Poling of an artificial magneto-toroidal crystal.
Although ferromagnetism is known to be of enormous importance, the exploitation of materials with a compensated (for example, antiferromagnetic) arrangement of long-range ordered magnetic moments is still in its infancy. Antiferromagnetism is more robust against external perturbations, exhibits ultrafast responses of the spin system1 and is key to phenomena such as exchange bias2,3, magnetically induced ferroelectricity4 or certain magnetoresistance phenomena5. However, there is no conjugate field for the manipulation of antiferromagnetic order, hindering both its observation and direct manipulation. Only recently, direct poling of a particular antiferromagnet was achieved with spintronic approaches6. An interesting alternative to antiferromagnetism is ferrotoroidicity-a recently established fourth form of ferroic order7,8. This is defined as a vortex-like magnetic state with zero net magnetization, yet with a spontaneously occurring toroidal moment9. As a hallmark of ferroic order, there must be a conjugate field that can manipulate the order parameter. For ferrotoroidic materials, this is a toroidal field-a magnetic vortex field violating both space-inversion and time-reversal symmetry analogous to the toroidal moment10. However, the nature and generation of the toroidal field remain elusive for conventional crystalline systems. Here, we demonstrate the creation of an artificial crystal11,12 consisting of mesoscopic planar nanomagnets with a magneto-toroidal-ordered ground state. Effective toroidal fields of either sign are applied by scanning a magnetic tip over the crystal. Thus, we achieve local control over the orientation of the toroidal moment despite its zero net magnetization.


NbSOBIR1 Partitions Into Plasma Membrane Microdomains and Binds ER-Localized NbRLP1.
The receptor-like kinase Suppressor of BIR1 (SOBIR1) binds various receptor-like proteins (RLPs) that perceive microbe-associated molecular patterns (MAMPs) at the plasma membrane, which is thought to activate plant pattern-triggered immunity (PTI) against pathogen invasion. Despite its potentially crucial role, how SOBIR1 transmits immune signaling to ultimately elicit PTI remains largely unresolved. Herein, we report that a Nicotiana benthamiana gene NbRLP1, like NbSOBIR1, was highly induced upon Phytophthora parasitica infection. Intriguingly, NbRLP1 is characterized as a receptor-like protein localizing to the endoplasmic reticulum (ER) membrane rather than the plasma membrane. Using bimolecular fluorescence complementation and affinity purification assays, we established that NbRLP1 is likely to associate with NbSOBIR1 through the contact between the ER and plasma membrane. We further found that NbSOBIR1 at the plasma membrane partitions into mobile microdomains that undergo frequent lateral movement and internalization. Remarkably, the dynamics of NbSOBIR1 microdomain is coupled to the remodeling of the cortical ER network. When NbSOBIR1 microdomains were induced by the P. parasitica MAMP ParA1, tobacco cells overexpressing NbRLP1 accelerated NbSOBIR1 internalization. Overexpressing NbRLP1 in tobacco further exaggerated the ParA1-induced necrosis. Together, these findings have prompted us to propose that ER and the ER-localized NbRLP1 may play a role in transmitting plant immune signals by regulating NbSOBIR1 internalization.


Immunological stimuli change expression of genes and neutrophil function in fathead minnow Pimephales promelas Rafinesque.
Fathead minnows Pimephales promelas were exposed to lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [poly(I:C)] to observe immunological responses during simulated bacterial and viral challenge at the level of gene expression and granulocyte function. Complementary DNA libraries were created from LPS- and poly(I:C)-treated fish and c. 5000 expressed sequence tags (ESTs) were sequenced. The ESTs were subjected to BLASTx analysis and 1500 genes were annotated, grouped by function and 20 immune genes were selected for expression studies by real-time PCR. Lipopolysaccharide treatment significantly downregulated expression of interferon regulatory factor 2 binding protein 1 (nine-fold), Chemokine (C-X-C motif) ligand 12a (three-fold) and TNF-related apoptosis-inducing ligand, TRAIL (two-fold). In poly(I:C)-treated fish, a significant upregulation was observed for IFN-inducible and antiviral proteins belonging to the family of Mx proteins (73-fold) and chemokine CCL-C5a (28-fold). Blood neutrophil count was significantly increased in poly(I:C)-treated fish at 24 and 48 h post-injection. Neutrophil extracellular trap release and respiratory burst of kidney granulocytes were suppressed in poly(I:C)-treated fish, while degranulation of primary granules was not affected significantly by the treatment. The changes in gene expression and neutrophil function in P. promelas exposed to LPS and poly(I:C) support the use of this species as an alternative model for studies of pathogen effects on the innate immune system of fishes.


Differential effects of unusual climatic stress on capuchin (Cebus capucinus) and howler monkey (Alouatta palliata) populations on Barro Colorado Island, Panama.
Though the harmful effects anthropogenic disturbances pose to wild primates are well appreciated, comparatively little is known about the effects of natural disturbances. From December 2010 to January 2011, different mortality patterns were observed for two primate species, capuchins and howler monkeys, on Barro Colorado Island (BCI), Panama. Unusually high rainfall in 2010 was associated with census and cadaver data indicating the rapid loss of >70% of the capuchin population in late 2010 to early 2011. In contrast, over this same period, no decline was documented for howler monkeys and cadaver data for howlers was unexceptional. The high mortality experienced by the capuchin population was unexpected and its extent was not fully appreciated until the event was largely over. Explanations proposed for it included effects of hypothermia, disease or a shortage of some essential nutrient(s). Of these, the dietary explanation seems most probable. BCI capuchins depend most heavily on arthropod foods in December, when few higher quality ripe fruits are available. The unprecedented high rainfall in December 2010 is hypothesized to have largely eliminated the arthropod peak expected on BCI each December. A lack of protein-rich arthropods, when coupled with the climatic and nutritional stress capuchins generally experience at this time of year, appears to have precipitated the rapid die-off of most of the island's capuchin population. As howler monkeys obtain dietary protein primarily from leaves, a shortage of edible arthropods would not affect howler numbers. Comparison of our 2010 data with similar data on earlier primate/mammalian mortality events reported for BCI and for Corcovado, Costa Rica indicates that our understanding of the effects of natural disturbances on wild primate populations is not profound. We suggest that more research be devoted to this increasingly timely topic, so important to conservation policy.


Super-acute onset of tumor lysis syndrome accompanied by hypercytokinemia during treatment of Hodgkin's lymphoma with ABVD chemotherapy.
Tumor lysis syndrome (TLS) is a group of life-threatening metabolic complications that can occur after initiation of cancer chemotherapy. Onset of TLS in the middle of chemotherapy, however, has not been reported previously in patients with hematologic malignancies. We report a case of a patient who experienced TLS of super-acute onset accompanied by hypercytokinemia during chemotherapy treatment with a combination of doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD). A 36-year-old Japanese man (height, 182 cm; weight, 83 kg; body surface area, 2.04 m(2)) was admitted to the hospital for the treatment of malignant lymphoma (clinical stage IVB Hodgkin's lymphoma). Chemotherapy was initiated using the ABVD regimen (doxorubicin [Adriamycin] 25 mg/m(2) by 30-minute infusion, bleomycin 9 mg/m(2) by 30-minute infusion, vinblastine 6 mg/m(2) by bolus injection, and dacarbazine 375 mg/m(2) by 2-hour infusion). During the dacarbazine infusion, the patient's body temperature rose from 36.5 degrees C to 42 degrees C; he experienced a convulsion and then lost consciousness. The convulsion was not suppressed despite the use of diazepam (5 mg IV twice) and phenytoin (500 mg IV). The patient was then transferred to the intensive care unit and sedated using a continuous infusion of midazolam (10 mg/h). Levels of serum lactate dehydrogenase, aspartate aminotransferase, uric acid, blood urea nitrogen, and creatinine evaluated shortly after the ABVD regimen were outside normal limits. In addition, interleukin-6 (IL-6) concentrations were elevated to 54,220 pg/mL. Continuous hemodiafiltration was immediately performed to lower the elevated levels of IL-6. The next day, IL-6 concentrations decreased to 97 pg/mL, and the patient was weaned from ventilator support and sedation. The patient had no adverse effects after the event. According to the results of an assessment using the Naranjo adverse drug reaction probability scale (score = 3), the development of TLS in this patient was possibly related to the chemotherapy regimen. ABVD chemotherapy was possibly associated with the super-acute onset of TLS in this patient. In addition, hypercytokinemia occurred with TLS, which led to pyrexia, convulsion, and loss of consciousness.


