based psychosocial interventions that adopt the functional approach to treating challenging behavior are increasing. However, in order to effectively implement such interventions in educational settings and welfare facilities, it is essential to develop staff training programs and usable psychometric assessments. Accordingly, a brief overview of research studies on challenging behavior that have been conducted in Japan, as well as the various support systems that are available to individuals who exhibit challenging behavior, are presented in this article. The discussion makes it apparent that, in order to improve treatment systems in Japan that are aimed at addressing challenging behavior, it is necessary to establish not only better staff training programs, but also reliable and valid assessments measuring challenging behavior that can be readily used by teachers and parents. On the basis of this discussion, it is proposed that technological advancements must be applied to psychosocial approaches in the study of problem behaviors, in order to develop assessment system using software applications and automatic measurement system of target behaviors using sensing technology.


Enhanced modeling via network theory: Adaptive sampling of Markov state models.
Computer simulations can complement experiments by providing insight into molecular kinetics with atomic resolution. Unfortunately, even the most powerful supercomputers can only simulate small systems for short timescales, leaving modeling of most biologically relevant systems and timescales intractable. In this work, however, we show that molecular simulations driven by adaptive sampling of networks called Markov State Models (MSMs) can yield tremendous time and resource savings, allowing previously intractable calculations to be performed on a routine basis on existing hardware. We also introduce a distance metric (based on the relative entropy) for comparing MSMs. We primarily employ this metric to judge the convergence of various sampling schemes but it could also be employed to assess the effects of perturbations to a system (e.g. determining how changing the temperature or making a mutation changes a system's dynamics).


Photoredox Catalysis for the Fabrication of Water-Repellent Surfaces with Application for Oil/Water Separation.
Silanization processes with perfluoroalkyl silanes have been demonstrated to be effective in developing advanced materials with many functional properties, including hydrophobicity, water repellency, and self-cleaning properties. However, practical industrial applications of perfluoroalkyl silanes are limited by their extremely high cost. On the basis of our recent work on photoredox catalysis for amidation with perfluoroalkyl iodides, its application for surface chemical modification on filter paper, as an illustrative example, has been developed and evaluated. Before photocatalytic amidation, the surface is functionalized with amine functional groups by silanization with 3-(trimethoxysilyl)propylamine. All chemically modified surfaces have been fully characterized by attenuated total reflection infrared (ATR-IR), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy with energy-dispersive spectroscopy (SEM-EDS), and three-dimensional (3D) profiling to confirm the successful silanization and photocatalytic amidation. After surface modification of the filter papers with perfluoroalkanamide, they show high water repellency and hydrophobicity with contact angles over 120°. These filter papers possess high wetting selectivity, which can be used to effectively separate the organic and aqueous biphasic mixtures. The perfluoroalkanamide-modified filter papers can be used for separating organic/aqueous biphasic mixtures over many cycles without lowering the separating efficiency, indicating their reusability and excellent durability.


Interstitial nephritis in Aleutian mink disease. Possible role of cell-mediated immunity against virus-infected tubular epithelial cells.
Aleutian mink disease (AD) has been characterized by immune complex glomerulonephritis associated with persistent infection of Aleutian mink disease parvovirus (ADV). Histopathological examination of kidneys from ADV-infected mink in this study revealed that interstitial nephritis characterized by prominent damage of renal tubuli and lymphocyte infiltration was also common in AD along with glomerulonephritis. By using strand-specific in situ molecular hybridization technique, replication of ADV was observed in tubular epithelial cells, in addition to epithelial cells of Bowman's capsules and some glomerular cells of the infected mink. Analysis of tubular lesions by a combination of immunohistochemistry and in situ hybridization revealed that the renal tubuli positive for virion DNA or replicative form DNA/mRNA of ADV were also positive for an activation marker of immunocompetent cells, which is shared by B lymphocytes and thymic epithelial cells. Infiltration of a subpopulation of T lymphocytes around infected renal tubuli were observed but deposition of immune complexes in these tubular lesions was not demonstrable. ADV replication in epithelial cells of renal tubuli and cell-mediated immune responses to the infected epithelial cells may play a role in the pathogenesis of interstitial nephritis in Aleutian mink disease.