[Effect of sodium selenite on the antitumor function of spleen lymphocytes in mice].
Sodium selenite in drinking water (1 ppm) was given to normal and hepatoma-bearing mice for 14 days. Spleen lymphocytes were incubated with hepatoma cells and 3H-TdR incorporation was measured. Sodium selenite increased the ability of spleen cells to inhibit 3H-TdR incorporation into hepatoma cells by more than 40%. In the meantime, in the spleen lymphocytes of normal and hepatoma-bearing mice, the activities of ATPase, acid phosphatase and alkaline phosphatase were definitely higher than that of the control (ATPase increased by 35.5% and 65.0%; acid phosphatase increased by 113.0% and 93.0%; alkaline phosphatase by 64.7% and 69.0%, respectively). These results suggest that sodium selenite (1 ppm), like immunologic stimulator such as bacillus Calmette Guérin (BCG), be able to stimulate the immunologic function of organism against hepatoma.


Diagnosis and treatment of rheumatoid arthritis in the Emilia Romagna region: a prospective population-based study.
To perform a population-based study in rheumatoid arthritis (RA) patients, in order to evaluate the efficacy and safety of pharmacologic treatments. 1087 patients with RA were enrolled; inclusion criteria were: newly diagnosed RA, already diagnosed RA with high disease activity (HDA) (DAS28≥4.2) starting biologic DMARDs (bDMARDs), already diagnosed RA with HDA continuing with conventional DMARDs (cDMARDs). The following data were collected: demographics, clinical and laboratory features, imaging and prescribed drugs. All parameters except immunology and imaging (performed yearly) were repeated at each follow-up evaluations (after 3, 6 and 12 months, and thereafter every 12 months). In order to evaluate clinical response, the EULAR response criteria were used as the gold standard. 414 (38.1%) newly diagnosed patients with RA, 477 (43.9%) RA patients who started bDMARDs and 196 (18.0%) RA patients who continued with cDMARDs were enrolled from April 2012 to March 2015 at 12 Rheumatology Centres in the Emilia Romagna Region. Statistical analyses showed a relative risk ratio (RRR) for moderate response of 1.65 in RA patients who started bDMARDs (p=0.16) and 2.49 for newly diagnosed RA (p=0.01). Sex, age and Health Assessment Questionnaire were not statistically significant. A RRR of 2.00 has been confirmed for RA patients who started bDMARDs (p<0.0005) for a good response as well as 2.20 for newly diagnosed RA (p<0.0005). An increase in adverse events among bDMARDs was found, but when looking at infections or neoplasia, no differences were highlighted between RA which started bDMARDs and RA who continued with cDMARDs. Our results are in line with already published papers from British and Swedish Registries: a greater likelihood to have a good response is demonstrated for not longstanding RA starting cDMARDs or RA with HDA when a bDMARD is started. Also a good safety profile is demonstrated.


Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells.
Two major receptors involved in human natural cytotoxicity, NKp46 and NKp44, have recently been identified. However, experimental evidence suggested the existence of additional such receptor(s). In this study, by the generation of monoclonal antibodies (mAbs), we identified NKp30, a novel 30-kD triggering receptor selectively expressed by all resting and activated human natural killer (NK) cells. Although mAb-mediated cross-linking of NKp30 induces strong NK cell activation, mAb-mediated masking inhibits the NK cytotoxicity against normal or tumor target cells. NKp30 cooperates with NKp46 and/or NKp44 in the induction of NK-mediated cytotoxicity against the majority of target cells, whereas it represents the major triggering receptor in the killing of certain tumors. This novel receptor is associated with CD3zeta chains that become tyrosine phosphorylated upon sodium pervanadate treatment of NK cells. Molecular cloning of NKp30 cDNA revealed a member of the immunoglobulin superfamily, characterized by a single V-type domain and a charged residue in the transmembrane portion. Moreover, we show that NKp30 is encoded by the previously identified 1C7 gene, for which the function and the cellular distribution of the putative product were not identified in previous studies.


Modeling Solution Drying by Moving a Liquid-Vapor Interface: Method and Applications.
A method of simulating the drying process of a soft matter solution with an implicit solvent model by moving the liquid-vapor interface is applied to various solution films and droplets. For a solution of a polymer and nanoparticles, we observe "polymer-on-top" stratification, similar to that found previously with an explicit solvent model. Furthermore, "polymer-on-top" is found even when the nanoparticle size is smaller than the radius of gyration of the polymer chains. For a suspension droplet of a bidisperse mixture of nanoparticles, we show that core-shell clusters of nanoparticles can be obtained via the "small-on-outside" stratification mechanism at fast evaporation rates. "Large-on-outside" stratification and uniform particle distribution are also observed when the evaporation rate is reduced. Polymeric particles with various morphologies, including Janus spheres, core-shell particles, and patchy particles, are produced from drying droplets of polymer solutions by combining fast evaporation with a controlled interaction between the polymers and the liquid-vapor interface. Our results validate the applicability of the moving interface method to a wide range of drying systems. The limitations of the method are pointed out and cautions are provided to potential practitioners on cases where the method might fail.


Ischemic stroke related to an amniotic fluid embolism during labor.
We report a young woman who survived multiple cerebral infarctions related to an amniotic fluid embolism (AFE) during labor. To our knowledge, an embolic stroke due to the coexistence of an AFE and patent foramen ovale (PFO) has not been reported. We describe the patient's clinical and radiological features and discuss the stroke mechanism in relation to our AFE hypothesis. A 32-year-old woman presented to the emergency room after experiencing convulsions during labor (blood pressure, 64/28mmHg; oxygen saturation, 67%). She was in a stupor, and her response to painful stimuli on the right side was weaker than on the left side. Acute stroke was considered as a possible cause. Additionally, an AFE was suspected due to cardiopulmonary arrest during labor. Brain MRI revealed multiple territory embolic infarctions. The transcranial Doppler with bubble study demonstrated a right-to-left shunt during the Valsalva maneuver. A transesophageal echocardiogram revealed a PFO with a right-to-left shunt. The elevated intrathoracic pressure during labor may have caused blood to flow backward through the heart, shunting blood from the right side to the left through the PFO. In cases such as this, an amniotic fluid embolus may travel directly from the venous to the arterial circulation via the PFO, leading to multiple cerebral infarctions.


Structure and vacancy distribution in copper telluride nanoparticles influence plasmonic activity in the near-infrared.
Copper chalcogenides find applications in different domains including photonics, photothermal therapy and photovoltaics. CuTe nanocrystals have been proposed as an alternative to noble metal particles for plasmonics. Although it is known that deviations from stoichiometry are a prerequisite for plasmonic activity in the near-infrared, an accurate description of the material and its (optical) properties is hindered by an insufficient understanding of the atomic structure and the influence of defects, especially for materials in their nanocrystalline form. We demonstrate that the structure of Cu1.5±xTe nanocrystals can be determined using electron diffraction tomography. Real-space high-resolution electron tomography directly reveals the three-dimensional distribution of vacancies in the structure. Through first-principles density functional theory, we furthermore demonstrate that the influence of these vacancies on the optical properties of the nanocrystals is determined. Since our methodology is applicable to a variety of crystalline nanostructured materials, it is expected to provide unique insights concerning structure-property correlations.


Rapid detection of cocaine using aptamer-based biosensor on an evanescent wave fibre platform.
The rapid detection of cocaine has received considerable attention because of the instantaneous and adverse effects of cocaine overdose on human health. Aptamer-based biosensors for cocaine detection have been well established for research and application. However, reducing the analytic duration without deteriorating the sensitivity still remains as a challenge. Here, we proposed an aptamer-based evanescent wave fibre (EWF) biosensor to rapidly detect cocaine in a wide working range. At first, the aptamers were conjugated to complementary DNA with fluorescence tag and such conjugants were then immobilized on magnetic beads. After cocaine was introduced to compete against the aptamer-DNA conjugants, the released DNA in supernatant was detected on the EWF platform. The dynamic curves of EWF signals could be interpreted by the first-order kinetics and saturation model. The semi-log calibration curve covered a working range of 10-5000 µM of cocaine, and the limit of detection was approximately 10.5 µM. The duration of the full procedure was 990 s (16.5 min), and the detection interval was 390 s (6.5 min). The specified detection of cocaine was confirmed from four typical pharmaceutic agents. The analysis was repeated for 50 cycles without significant loss of sensitivity. Therefore, the aptamer-based EWF biosensor is a feasible solution to rapidly detect cocaine.


Inactive methyl indole-3-acetic acid ester can be hydrolyzed and activated by several esterases belonging to the AtMES esterase family of Arabidopsis.
The plant hormone auxin (indole-3-acetic acid [IAA]) is found both free and conjugated to a variety of carbohydrates, amino acids, and peptides. We have recently shown that IAA could be converted to its methyl ester (MeIAA) by the Arabidopsis (Arabidopsis thaliana) enzyme IAA carboxyl methyltransferase 1. However, the presence and function of MeIAA in vivo remains unclear. Recently, it has been shown that the tobacco (Nicotiana tabacum) protein SABP2 (salicylic acid binding protein 2) hydrolyzes methyl salicylate to salicylic acid. There are 20 homologs of SABP2 in the genome of Arabidopsis, which we have named AtMES (for methyl esterases). We tested 15 of the proteins encoded by these genes in biochemical assays with various substrates and identified several candidate MeIAA esterases that could hydrolyze MeIAA. MeIAA, like IAA, exerts inhibitory activity on the growth of wild-type roots when applied exogenously. However, the roots of Arabidopsis plants carrying T-DNA insertions in the putative MeIAA esterase gene AtMES17 (At3g10870) displayed significantly decreased sensitivity to MeIAA compared with wild-type roots while remaining as sensitive to free IAA as wild-type roots. Incubating seedlings in the presence of [(14)C]MeIAA for 30 min revealed that mes17 mutants hydrolyzed only 40% of the [(14)C]MeIAA taken up by plants, whereas wild-type plants hydrolyzed 100% of absorbed [(14)C]MeIAA. Roots of Arabidopsis plants overexpressing AtMES17 showed increased sensitivity to MeIAA but not to IAA. Additionally, mes17 plants have longer hypocotyls and display increased expression of the auxin-responsive DR5:beta-glucuronidase reporter gene, suggesting a perturbation in IAA homeostasis and/or transport. mes17-1/axr1-3 double mutant plants have the same phenotype as axr1-3, suggesting MES17 acts upstream of AXR1. The protein encoded by AtMES17 had a K(m) value of 13 microm and a K(cat) value of 0.18 s(-1) for MeIAA. AtMES17 was expressed at the highest levels in shoot apex, stem, and root of Arabidopsis. Our results demonstrate that MeIAA is an inactive form of IAA, and the manifestations of MeIAA in vivo activity are due to the action of free IAA that is generated from MeIAA upon hydrolysis by one or more plant esterases.


Irritable Bowel Syndrome on Inflammatory Bowel Disease in Deep Remission: No Relation with Remission Deepening and Inflammation.
The aim of the study was to establish the frequency of irritable bowel syndrome (IBS) in patients with inflammatory bowel disease (IBD) in clinical, endoscopic, and histologic remission and in relation to both the depth of remission and inflammation markers. Patients with ulcerative colitis (UC) and with Crohn's disease (CD) in clinical remission for at least 6 months were enrolled in the study. All of the patients underwent colonoscopy, and biopsy specimens were taken to evaluate endoscopic and histopathologic remission. Patients were evaluated according to Rome III criteria for IBS. Fecal calprotectin level and blood samples for C-reactive protein (CRP), sedimentation rate, and fibrinogen levels were studied. IBS frequency was 20.9% in UC cases and 28.9% in CD cases in clinical remission. Rates with and without endoscopic remission in UC (20.5% vs. 22.2%, P = .727) and CD (25% vs. 33.3%, P = .837, respectively) were not different. Similarly, rates with and without histopathologic remission in UC (15.7% vs. 26.6%, P = .723), and CD (21.4% vs. 33.3%, P = .999) were not statistically different. Also, it was not related to inflammation markers. IBS frequency among IBD patients with remission was in a substantial rate; these rates kept up with the process of deep remission and even complete mucosal healing and were irrelevant to inflammation.


Clinical uses of radiosurgery.
Radiosurgery uses stereotactic targeting methods to precisely deliver highly focused, large doses of radiation to small intracranial tumors and arteriovenous malformations (AVMs). This article reviews the most common clinical applications of radiosurgery and the clinical results reported from a number of series using either a cobalt-60 gamma knife or linear accelerator as radiation sources. Radiosurgery is used to treat malignant tumors, such as selected cases of brain metastases and malignant gliomas (for which stereotactic radiosurgical boosts are utilized in conjunction with fractionated radiation therapy), as well as benign tumors, such as meningiomas, acoustic neuromas, and pituitary adenomas. Treatment of small AVMs is also highly effective. Although radiosurgery has the potential to produce complications, the majority of patients experience clinical improvement with less morbidity than occurs with surgical resection.


Depressive symptoms in coronary artery disease patients after hypertension treatment.
Depression is highly prevalent and frequently recurs in patients with coronary artery disease (CAD) and hypertension. Certain medications used to treat hypertension are alleged to be associated with higher risk of depression. To compare depressive symptoms before and during treatment with 2 equivalent hypertension treatment strategies in patients with CAD stratified according to a self-reported history of physician-diagnosed depression. Patients enrolled in a randomized hypertension treatment study were mailed baseline and one year follow-up surveys and stratified according to a self-reported history of depression. Patients (N = 1152) were 50 years old or older with hypertension and clinically stable CAD. Depressive symptoms were measured using the Center for Epidemiologic Studies-Depression (CES-D). High risk of depression was defined as a history of physician-diagnosed depression reported by patients on the baseline survey. Depressive symptoms were compared for verapamil sustained-release (SR)- and atenolol-based hypertension treatment. Among patients with a previous history of depression, depressive symptoms improved over the one year follow-up period for patients assigned to both treatment regimens. Depressive symptoms improved for patients with no depression history in the verapamil SR group (p < 0.001) and were unchanged in the atenolol group (p = 0.52). Patients assigned to the atenolol-based strategy without prior history of depression were more likely to worsen 5 or more points on the CES-D. When antihypertensive treatment options are clinically equivalent, prescribers may first consider using a verapamil SR-based strategy, especially in patients with CAD who have no history of depression.


Case report: prolonged match chewing: an unusual case of tooth wear.
A case is reported of the diagnosis and clinical management of a patient with an obsessional neurosis resulting in extensive tooth and denture acrylic wear partially caused by prolonged match chewing.


Injury Mechanisms, Activities, and Limited Work Days in US Army Infantry Units.
Injuries are a leading health and readiness concern for the US Army. For effective prevention planning, details concerning circumstances associated with injuries are needed. Over 5,000 Soldiers were surveyed to collect demographic and injury details (type, body part, mechanism, activity, limited duty days); 874 reported an injury within 6 months of survey administration. The greatest proportion of limited duty time was associated with knee (19.2%), ankle (14.8%), and lower back injuries (12.9%). Overexertion was the leading injury mechanism (43.9%), followed by falls, jumps, trips, and slips (35.2%), which accounted for the highest average limited duty days per injury (42±43 days). Running was the leading activity associated overexertion injuries (39.3%) and falls (30.5%). Running also accounted for the greatest total limited duty days (5,844 days, 29.8%). For Army infantry units, results suggested a focus of prevention activities on running-related injuries resulting in overexertion or falls. Healthcare providers can facilitate injury prevention with contributions to initiatives providing details on injury mechanisms and activities associated with injuries.


[Various anatomic and functional characteristics of the urinary system in patients with a history of adnexitis].
Anatomical and functional urinary parameters were assessed, by means of radioisotopic dynamic renal scintigraphy, in 60 female patients with a history of chronic adnexitis. Most of the patients showed anatomical of functional urinary disorders, such as nephroptosis, an enlargement of one of the kidneys, ureteral dilatation, bladder reflux and reduced renal excretion. The disorders were more marked in those cases where chronic adnexitis had been accompanied by genital tumor growth.


Identification and validation of an immune-relevant risk signature predicting survival outcome and immune infiltration in uveal melanoma.
The current study aimed to reveal a novel immune-related signature to evaluate immune infiltration status and the survival outcome for patients with uveal melanoma (UM). Based on 80 UM samples from the Cancer Genome Atlas, the transcriptome gene expression and clinical characteristics were analyzed to identify immune-related genes that contributed most to prognosis based on LASSO Cox regression. By combining the gene expression level with the corresponding regression coefficient, a risk score was calculated and all patients were divided into high- and low-risk groups. Survival, tumor-infiltrating immune cell abundance, dysregulated signaling pathways, immunophenoscore and tumor mutation burden were compared between two groups. Validation of the risk signature was performed in GSE22138 and GSE44295 cohort. For evaluating the immunotherapy efficacy, 348 advanced urothelial cancer patients treated with immune checkpoint inhibitor (ICI) were used for external validation. Nine immune-related prognostic genes were identified under the LASSO Cox regression in the TCGA cohort; they are ACKR2, AREG, CCL5, CLEC11A, IGKV1-33, IL36B, NROB1, TRAV8-4 and TRBV28. Better prognosis, elevated immune cell infiltration, decreased immune-suppressive cell infiltration, immune response-related pathways and higher immunophenoscore were found in low-risk patients, with better ICI treatment response rate. The identified immune risk signature was demonstrated to be associated with the favorable immune infiltration, prognosis and immunotherapeutic efficacy, which may provide clues for survival evaluation and immune treatment.