Motor unit firing frequency of lower limb muscles during an incremental slide board skating test.
This study investigated how the combination of workload and fatigue affected the frequency components of muscle activation and possible recruitment priority of motor units during skating to exhaustion. Ten male competitive speed skaters performed an incremental maximal test on a slide board. Activation of six muscles from the right leg was recorded throughout the test. A time-frequency analysis was performed to compute overall, high, and low frequency bands from the whole signal at 10, 40, 70, and 90% of total test time. Overall activation increased for all muscles throughout the test (p < 0.05 and ES > 0.80). There was an increase in low frequency (90 vs. 10%, p = 0.035, ES = 1.06) and a decrease in high frequency (90 vs. 10%, p = 0.009, ES = 1.38, and 90 vs. 40%, p = 0.025, ES = 1.12) components of gluteus maximus. Strong correlations were found between the maximal cadence and vastus lateralis, gluteus maximus and gluteus medius activation at the end of the test. In conclusion, the incremental skating test lead to an increase in activation of lower limb muscles, but only gluteus maximus was sensitive to changes in frequency components, probably caused by a pronounced fatigue.


Departments and Disciplines: Stasis and Change: Significant multidisciplinary activity requires a redistribution of power within universities.
Because I believe that the departmental power base of universities has been a major factor in resisting inevitable and continuing changes in the disciplinary boundaries of research and teaching, I predict that significant changes in the nature of departments are inevitable. Departments will either permit, or even seek, a realignment of their spheres of control over disciplinary activity or they will lose the power of control over basic academic decisions and rewards. To the extent that society at large expresses resistance to change, the status quo of departments may have a temporary lease on life. On the other hand, society's current disenchantment with academia may make radical internal change seem vital to the maintenance of public support, and even the survival of universities, and thus hasten changes in either departmental structure or departmental power. Within universities, resistance to such change is generally supported on the assumption that academic freedom will be threatened. Obviously, all change involves some risk, but a very significant limitation to academic freedom already exists in the pressures that many departments exert on members to restrict their intellectual activity to fit the departmental mold. Departments can regain their important role in fostering both academic freedom and academic responsibility for excellence if they will redefine their discipline-oriented identities and realign their priorities to include cross-disciplinary inquiry and teaching and greater responsiveness to the responsibilities and expectations of the university and society.


Rapid chloride and bicarbonate determination by capillary electrophoresis for confirmatory testing of cystic fibrosis infants with volume-limited sweat specimens.
Objectives Cystic fibrosis (CF) is a debilitating genetic disorder that benefits from early detection. CF diagnosis relies on measuring elevated sweat chloride that is difficult in neonates with low sweat rates. We introduce a new method for sweat chloride determination from volume-limited specimens, and explore the potential utility of sweat bicarbonate in neonatal CF screening. Methods A rapid assay (< 5 min) was developed to analyze chloride and bicarbonate using capillary electrophoresis with indirect UV detection (CE-iUV). Pilocarpine-stimulated sweat samples from screen-positive CF infants were collected at two hospital sites, including confirmed CF (n = 12), CF screen-positive inconclusive diagnosis (n = 4), and unaffected non-CF cases (n = 37). All sweat chloride samples were analyzed by a coulometric titrator and CE-iUV, and the viability to measure acid-labile bicarbonate was also evaluated. Results Stability studies revealed that bicarbonate can be reliably assessed in sweat if acidification and heating were avoided. Method validation demonstrated that sweat chloride and bicarbonate were quantified with acceptable accuracy (recovery of 102%), precision (CV = 3.7%) and detection limits (∼ 0.1 mM). An inter-laboratory comparison confirmed a mean bias of 6.5% (n = 53) for sweat chloride determination by CE-iUV relative to a commercial chloridometer. However, sweat bicarbonate did not discriminate between CF and non-CF infants (AUC = 0.623, p = 0.215) unlike chloride (AUC = 1.00, p = 3.00 × 10-7). Conclusions CE-iUV offers a robust method for sweat chloride testing from presumptive CF infants that may reduce testing failure rates. However, sweat bicarbonate does not have clinical value in newborn CF diagnosis.


How to improve the hygienic quality of forages for horse feeding.
Improving the hygienic quality of forages for horse nutrition seems to be a reasonable target for decreasing the prevalence of pulmonary diseases. The aim of the experiment was to study the effects of different agricultural practices on the main aero-allergens contained in forages, including breathable dust, fungi, mycotoxins and pollens. Results showed that the late harvest of hay, a second crop or a haylage production provides a good alternative to increase hygienic quality by reducing fungi contamination and breathable dust content. Barn drying of hay, while having no effect on breathable dust, similarly reduced fungi contamination. In contrast, when hay was harvested at a lower dry mass content (750 g DM kg⁻¹ versus 850 g DM kg⁻¹), both breathable dust and fungi contaminations were increased, which could at least be reversed by adding propionic acid just before baling. Zearalenone was detected in different hays, and even in one case, in breathable dust. Overall, our data suggest that different approaches can be used to increase forage hygienic quality for horse feeding and thus reduce their exposure to factors involved in equine pulmonary disease.


ABHD5 stimulates PNPLA1-mediated ω-O-acylceramide biosynthesis essential for a functional skin permeability barrier.
Mutations in the genes coding for patatin-like phospholipase domain-containing 1 (PNPLA1) and α/β-hydrolase domain-containing 5 (ABHD5), also known as comparative gene identification 58, are causative for ichthyosis, a severe skin barrier disorder. Individuals with mutations in either of these genes show a defect in epidermal ω-O-acylceramide (AcylCer) biosynthesis, suggesting that PNPLA1 and ABHD5 act in the same metabolic pathway. In this report, we identified ABHD5 as a coactivator of PNPLA1 that stimulates the esterification of ω-hydroxy ceramides with linoleic acid for AcylCer biosynthesis. ABHD5 interacts with PNPLA1 and recruits the enzyme to its putative triacylglycerol substrate onto cytosolic lipid droplets. Conversely, alleles of ABHD5 carrying point mutations associated with ichthyosis in humans failed to accelerate PNPLA1-mediated AcylCer biosynthesis. Our findings establish an important biochemical function of ABHD5 in interacting with PNPLA1 to synthesize crucial epidermal lipids, emphasizing the significance of these proteins in the formation of a functional skin permeability barrier.


Compliance of blood sampling procedures with the CLSI H3-A6 guidelines: An observational study by the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) working group for the preanalytical phase (WG-PRE).
An observational study was conducted in 12 European countries by the European Federation of Clinical Chemistry and Laboratory Medicine Working Group for the Preanalytical Phase (EFLM WG-PRE) to assess the level of compliance with the CLSI H3-A6 guidelines. A structured checklist including 29 items was created to assess the compliance of European phlebotomy procedures with the CLSI H3-A6 guideline. A risk occurrence chart of individual phlebotomy steps was created from the observed error frequency and severity of harm of each guideline key issue. The severity of errors occurring during phlebotomy was graded using the risk occurrence chart. Twelve European countries participated with a median of 33 (18-36) audits per country, and a total of 336 audits. The median error rate for the total phlebotomy procedure was 26.9 % (10.6-43.8), indicating a low overall compliance with the recommended CLSI guideline. Patient identification and test tube labelling were identified as the key guideline issues with the highest combination of probability and potential risk of harm. Administrative staff did not adhere to patient identification procedures during phlebotomy, whereas physicians did not adhere to test tube labelling policy. The level of compliance of phlebotomy procedures with the CLSI H3-A6 guidelines in 12 European countries was found to be unacceptably low. The most critical steps in need of immediate attention in the investigated countries are patient identification and tube labelling.