Invasive infections due to filamentous fungi other than Aspergillus: epidemiology and determinants of mortality.
The epidemiology of invasive fungal disease (IFD) due to filamentous fungi other than Aspergillus may be changing. We analysed clinical, microbiological and outcome data in Australian patients to determine the predisposing factors and identify determinants of mortality. Proven and probable non-Aspergillus mould infections (defined according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria) from 2004 to 2012 were evaluated in a multicentre study. Variables associated with infection and mortality were determined. Of 162 episodes of non-Aspergillus IFD, 145 (89.5%) were proven infections and 17 (10.5%) were probable infections. The pathogens included 29 fungal species/species complexes; mucormycetes (45.7%) and Scedosporium species (33.3%) were most common. The commonest comorbidities were haematological malignancies (HMs) (46.3%) diabetes mellitus (23.5%), and chronic pulmonary disease (16%); antecedent trauma was present in 21% of cases. Twenty-five (15.4%) patients had no immunocompromised status or comorbidity, and were more likely to have acquired infection following major trauma (p <0.01); 61 (37.7%) of cases affected patients without HMs or transplantation. Antifungal therapy was administered to 93.2% of patients (median 68 days, interquartile range 19-275), and adjunctive surgery was performed in 58.6%. The all-cause 90-day mortality was 44.4%; HMs and intensive-care admission were the strongest predictors of death (both p <0.001). Survival varied by fungal group, with the risk of death being significantly lower in patients with dematiaceous mould infections than in patients with other non-Aspergillus mould infections. Non-Aspergillus IFD affected diverse patient groups, including non-immunocompromised hosts and those outside traditional risk groups; therefore, definitions of IFD in these patients are required. Given the high mortality, increased recognition of infections and accurate identification of the causative agent are required.


In vitro characterisation of a pleconaril/pirodavir-like compound with potent activity against rhinoviruses.
Rhinovirus infections do not only cause common colds, but may also trigger severe exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Even though rhinoviruses have been the focus of extensive drug development efforts in the past, an anti-rhinoviral drug still has to make it to the market. In the past, the viral capsid protein VP1 has been shown to be an important target for the development of antiviral molecules. Furthermore, many different chemical scaffolds appear to possess the properties that are required to inhibit virus replication by this mechanism of action. I-6602, an analogue of the rhinovirus inhibitor pirodavir, was previously identified as a potent inhibitor of rhinovirus infection. Here, we describe the antiviral activity of its analogue ca603, a molecule with a modified linker structure, and corroborate its mechanism of action as a capsid binder. The molecule ca603 shows antiviral activity against a panel of rhino-and enteroviruses. Cross-resistance is observed against viruses with mutations that render them resistant to the inhibitory effect of the capsid binder pleconaril and thermostability assays demonstrate that the compound binds and stabilizes the viral capsid. Binding of the molecule to the VP1 protein is corroborated by in silico modeling. It is confirmed that ca603 inhibits rhinovirus replication by interaction with the VP1 protein and, by this, allows to further expand the chemical diversity of capsid-binding molecules.


Multi-stimuli responsive photonic hydrogel based on a novel photonic crystal template containing gold nanorods.
Multi-stimuli responsive photonic hydrogels (MRPHs) fabricated by doping nanoparticles into hydrogels show promising potential value in the fields of visual detection and drug delivery. However, complicated surface chemical modification is selected to improve the compatibility between nanoparticles and a pre-gel solution of hydrogel. Herein, we developed a simple and convenient vertical deposition method to prepare a novel photonic crystal (PC) template containing gold nanorods (Au NRs) (Au NRs/PC template), which could respond to near-infrared (NIR) light due to the conversion capability of Au NRs from NIR light to heat. Additionally, carboxyl groups on the surface of polystyrene (PS) colloids endowed the Au NRs/PC template with pH-stimulus responsiveness. Based on the Au NRs/PC template, MRPH film was fabricated by infiltrating the pre-gel solution of poly(N-isopropylacrylamide) (PNIPAM) hydrogel into the gap of a 'sandwich' structure through capillary forces and then polymerizing at 25 °C for 24 h. The obtained MRPH film could respond to NIR light, pH and temperature. Under the irradiation of NIR light, only the irradiated position lost structural color while the film volume had no distinct change. With the increase of ambient temperature, the whole MRPH film completely lost structural color and shrank significantly, which was greatly different from the phenomenon irradiated by NIR light. Besides, the structural color of the MRPH film exhibited a red shift from green to orange-red as the pH increased. Overall, both the Au NRs/PC template and the MRPH film may have potential applications in visual detection, due to their multi-stimuli responsiveness.


Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors.
While estrogen-related receptors (ERRalpha, ERRbeta, and ERRgamma) share a high amino acid sequence homology with estrogen receptors (ERs), estrogens are not ligands of ERRs. Structure-function studies from this and other laboratories have revealed that ERRs have small ligand-binding pockets and have provided evidence to show that these receptors can activate gene transcription in a constitutive manner. To address the question as to whether there is any agonist for ERRs, our laboratory recently performed virtual ligand screening on ERRalpha that predicted flavone and isoflavone phytoestrogens to be ligands of this receptor. Our mammalian cell transfection and mammalian two-hybrid experiments revealed that three isoflavones (genistein, daidzein, and biochanin A) and one flavone (6,3',4'-trihydroxyflavone) behaved as agonists of ERRs. These phytoestrogens induced the activity of ERRalpha at concentrations that are comparable to those for the activation of ERalpha and ERbeta. In this study, we also used the results of ERRalpha ligand-binding site mutant, F232A, to verify our ERRalpha hypothetical computer model. Our recent ERR research has determined for the first time that flavone and isoflavone phytoestrogens are agonists of ERRs. In addition, our studies have demonstrated that an approach that combines structure-based virtual screening and receptor functional assays can identify novel ligands of orphan nuclear receptors.


Silibinin protects H9c2 cardiac cells from oxidative stress and inhibits phenylephrine-induced hypertrophy: potential mechanisms.
Cardiac hypertrophy is the main response of the heart to various extrinsic and intrinsic stimuli, and it is characterized by specific molecular and phenotypic changes. Recent in vitro and in vivo studies indicate the involvement of reactive oxygen species in the hypertrophic response. In this study, silibinin, a plant flavonolignan extracted from milk thistle with potent antioxidant activity, was evaluated for its effects in (a) preventing hydrogen peroxide (H2O2)-induced cellular damage and (b) blocking the phenylephrine-induced hypertrophic response. Using the in vitro model of embryonic rat heart-derived H9c2 cells, we showed that silibinin has a rather safe profile as concentrations up to 200μM did not affect cell viability. Pretreatment of H9c2 cells with silibinin resulted in better protection of H9c2 cells under conditions of H2O2-induced cellular stress compared to untreated cells as indicated by cell viability and DNA fragmentation assays. Furthermore, silibinin attenuated the phenylephrine-induced hypertrophic response as evidenced by the measurement of cell surface, up-regulation of atrial natriuretic peptide and increase of cellular protein levels. Moreover, silibinin repressed the phenylephrine-induced phosphorylation of ERK1/2 kinases, while it appeared to inhibit the weakly activated by phenylephrine phosphorylation of Akt. Based on our results, silibinin may attenuate the phenylephrine-induced hypertrophic response of H9c2 cells via antioxidant mechanisms involving mainly the inhibition of the intracellular signaling pathways mediated by ERK1/2 MAPKs and Akt.


Aberrant resting-state functional connectivity underlies cognitive and functional impairments in remitted patients with bipolar disorder.
Bipolar disorder (BD) is commonly associated with cognitive impairments, that directly contribute to patients' functional disability. However, there is no effective treatment targeting cognition in BD. A key reason for the lack of pro-cognitive interventions is the limited insight into the brain correlates of cognitive impairments in these patients. This is the first study investigating the resting-state neural underpinnings of cognitive impairments in different neurocognitive subgroups of patients with BD. Patients with BD in full or partial remission and healthy controls (final sample of n = 144 and n = 50, respectively) underwent neuropsychological assessment and resting-state functional magnetic resonance imaging. We classified the patients into cognitively impaired (n = 83) and cognitively normal (n = 61) subgroups using hierarchical cluster analysis of the four cognitive domains. We used independent component analysis (ICA) to investigate the differences between the neurocognitive subgroups and healthy controls in resting-state functional connectivity (rsFC) in the default mode network (DMN), executive central network (ECN), and frontoparietal network (FPN). Cognitively impaired patients displayed greater positive rsFC within the DMN and less negative rsFC within the ECN than healthy controls. Across cognitively impaired patients, lower positive connectivity within DMN and lower negative rsFC within ECN correlated with worse global cognitive performance. Cognitive impairments in BD seem to be associated with a hyper-connectivity within the DMN, which may explain the failure to suppress task-irrelevant DMN activity during the cognitive performance, and blunted anticorrelation in the ECN. Thus, aberrant connectivity within the DMN and ECN may serve as brain targets for pro-cognitive interventions.


Electrochemical determination of the procyanidins in peanut skin using a carbon nanotube electrode.
We demonstrated the electrochemical detection of procyanidins in peanut skin, which is often a waste product of the food industry, using a carbon nanotube electrode. Procyanidins, the main ingredients of peanut skin, are oligomers of catechin or epicatechin; therefore, they have various forms such as dimers, trimers, and a different number of linkages between monomers. Quantification using traditional high-performance liquid chromatography-mass spectroscopy (HPLC-MS) is tedious, because many peaks can be traced. The use of CNT electrodes for procyanidin sensing is promising, because CNT's properties, such as high conductivity, catalytic ability, and special geometry (high ratio of surface area to volume), enable common and specific profiles of the cyclic voltammograms (CVs) of procyanidins. Furthermore, the intensity of the anodic peaks (+ 0.32 V) due to the oxidation of catechol groups is proportional to the concentration of procyanidin (linear rang: 2.8-88 mg L-1, sensitivity: 1.4 mA mg-1 L cm-2), and does not depend on the type of procyanidin. The amount of procyanidins in the peanut skin estimated by CV was similar to that estimated by HPLC-MS. This study may contribute to accelerating the utilization of peanut skin for animal food, drugs, and supplementation.


Rapid detection of Pneumocystis carinii using a direct fluorescent monoclonal antibody stain.
A collaborative study was undertaken at two institutions to assess the performance of a direct fluorescent-antibody stain for the detection of Pneumocystis carinii in respiratory specimens from patients with known or suspected human immunodeficiency virus type 1 infections. A total of 163 specimens (125 induced sputa, 37 bronchoalveolar lavage fluids, and 1 tracheal aspirate) from 124 patients were examined by using modified Giemsa (Diff-Quik; Baxter American Scientific Products, Chicago, Ill.) and direct fluorescent-antibody stains. A total of 73 specimens contained P. carinii, which was detected in 66 (92%) of the specimens by using the modified Giemsa and in 71 (97%) of the specimens by using the fluorescent-antibody stain. One bronchoalveolar lavage fluid specimen in which P. carinii was detected only with the fluorescent-antibody stain was determined to be a false-positive based on subsequent clinical evaluation of the patient. Although the overall time for processing and examining specimens stained with either stain was not significantly different for those specimens containing P. carinii, considerably less time was required for microscopic examination of those fluorescent-antibody-stained specimens lacking P. carinii.


A personal (biased) perspective on cancer "vaccines".
The use of active specific immunotherapy (ASI) for cancer (cancer "vaccines") is still in its scientific infancy despite several decades of clinical and basic research. What has been established is the principle that stimulation of the immune response by "crude" (i.e., whole cell-derived) vaccines has led, in a proportion of patients, to rejection of tumor masses, in some instances for 10 years or more. Scientific investigations into the nature of recognition of tumor antigenic determinants (epitopes) by cytolytic T cells have begun to elucidate the mechanisms underlying rejection, making more precise vaccines possible. Yet there should be caution about assuming that a single epitope or even a few epitopes combined will be as effective as the "crude" materials, which might better be thought of as "polyvalent." ASI in at least one instance may have cured melanoma in a patient with metastatic disease, but that patient developed another immunologically and genetically distinct melanoma. This may provide an example of both immunological surveillance against the emergence of new melanomas and immunological selection of an immunologically resistant tumor. Combinations of vaccines with cytokines, cytolytic T cell infusions, or chemotherapy may improve the response rates and durations of survival achievable with vaccines alone. The best rationale for synthetically derived vaccines may be for prophylaxis-that is, as a true vaccine-where the use of tumor-derived materials in normal individuals is difficult to justify ethically.


Microbiology and laboratory diagnosis of upper respiratory tract infections.
In the article that follows, Carroll and Reimer address a number of issues related to the clinical and laboratory diagnosis of upper respiratory tract infections. These syndromes occur with great frequency in both adults and children and have tremendous economic impact, related not only to lost productivity in the workplace but also to the frequent prescription by physicians of antibiotics, even when the etiologic agents of infection almost certainly are not bacteria. Most of these infections are diagnosed clinically, and specimens for microbiological identification are not obtained. Indeed, the difficulty in obtaining microbiological specimens that are not contaminated by resident colonizing flora often results in laboratory culture reports of dubious clinical value. As the authors note, the most standardized procedures are for the diagnosis of pharyngitis due to Streptococcus pyogenes. The preferred culture methods are reviewed as are the sensitivities, specificities, and limitations of rapid direct tests for group A streptococcal antigens. Currently, as the authors emphasize, a negative direct test mandates a conventional culture for S. pyogenes. More problematic are requests for isolation of other streptococci, Haemophilus species, corynebacteria, and gram-negative bacteria. Given limited resources, cost-containment imperatives, and the absence of clear evidence that these organisms are pharyngeal pathogens associated with important sequelae, my laboratory does not attempt to isolate these bacteria unless the ordering physician has directly consulted with me (the laboratory director). Carroll and Reimer emphasize that nasopharyngeal cultures have no place in the microbiological diagnosis of otitis media and that diagnostic tympanocentesis is the only procedure for obtaining specimens that yield reliable microbiological findings. They also point out the futility of using swabs to obtain material for the diagnosis of otitis externa, since the external auditory canal cannot be decontaminated sufficiently to obtain a meaningful culture result. Finally, the authors address the available methods for obtaining specimens to establish the etiology of sinusitis. For microbiological diagnosis, direct antral puncture has been the method of choice for many years. However, otorhinolaryngologists now obtain many specimens endoscopically. It probably is not possible to obtain specimens by this method without contamination by normal upper respiratory flora. Thus, results of cultures of endoscopic specimens are more difficult to interpret. For patients with complicated illnesses, use of the diagnostic "gold standard" of antral puncture, as well as biopsy with histopathologic correlation, should be encouraged.


Unusual Case of Splenic Metastasis in Adenosquamous Carcinoma of the Cervix Uteri: Diagnosis and Treatment Considerations.
BACKGROUND Due to several factors such as its specific cellular and biochemical microenvironment, the spleen is not a predestined organ of frequent metastatic colonization in the case of primary solid carcinoma. Hence, the mode of diagnosis and the preferred treatment of a lesion highly suspicious of splenic metastasis must be decided on a case-by-case basis, considering not only the biological tumor entity but also the stage of the primary disease. CASE REPORT In the present case, we demonstrate the clinical course of a 37-year-old female patient who initially presented to our clinic with irregular vaginal bleeding. A consecutive gynecological examination revealed a 3×3-cm large mass of the cervix uteri, and the subsequent histomorphological workup led to the diagnosis of an adenosquamous carcinoma of the cervix uteri. Therapeutically, the patient received multimodal treatment, namely radical hysterectomy with adjuvant radio-chemotherapy. After 1.5 years, the patient presented to our Emergency Department with intermittent left-sided abdominal pain. Subsequent abdominal imaging (computed tomography scan, magnetic resonance imaging, positron emission tomography) determined a metabolically active splenic lesion with a central necrosis - signs of malignancy in line with a splenic metastasis. Presentation and discussion of the case within our interdisciplinary tumor board led to the decision of splenectomy followed by chemotherapy, a procedure that could be considered as therapeutic treatment in such exceptional cases. CONCLUSIONS The collection and reporting of atypical clinical courses remains a key factor in precision medicine to enable the most evidence-based decision making in such cases.


Comparison of the inhibitory potencies of N(G)-methyl-, N(G)-nitro- and N(G)-amino-L-arginine on EDRF function in the rat: evidence for continuous basal EDRF release.
The relative potencies of the argininolytic agents NG-methyl-L-arginine (L-NMA), NG-nitro-L-arginine (L-NNA) and NG-amino-L-arginine (L-NAA) were assayed by their inhibitory effect on both basal and stimulated release of endothelium-derived NO in vitro and in vivo. Basal NO release was indirectly assessed by the ability of the analogs to contract phenylephrine-preconstricted rat aortic rings and their ability to produce a hypertensive response in awake, unanesthetized normotensive rats. In aortic rings, the three analogs induced vasocontraction and inhibited the vasorelaxation mediated by ACh-stimulated endothelial NO release. In this latter assay, L-NNA was 30 times more potent than either L-NMA or L-NAA. In free-moving rats, the agents caused dose-dependent increases in arterial pressure due to the blockade of endogenous NO formation. Dose-response analysis indicated that L-NNA was 87 and 230 times more potent than L-NMA and L-NAA, respectively. Pretreatment with L-NNA was also found to selectively inhibit, but not abolish, the depressor effects of acetylcholine in unanesthetized and phenylephrine- or vasopressin-infused normotensive-pithed rats. These studies indicate that L-NNA is a potent antagonist of endothelium-derived relaxing factor formation in vitro and in vivo. The contractile and hypertensive effects of the argininolytic agents clearly demonstrates that a continuous basal release of endothelium-derived relaxing factor/NO occurs in both isolated vascular rings and whole animals.