On special relativistic effects via classical physics.
We present an analytic study of light propagation in a simple Michelson-Morley interferometer as observed by inertial observers to understand any connections among classical physics, optical physics, and special relativity. To that end, we develop coordinate transformations of wave propagation as observed in inertial frames (i.e., non-accelerating reference frames). We find that relativistic and other effects appear naturally as a result of finite light speed. Such effects include wavefront tilt relative to the normal of energy flow with the wavefront normal tilting relative to the Poynting vector.


Ten-year risk of diagnostic mammograms and invasive breast procedures after breast-conserving surgery for DCIS.
Breast-conserving surgery (BCS) is the most common treatment for ductal carcinoma in situ (DCIS); however, how often women experience subsequent diagnostic evaluations over time is not known. We identified 2948 women with DCIS who were treated with BCS from 1990 to 2001 and followed for up to 10 years at three integrated health-care delivery systems. We calculated the percentages of diagnostic mammograms and ipsilateral invasive procedures following the initial breast excision to treat DCIS, estimated the 10-year cumulative incidence of these procedures, and determined hazard ratios for both types of procedures with Cox regression modeling. All statistical tests were two-sided. Over 10 years, 907 women (30.8%) had 1422 diagnostic mammograms and 1813 (61.5%) had 2305 ipsilateral invasive procedures. Diagnostic mammograms occurred in 7.3% of women in the first 6 months and continued at a median annual rate of 4.3%. Ipsilateral invasive procedures occurred in 51.5% of women in the first 6 months and continued at a median annual rate of 3.1%. The estimated 10-year cumulative risk of having at least one diagnostic mammogram after initial DCIS excision was 41.0% (95% confidence interval [CI] = 38.5% to 43.5%); at least one invasive procedure, 65.7% (95% CI = 63.7% to 67.8%); and either event, 76.1% (95% CI = 74.1% to 78.1%). Excluding events in the first 6 months following initial DCIS excision, corresponding risks were 36.4% (95% CI = 33.8% to 39.0%) for diagnostic mammograms, 30.4% (95% CI = 26.9% to 33.8%) for invasive procedures, and 49.5% (95% CI = 45.6% to 53.5%) for either event. Women with DCIS treated with BCS continue to have diagnostic and invasive breast procedures in the conserved breast over an extended period. The frequency of ongoing diagnostic breast evaluations should be included in discussions about treatment.


[Estimating the costs associated with nosocomial urinary tract infection. A case-control study].
Nosocomial infection (NI) is associated with increased resource use. The current study addressed the cost excess attributable to nosocomial urinary tract infection (NUTI). Case-control study conducted in a cohort population. For matching, the Diagnostic Related Group (DRG) to which the episode of case patient was ascribed was used. Then, a further search was conducted in the hospital discharge database with the following parameters: DRG, gender, age, admission date, department, comparison of length of stays, main diagnosis, co-morbidities, number of secondary diagnoses and procedures. Matching was achieved for 64 episodes (71%), and upon them an estimation of costs was performed. The mean length of stay for cases were 15.3 (median: 12) and 12.3 (median: 11) days for cases and controls, respectively (p = 0.0001). The excess of length of stay attributable to NUTI was 3 days (95% CI 1.6-4.7), longer for patients admitted to Medical Departments (5.3 days) than for patients admitted to Surgical Departments (2 days) (p = 0,03). The use of diagnostic resources was significantly higher for bacteriological testing only. The use of antibiotics and fluid therapy was higher among infected patients. Out of the total excess of the estimated costs per episode, 132,047 ptas, 93% corresponded to the increase in hospital stay. Ten patients (15.6%) were responsible for 68% of the total of extra-costs. In 17 occasions (26.6%), the control patient used more resources than the infected patient. Nosocomial urinary tract infection is associated with a resource use directly related to its presence. For the most part, it is related to the prolongation of hospital stay.