High thermoelectric performance of p-type SnTe via a synergistic band engineering and nanostructuring approach.
SnTe is a potentially attractive thermoelectric because it is the lead-free rock-salt analogue of PbTe. However, SnTe is a poor thermoelectric material because of its high hole concentration arising from inherent Sn vacancies in the lattice and its very high electrical and thermal conductivity. In this study, we demonstrate that SnTe-based materials can be controlled to become excellent thermoelectrics for power generation via the successful application of several key concepts that obviate the well-known disadvantages of SnTe. First, we show that Sn self-compensation can effectively reduce the Sn vacancies and decrease the hole carrier density. For example, a 3 mol % self-compensation of Sn results in a 50% improvement in the figure of merit ZT. In addition, we reveal that Cd, nominally isoelectronic with Sn, favorably impacts the electronic band structure by (a) diminishing the energy separation between the light-hole and heavy-hole valence bands in the material, leading to an enhanced Seebeck coefficient, and (b) enlarging the energy band gap. Thus, alloying with Cd atoms enables a form of valence band engineering that improves the high-temperature thermoelectric performance, where p-type samples of SnCd(0.03)Te exhibit ZT values of ~0.96 at 823 K, a 60% improvement over the Cd-free sample. Finally, we introduce endotaxial CdS or ZnS nanoscale precipitates that reduce the lattice thermal conductivity of SnCd(0.03)Te with no effect on the power factor. We report that SnCd(0.03)Te that are endotaxially nanostructured with CdS and ZnS have a maximum ZTs of ~1.3 and ~1.1 at 873 K, respectively. Therefore, SnTe-based materials could be ideal alternatives for p-type lead chalcogenides for high temperature thermoelectric power generation.


Overview: the psychology of grandparenthood.
Grandparenthood as a separate and unique phase in the life cycle has received moderate attention in the literature. The literature is reviewed and found to focus on social aspects, intrapsychic aspects, and symbolic aspects of grandparenthood. Lacking is a cohesive definition of this phase in terms of its particular developmental tasks, conflicts, developmental arrests, and maturational course. Suggestions are made for how grandparenthood might be viewed in the context of important growth and development of individuals over their life cycles.


Extreme ultraviolet lensless imaging without object support through rotational diversity in diffractive shearing interferometry.
We report on a method that allows microscopic image reconstruction from extreme-ultraviolet diffraction patterns without the need for object support constraints or other prior knowledge about the object structure. This is achieved by introducing additional diversity through rotation of an object in a rotationally asymmetric probe beam, produced by the spatial interference between two phase-coherent high-harmonic beams. With this rotational diffractive shearing interferometry method, we demonstrate robust image reconstruction of microscopic objects at wavelengths around 30 nm, using images recorded at only three to five different object rotations.


Cystatin C, a novel indicator of renal function, reflects severity of cerebral microbleeds.
Chronic renal insufficiency, diagnosed using creatinine based estimated glomerular filtration rate (GFR) or microalbumiuria, has been associated with the presence of cerebral microbleeds (CMBs). Cystatin C has been shown to be a more sensitive renal indicator than conventional renal markers. Under the assumption that similar pathologic mechanisms of the small vessel exist in the brain and kidney, we hypothesized that the levels of cystatin C may delineate the relationship between CMBs and renal insufficiency by detecting subclinical kidney dysfunction, which may be underestimated by other indicators, and thus reflect the severity of CMBs more accurately. Data was prospectively collected for 683 patients with ischemic stroke. The severity of CMBs was categorized by the number of lesions. Patients were divided into quartiles of cystatin C, estimated GFR and microalbumin/creatinine ratios. Ordinal logistic regression analysis was used to examine the association of each renal indicator with CMBs. In models including both quartiles of cystatin C and estimated GFR, only cystatin C quartiles were significant (the highest vs. the lowest, adjusted OR, 1.88; 95% CI 1.05-3.38; p = 0.03) in contrast to estimated GFR (the highest vs. the lowest, adjusted OR, 1.28; 95% CI 0.38-4.36; p = 0.70). A model including both quartiles of cystatin C and microalbumin/creatinine ratio also showed that only cystatin C quartiles was associated with CMBs (the highest vs. the lowest, adjusted OR, 2.06; 95% CI 1.07-3.94; p = 0.03). These associations were also observed in the logistic models using log transformed-cystatin C, albumin/creatinine ratio and estimated GFR as continuous variables. Cystatin C was a significant indicator of deep or infratenorial CMBs, but not strictly lobar CMBs. In addition, cystatin C showed the greatest significance in c-statistics for the presence of CMBs (AUC = 0.73 ± 0.03; 95% CI 0.66-0.76; p = 0.02). Cystatin C may be the most sensitive indicator of CMB severity among the renal disease markers.


Ca2+-independent cyclic GMP phosphodiesterases from rat liver and HTC hepatoma cells.
We have separated and characterized a Ca2+- and calmodulin-insensitive cyclic nucleotide phosphodiesterase from rat liver supernatant as well as an analogous enzyme from HTC hepatoma cells. Chromatography of rat liver supernatant on DEAE-cellulose in the presence and subsequently in the absence of 0.1 mM-CaCl2 resulted in the separation of two distinct phosphodiesterase activities, both of which preferentially hydrolysed cyclic GMP rather than cyclic AMP. One enzyme, E-Ib, was activated in the presence of Ca2+ and calmodulin, and the other, E-Ia, was not. The E-Ia enzyme, which did not bind to calmodulin-Sepharose, had Mr 325 000 and displayed anomalous kinetic behaviour [Km (cyclic GMP) 1.2 microM; Km (cyclic AMP) 15.4 microM]. The E-Ib enzyme, which bound to calmodulin-Sepharose in the presence of Ca2+, had Mr 150 000 and exhibited Michaelis-Menten kinetics for hydrolysis of cyclic GMP [Km (basal) 6.5 microM; Km (activated) 12.0 microM]. E-Ia activity was diminished by incubation with alpha-chymotrypsin and was unaffected by the action of a rat kidney lysosomal proteinase. Partial hydrolysis of E-Ib enzyme by alpha-chymotrypsin or the kidney proteinase resulted in irreversible activation of the enzyme. The E-I enzyme isolated from HTC hepatoma cells was similar to the rat liver E-Ia enzyme in many respects. Its apparent Mr was 325 000. Its activity was unaffected by calmodulin in the presence of Ca2+ or by incubation with the kidney proteinase, and was decreased by digestion with alpha-chymotrypsin. Unlike the liver E-Ia enzyme, however, the hepatoma enzyme exhibited normal kinetic behaviour, with Km (cyclic GMP) 3.2 microM. Although HTC cells contain two other phosphodiesterases analogous to those in rat liver and a calmodulin-like activator of phosphodiesterase, no calmodulin-sensitive phosphodiesterase was detected.


The results of treatment of posttraumatic avascular necrosis of the femoral head in young adults: report of 31 patients.
A series of 31 adult patients less than 42 years of age who were treated for avascular necrosis (AVN) following a healed femoral neck fracture were followed for an average of 14.6 years, and the results of their treatment were analyzed. The average age at fracture was 26.3 years (range: 12.2 to 41.4 years). The mechanism of injury was a motor vehicle accident in 18 and a fall in 13. Sixteen patients had multiple injuries. The average time from fracture to diagnosis of AVN was 19.1 months. The management of AVN included one or a combination of the following: non-weightbearing ambulation, decompression and bone grafting, electrical stimulation, femoral osteotomy, cup arthroplasty, resurface arthroplasty, arthrodesis, hemiarthroplasty, and total hip arthroplasty (THA). The average number of hip operations after initial fracture treatment was 2.9 per patient (range: 0-7). Current follow-up was possible in 97% (30 out of 31) of the patients. THA was performed either primarily or following other treatment in 23 patients at an average age of 31.9 years (range: 16.9-55.3 years). The survivorship of these THAs was 89% at five years and 49% at ten years. Revisions have been done for aseptic loosening of cemented components with the exception of two infections and one loose metal-on-metal press-fit THA. The results of this study indicate that total hip arthroplasty has a high long-term failure rate in this population, and alternate treatment should be considered in order to improve the long-term results.


The International Scientific Association for Probiotics and Prebiotics (ISAPP) consensus statement on fermented foods.
An expert panel was convened in September 2019 by The International Scientific Association for Probiotics and Prebiotics (ISAPP) to develop a definition for fermented foods and to describe their role in the human diet. Although these foods have been consumed for thousands of years, they are receiving increased attention among biologists, nutritionists, technologists, clinicians and consumers. Despite this interest, inconsistencies related to the use of the term 'fermented' led the panel to define fermented foods and beverages as "foods made through desired microbial growth and enzymatic conversions of food components". This definition, encompassing the many varieties of fermented foods, is intended to clarify what is (and is not) a fermented food. The distinction between fermented foods and probiotics is further clarified. The panel also addressed the current state of knowledge on the safety, risks and health benefits, including an assessment of the nutritional attributes and a mechanistic rationale for how fermented foods could improve gastrointestinal and general health. The latest advancements in our understanding of the microbial ecology and systems biology of these foods were discussed. Finally, the panel reviewed how fermented foods are regulated and discussed efforts to include them as a separate category in national dietary guidelines.


Pediatric psoriasis induced by HLA-B46-Cw1 haplotype: A retrospective study of psoriasis onset after hematopoietic stem cell transplantation.
Genome-wide association studies have identified more than 60 susceptibility loci for psoriasis, highlighting the role of genetics in psoriasis development. Although the HLA region is suggested as the most prominent susceptibility locus, the role of the HLA haplotype in the development of psoriasis is unclear. The aim of this study is to investigate how HLA haplotype changes affect the onset of psoriasis and which HLA haplotypes are associated with the development of psoriasis. A longitudinal, retrospective case series study of children was conducted at Tohoku University Hospital in Japan, between November 1981 and October 2020. We evaluated a total of 378 pediatric patients who underwent hematopoietic stem cell transplantation in the Department of Pediatrics. The background of these patients and their HLA haplotypes before and after transplantation was assessed. Among the 378 cases, aged 0-22 years old (median age 6) identified, 117 cases received autologous transplantation, 260 cases received allogeneic transplantation, and one case received syngeneic transplantation. Only two cases developed de novo psoriasis, and these cases had acquired HLA-B46-Cw1 after allogeneic transplantation. Others who had HLA-B46-Cw1 before and after allogeneic transplantation did not develop psoriasis. Our findings suggest that the HLA-B46 and HLA-Cw1 combination contributes to the development of psoriasis in this Asian population.


Expression of miR-148b-3p is correlated with overexpression of biomarkers in prostate cancer.
Prostate cancer (PCa) is one of the leading causes of death among men. Genes such as PCA3, PSA, and Fra-1 are suggested to serve as potential tools for the detection of PCa, as they are deregulated during this pathology. A similar event occurs with small non-coding RNAs, called miRNAs, specifically miR-195-5p, miR-133a-3p, and miR-148b-3p, which were analyzed in a Chinese population and suggested to be possible candidates for PCa diagnosis. We evaluated the expression levels of three miRNAs and three genes in tissue samples of PCa and benign prostate disease, such as benign prostatic hyperplasia, or prostatitis, in order to determine their potential as candidates for PCa detection. Our results showed a statistically significant overexpression of 279-fold increase in PSA levels and a 1,012-fold increase in PCA3 levels in PCa patients compared to benign prostate disease patients (p = 0.001 and p = 0.002, respectively). We observed a positive correlation between the expression of miR-148b-3p and the expression of PSA and PCA3 genes, two established biomarkers in PCa. The expression of miR-148b-3p was not related to clinical characteristics, such as age and weight, as observed for the other miRNAs analyzed, suggesting its potential as a biomarker for detection of this pathology.


Poor Obstetric and Infant Outcomes in Human Immunodeficiency Virus-Infected Pregnant Women With Tuberculosis in South Africa: The Tshepiso Study.
Before the wide availability of antiretroviral therapy (ART), tuberculosis and human immunodeficiency virus (HIV) disease among pregnant women resulted in poor maternal and neonatal outcomes, including high rates of mother-to-child transmission of both HIV and tuberculosis. We aimed to describe the impact of tuberculosis among HIV-infected mothers on obstetric and infant outcomes in a population with access to ART. In this prospective cohort study, we followed up HIV-infected pregnant women with or without tuberculosis disease from January 2011 through January 2014 in Soweto, South Africa. Two controls were enrolled for each case patient, matched by enrollment time, maternal age, gestational age, and planned delivery clinic and followed up for 12 months after delivery. We recruited 80 case patients and 155 controls, resulting in 224 live-born infants. Infants of mothers with HIV infection and tuberculosis disease had a higher risk of low birth weight (20.8% vs 10.7%; P = .04), prolonged hospitalization at birth (51% vs 16%; P < .001), infant death (68 vs 7 deaths per 1000 births; P < .001), and tuberculosis disease (12% vs 0%; P < .001) despite appropriate maternal therapy and infant tuberculosis preventive therapy. HIV transmission was higher among these infants (4.1% vs 1.3%; P = .20), though this difference was not statistically significant. Obstetric outcomes in coinfected women were also poorer with higher risks of maternal hospitalization (25% vs 11%; P = .005) and preeclampsia (5.5% vs 0.7%; P = .03). Tuberculosis in HIV coinfected pregnant women remains a significant threat to the health of both mothers and infants. Improving tuberculosis prevention and early diagnosis among pregnant women is critical.


[Prospects in the treatments of stomach neoplasms].
Highlighted in the paper are basic treatment modalities for carcinoma of the stomach at the present stage of development of abdominal oncology, including original developments of the Ukrainean Research Institute of Oncology and Radiobiology of the Ministry of Health of Ukraine as the head institution of the country. The main index of references reflect potentialities of and prospects for treatment of gastric carcinoma over the last ten years.


Comparison of work related fatal injuries in the United States, Australia, and New Zealand: method and overall findings.
To compare the extent, distribution, and nature of fatal occupational injury in New Zealand, Australia, and the United States. Workplaces in New Zealand, Australia, and the United States. Data collections based on vital records were used to compare overall rates and distribution of fatal injuries covering the period 1989-92 in Australia and the United States, and 1985-94 in New Zealand. Household labour force data (Australia and the United States) and census data (New Zealand) provided denominator data for calculation of rates. Case definition, case inclusion criteria, and classification of occupation and industry were harmonised across the three datasets. New Zealand had the highest average annual rate (4.9/100,000), Australia an intermediate rate (3.8/100,000), and the United States the lowest rate (3.2/ 100,000) of fatal occupational injury. Much of the difference between countries was accounted for by differences in industry distribution. In each country, male workers, older workers, and those working in agriculture, forestry and fishing, in mining and in construction, were consistently at higher risk. Intentional fatal injury was more common in the United States, being rare in both Australia and New Zealand. This difference is likely to be reflected in the more common incidence of work related fatal injuries for sales workers in the United States compared with Australia and New Zealand. The present results contrasted with those obtained by a recent study that used published omnibus statistics, both in terms of absolute rates and relative ranking of the three countries. Such differences underscore the importance of using like datasets for international comparisons. The consistency of high risk areas across comparable data from comparable nations provides clear targets for further attention. At this stage, however, it is unclear whether the same specific occupations and/or hazards are contributing to the aggregated industry and occupation group rates reported here.


Effects of Cognitive Functioning and Education on Later-Life Health Numeracy.
Previous studies have shown an association between a high health numeracy and good cognitive functioning. To investigate the moderation effect of education on this relationship and which brain structures support health numeracy. We examined 70 healthy older persons (66% females; mean ± SD: age, 75.73 ± 4.52 years; education, 12.21 ± 2.94 years). The participants underwent a T1-weighted 3-T MRI and a neuropsychological assessment including a health numeracy task. Statistical parametric mapping was applied to identify focal changes in cortical thickness throughout the entire brain and to correlate image parameters with behavioral measures. Executive functions and mental calculation emerged as predictors of health numeracy (B = 0.22, p < 0.05, and B = 0.38, p < 0.01). An interaction was found between education and executive functions (B = -0.16, p = 0.01) and between education and mental calculation (B = -0.11, p < 0.05). Executive functions and mental calculation had an impact on health numeracy in participants with a low to intermediate edu-cation (≤12 years) but not in those with a higher education (>12 years). Health numeracy scores were associated with cortical thickness in the right dorsomedial prefrontal cortex and the right superior temporal gyrus (p = 0.01). Older people with a higher education perform better in health numeracy tasks than those with a lower education. They have access to previously acquired knowledge about ratio concepts and do not need to rely on executive functions and computational skills. This is highly relevant when decisions about health care have to be made.