RASSF6 expression in adipocytes is down-regulated by interaction with macrophages.
Macrophage infiltration into adipose tissue is associated with obesity and the crosstalk between adipocytes and infiltrated macrophages has been investigated as an important pathological phenomenon during adipose tissue inflammation. Here, we sought to identify adipocyte mRNAs that are regulated by interaction with infiltrated macrophages in vivo. An anti-inflammatory vitamin, vitamin B6, suppressed macrophage infiltration into white adipose tissue and altered mRNA expression. We identified >3500 genes whose expression is significantly altered during the development of obesity in db/db mice, and compared them to the adipose tissue mRNA expression profile of mice supplemented with vitamin B6. We identified PTX3 and MMP3 as candidate genes regulated by macrophage infiltration. PTX3 and MMP3 mRNA expression in 3T3-L1 adipocytes was up-regulated by activated RAW264.7 cells and these mRNA levels were positively correlated with macrophage number in adipose tissue in vivo. Next, we screened adipose genes down-regulated by the interaction with macrophages, and isolated RASSF6 (Ras association domain family 6). RASSF6 mRNA in adipocytes was decreased by culture medium conditioned by activated RAW264.7 cells, and RASSF6 mRNA level was negatively correlated with macrophage number in adipose tissue, suggesting that adipocyte RASSF6 mRNA expression is down-regulated by infiltrated macrophages in vivo. Finally, this study also showed that decreased RASSF6 expression up-regulates mRNA expression of several genes, such as CD44 and high mobility group protein HMGA2. These data provide novel insights into the biological significance of interactions between adipocytes and macrophages in adipose tissue during the development of obesity.


Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection.
Our objective was to investigate in cardiac muscle the contribution of NADPH oxidase to (a) ryanodine receptor-2 (RyR2) S-glutathionylation and (b) the preconditioning effects of exercise and tachycardia on infarct size following coronary artery occlusion. We measured NADPH oxidase activity, RyR2 S-glutathionylation, and calcium release kinetics in sarcoplasmic reticulum (SR) vesicles isolated from dog ventricular muscle after exercise and tachycardia, plus or minus prior administration of the NADPH oxidase inhibitor apocynin. In ventricular muscle sections, we studied the colocalization of NADPH oxidase and RyR2 by confocal microscopy using fluorescent antibodies. We determined the effect of apocynin on the infarct size produced by occlusion of the descendent anterior coronary artery in animals preconditioned by exercise or tachycardia. Exercise and tachycardia increased NADPH oxidase activity, RyR2 S-glutathionylation, and calcium release rates in isolated SR vesicles. Cardiac muscle sections displayed significant colocalization of NADPH oxidase and RyR2, suggesting direct and specific effects of reactive oxygen species (ROS) produced by NADPH oxidase on RyR2 activation. The NADPH oxidase inhibitor apocynin prevented the increase in RyR2 S-glutathionylation, reduced calcium release activity, and completely prevented the protective effects of exercise and tachycardia on infarct size. The loss of cardioprotection induced by the NADPH oxidase inhibitor suggests that ROS generated by this enzyme are important mediators of the preconditioning response, which presumably involves NADPH oxidase-induced RyR2 S-glutathionylation.


The Canadian Congenital Diaphragmatic Hernia Collaborative Mobile App: A National Guideline Implementation Strategy.
Coinciding with the publication of the Canadian congenital diaphragmatic hernia (CDH) Collaborative's clinical practice guidelines (CPG), we developed a mobile smartphone app to increase guideline utilization and promote knowledge translation. This mobile app was organized into sections corresponding to the phases of CDH care (prenatal, perinatal/postnatal, and child/adolescent), and contained 22 recommendations supported by evidence summaries, PubMed links, levels of evidence, and strength of expert consensus. Download statistics were collected from September 2018 to June 2020 after release of two iOS versions and an Android platform. Data regarding user numbers/location, most visited sections, and individual session details were analyzed. During the study period, the CDH app had 1,586 users predominantly from Canada (40%), United States (30%), and Brazil (12%). The Android release increased app visibility, particularly in Brazil, which had the largest number of new users. Of 3,723 sessions, roughly one-third were returning users. The average session duration and screens viewed/session was 4 minutes and seven screens, respectively. Postnatal ventilation was the most frequently visited subsection after prenatal diagnosis/risk stratification. Measurement of observed-to-expected lung head ratio was the most visited individual recommendation. The guideline compliance checklist was the most frequently accessed resource highlighting its utility. The CDH app is an innovative platform to disseminate guidelines. The increasing global reach of the app suggests worldwide CPG relevance. With additional features planned, the CDH app will continue to support clinical decision-making and empower patients and families as they navigate the short and long-term challenges associated with CDH. · Mobile smartphone technology provides an optimal platform for guideline dissemination.. · International uptake supports worldwide CPG relevance.. · Future initiatives include the development of patient and family resources..


[Neonatal withdrawal symptoms following the use of clomipramine during pregnancy].
The case is described of a neonate who suffered from withdrawal symptoms within 24 hours after birth as a result of the use of clomipramine by the mother during pregnancy. The symptoms consisted of increased irritability, alternating hyper- en hypotonia, hyperreflexia, cyanosis and hypothermia. He was treated with clonazepam with good result. Prescription of clomipramine during pregnancy should be restricted to specific cases and the doses should be kept as low as possible. Because the symptoms are withdrawal symptoms, phenobarbital should not be used as treatment, as it increases drug metabolism by the liver causing an even faster decrease of plasma concentrations of clomipramine. Clonazepam is the drug of choice.


A calcium-binding protein, calbindin-D9k, is regulated through an estrogen-receptor mediated mechanism following xenoestrogen exposure in the GH3 cell line.
A variety of environmental chemicals may possess the potential to interact with various endocrine factors and consequently cause adverse effects on the reproductive, central nervous, and immune systems via the endocrine system(s). In this study, we used the GH3 cell line as an in vitro model to determine the effects of potential endocrine disruptors (EDs) on the induction of calbindin-D9k (CaBP-9k), a useful biomarker for detecting the estrogenic activities of EDs. A rat pituitary cell line, GH3, was treated with octyl-phenol (OP), nonyl-phenol (NP), and bisphenol A (BPA) in a dose-dependent manner (10(-5), 10(-6), and 10(-7)M) for 24 h. To determine the time dependency, the cells were exposed to a high concentration (10(-5)M) of OP, NP, and BPA and harvested at different time points (1, 3, 6, 12, and 24 h). An antiestrogen, ICI 182,780, was used to examine the potential involvement of the estrogen receptor (ER) in the induction of CaBP-9k by EDs via an ER-mediated pathway. Treatment with OP, NP, and BPA induced a significant increase in CaBP-9k expression at both the transcriptional and translational levels in a dose-dependent manner. Interestingly, ED exposure caused a significant increase in CaBP-9k messenger RNA (mRNA) expression at 6 h, whereas induction of CaBP-9k protein was observed as early as 1 h after treatment. However, both CaBP-9k mRNA and protein expression peaked at 24 h following treatment. The differential response of CaBP-9k mRNA and protein to EDs may be explained by translational efficiency. Cotreatment with ICI 182,780 significantly reversed ED-induced CaBP-9k expression in GH3 cells, suggesting that EDs may trigger the induction of CaBP-9k via an ER-mediated pathway in these cells. Taken together, these results demonstrate for the first time that a single in vitro exposure to OP, NP, or BPA results in an increase in CaBP-9k expression in GH3 cells, after 24 h. These results may contribute to our understanding of the relationship between the molecular events evoked by ED exposure and its biological effects on the pituitary gland in humans and animals. This in vitro model, in combination with a single injection in vivo method developed by us, may be important for elucidating additional details of the mode of action of xenoestrogens and may provide reliable tests for screening estrogenic agonists and antagonists.


Stochastic exponential stability for Markovian jumping BAM neural networks with time-varying delays.
This correspondence provides stochastic exponential stability for Markovian jumping bidirectional associative memory neural networks with time-varying delays. An approach combining the Lyapunov functional with linear matrix inequality is taken to study the problems. Some criteria for the stochastic exponential stability are derived. The results obtained in this correspondence are less conservative, less restrictive, and more computationally efficient than the ones reported so far in the literature.


Social categories as a context for the allocation of attentional control.
Recent studies of cognitive control have highlighted the idea that context can rapidly cue the control of attention. The present study shows that faces can be quickly categorized on the basis of gender, and these gender categories can be used as a contextual cue to allocate attentional control. Furthermore, the results reported here reveal processes implicated in the development and operation of implicit social stereotypes. Three of 4 faces from 1 gender group were associated with a high proportion of congruent trials in a flanker task, while 3 of 4 faces of the other gender group were associated with a low proportion of congruent trials. A single inconsistent face within each gender group was associated with the proportion congruency of the opposite gender group. A social context-specific proportion congruent effect (PCE) was observed (i.e., larger interference for the gender category associated with a high proportion of congruent trials), even for inconsistent members of the category. This effect is consistent with the view that a new implicit stereotype was created, linking gender with a specific proportion of congruency. In Experiment 2, the task goals modulated the use of the new created stereotype. Instructions to categorize versus individuate the target faces, respectively, led participants to allocate attention either toward the category-diagnostic or the identity-diagnostic facial features. Furthermore, and in line with stereotyping research, under instructions to categorize faces this social-context-specific PCE generalized to new faces of the same gender group with whom participants did not have previous experience. These results link attention with social categorization processes.


Thrombin generation assay in untreated whole human blood.
Present coagulation assays fail to detect mild coagulation disorders, while thrombin-generation (TG) assays solve this problem. However, most of them only work with threated blood samples, which makes them labor intensive, time consuming, unreliable, and expensive. We have developed a TG electrophoretic assay that uses a thrombin specific charge-changing fluorescent peptide substrate, electrophoretic separation, and requires a drop of blood. The limit of detection of the assay was 1.97 nM in phosphate buffer saline and 6.82 nM in citrated whole blood. The assay was used to determine the TG in whole blood from healthy volunteers (n = 6, one aspirin user), over 30 min, after the blood was drawn; the TG increased from a baseline level of 2 × 10(6) RFU to 1.2 × 10(13) RFU. The lag time between the blood draw and initial burst of TG was 6 min for the volunteers (n = 5) and 15 min for the aspirin user. Specificity of the assay was evaluated by reacting our substrate with the heparinized blood samples and other proteases. The TG electrophoretic assay was designed and tested in the whole human blood, requiring no sample preparation, 5 μL of blood, 45 min, and it detected differences in coagulation patterns between a volunteer taking aspirin and non-aspirin users.


New medium oxacyclic O,N-acetals and related open analogues: biological activities.
Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. Taking 1-[(2-oxepanyl)]-5-fluorouracil previously prepared by us, we committed ourselves to increase the lipophilicity of this upper cyclohomologue of Ftorafur and prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and to 14-membered aminal structures and acyclic compounds. All the cyclic aminals provoked a G(o)/G(1)-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (51) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells and, consequently, improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3-Dihydrobenzoxepin-2-yl)-5-fluorouracil (26) may be particularly useful in stimulating apoptosis in breast cancer. This compound is more potent as an apoptotic inductor than paclitaxel (Taxol). Finally, a fact that is worth emphasizing is that the cyclic and acyclic 5-FU O,N-acetals induce neither toxicity nor death in mice after one month's treatment when administered intravenously twice a week, with a 50 mg/kg dose each time. Taken together, the experimental findings provide evidence of specific anti-tumour activity of these new substances and warrant further evaluation in in vivo models of breast cancer to future clinical applications.