The behaviour of sensory ganglia in relation to their environment.
The nodose ganglion was removed from rats and transplanted into the denervated tongue and into the denervated or innervated sternocleidomastoid muscle. In another procedure the ganglion was sutured to the distal hypoglossal or sciatic nerve. The ganglia failed to develop motor end-plates on denervated muscle. They did, however, induce formation of taste buds on the lingual epithelium. The regenerated nerve fibres ramified extensively within the connective tissue, invading perivascular tissue and lingual epithelium. At a cellular level some ganglion cells were covered with a meshwork of axonal material while others were found outside the confines of the implanted ganglion. The latter cell group are thought to achieve their location by a process of migration.


Naturally Drug-Loaded Chitin: Isolation and Applications.
Naturally occurring three-dimensional (3D) biopolymer-based matrices that can be used in different biomedical applications are sustainable alternatives to various artificial 3D materials. For this purpose, chitin-based structures from marine sponges are very promising substitutes. Marine sponges from the order Verongiida (class Demospongiae) are typical examples of demosponges with well-developed chitinous skeletons. In particular, species belonging to the family Ianthellidae possess chitinous, flat, fan-like fibrous skeletons with a unique, microporous 3D architecture that makes them particularly interesting for applications. In this work, we focus our attention on the demosponge Ianthella flabelliformis (Linnaeus, 1759) for simultaneous extraction of both naturally occurring ("ready-to-use") chitin scaffolds, and biologically active bromotyrosines which are recognized as potential antibiotic, antitumor, and marine antifouling substances. We show that selected bromotyrosines are located within pigmental cells which, however, are localized within chitinous skeletal fibers of I. flabelliformis. A two-step reaction provides two products: treatment with methanol extracts the bromotyrosine compounds bastadin 25 and araplysillin-I N20 sulfamate, and a subsequent treatment with acetic acid and sodium hydroxide exposes the 3D chitinous scaffold. This scaffold is a mesh-like structure, which retains its capillary network, and its use as a potential drug delivery biomaterial was examined for the first time. The results demonstrate that sponge-derived chitin scaffolds, impregnated with decamethoxine, effectively inhibit growth of the human pathogen Staphylococcus aureus in an agar diffusion assay.


Pyrroloquinoline quinone against glutamate-induced neurotoxicity in cultured neural stem and progenitor cells.
Pyrroloquinoline quinone (PQQ), as a well-known redox enzyme cofactor, has been proven to play important roles in the regulation of cellular growth and development in mammals. Numerous physiological and medicinal functions of PQQ have so far been reported although its effect on neural stem and progenitor cells (NS/PCs) and the potential mechanism were even rarely investigated. In this study, the neuroprotective effects of PQQ were observed by pretreatment of NS/PCs with PQQ before glutamate injury, and the possible mechanisms were examined. PQQ stimulated cell proliferation and markedly attenuated glutamate-induced cell damage in a dose-dependent manner. By observing the nuclear morphological changes and flow cytometric analysis, PQQ pretreatment showed its significant effect on protecting NS/PCs against glutamate-induced apoptosis/necrosis. PQQ neuroprotection was associated with the decrease of intracellular reactive oxygen species (ROS) production, the increase of glutathione (GSH) levels, and the decrease of caspase-3 activity. In addition, pretreatment with PQQ also significantly enhanced the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) in the NS/PCs exposed to glutamate. These results suggest that PQQ can protect NS/PCs against glutamate toxicity associated with ROS-mediated mitochondrial pathway, indicating a useful chemical for the clinical application of NS/PCs.


Post-Translational Regulation of CYP450s Metabolism As Revealed by All-Atoms Simulations of the Aromatase Enzyme.
Phosphorylation by kinases enzymes is a widespread regulatory mechanism able of rapidly altering the function of target proteins. Among these are cytochrome P450s (CYP450), a superfamily of enzymes performing the oxidation of endogenous and exogenous substrates thanks to the electron supply of a redox partner. In spite of its pivotal role, the molecular mechanism by which phosphorylation modulates CYP450s metabolism remains elusive. Here by performing microsecond-long all-atom molecular dynamics simulations, we disclose how phosphorylation regulates estrogen biosynthesis, catalyzed by the Human Aromatase (HA) enzyme. Namely, we unprecedentedly propose that HA phosphorylation at Y361 markedly stabilizes its adduct with the flavin mononucleotide domain of CYP450s reductase (CPR), the redox partner of microsomal CYP450s, and a variety of other proteins. With CPR present at physiological conditions in a limiting ratio with respect to its multiple oxidative partners, the enhanced stability of the CPR/HA adduct may favor HA in the competition with the other proteins requiring CPR's electron supply, ultimately facilitating the electron transfer and estrogen biosynthesis. As a result, our work elucidates at atomic-level the post-translational regulation of CYP450s catalysis. Given the potential for rational clinical management of diseases associated with steroid metabolism disorders, unraveling this mechanism is of utmost importance, and raises the intriguing perspective of exploiting this knowledge to devise novel therapies.


Acute Effects of a Practical Blood Flow Restriction Device During Swimming Exercise.
Purpose: The present study aimed to analyze: 1) the reliability of the tissue saturation index (TSI) and ratings of perceived discomfort (RPD) responses wearing a neoprene practical cuff (PrC), comparing with the responses from traditional (TrC) pneumatic cuffs (study I); 2) the effects of PrC on metabolic (blood lactate concentration, BLC), perceptual (rate of perceived effort, RPE) and kinematic responses at sub-maximal swimming velocities (study II). Methods: Study I; 1) PrC test-retest at rest and during swimming ergometer exercise; 2) BFR at rest with TrC inflated to different percentages of the minimum arterial occlusion pressure (MAOP; 60, 80, 100, 120 and 140%). Test-retest reliability of TSI and RPD was assessed by the intraclass correlation coefficient (ICC) and comparisons among conditions were analyzed by one-way repeated-measures ANOVA. Study II; 1) 50, 200 and 400 m swimming performances; 2) sub-maximal incremental swimming protocol with and without PrC. Two-way repeated measures ANOVA was used to compare all variables during sub-maximal velocities. Results: TSI (ICC = 0.81; 95%CI 0.62-0.91) and RPD (ICC = 0.97; 95%CI 0.94-0.99) were reliable under restricted exercise using PrC. TSI during restricted exercise was lower (p <.001) compared to unrestricted exercise (6.8 ± 6.1% vs. 21.6 ± 8.2% of physiological normalization). PrC showed higher BLC only at or above 91% of critical velocity (p < .03), while stroke rate and RPE were higher (p < .005), and stroke length was lower (p < .03) during all swimming velocities. Conclusion: This easy-to-handle and affordable practical BFR device increased physiological stress at sub-maximal efforts which could be an additional training tool for swimmers.


Encapsulating propeller-like columnar liquid crystals with an aromatic outer shell: influence of phenoxy-terminated side chains on the phase behaviour of triphenylbenzenes.
Tailoring of phase transition temperatures of columnar liquid crystals by side chain variation is often associated with an undesired change in the mesophase type and/or geometry. To overcome this problem phenoxy-terminated side chains rather than alkyl side chains were grafted onto triphenylbenzenes, which resulted in reduced clearing points, while melting points were little affected. More importantly, helical columnar self-assembly was not compromised.


[Morphofunctional features of the microcirculatory bed of the skin in students from different climatogeographic zones].
By means of the vital microscopy method length, diameter, stipulated area of the longitudinal section have been studied in the nail torus capillaries of students from different regions of the world depending on the climatogeographic zones. The value of the structural parameters in the skin capillaries, which characterize their heat exchange surface, directly, depends on temperature factors of the environment. There is an increase of the heat exchange surface in the capillaris of the person-inhabitants beginning from the moderate towards the subtropical, tropical and subequatorial zone. The exception make the students from the equatorial zone: the structure parameters of their capillaries are less than in the persons from the subequatorial and even from the tropical zones. This is connected with the fact that the equatorial zone is characterized with some extermal amount of heat and moisture.


The bone behind a low areal bone mineral density: peripheral quantitative computed tomographic analysis in a woman with osteogenesis imperfecta.
Areal bone mineral density (BMD) is the most widely used densitometric parameter. However, this approach makes it difficult to understand the structural basis of bone diseases, because a large number of bone properties are integrated into a single number. This is exemplified in the present case of a 27-year-old woman with osteogenesis imperfecta type I. Peripheral quantitative computed tomographic analysis at the radial metaphysis and at the radial diaphysis revealed a decreased areal BMD at both sites (z score -3.9 and -3.4, respectively). Yet, the structural basis for this decrease was different for the two locations: At the distal radius areal BMD was decreased because volumetric BMD was very low, whereas bone size was above the mean of the reference range. At the proximal radius areal BMD was decreased, because bone size was very low but volumetric BMD was above average. Bone mineral content of the radial diaphysis was very low for forearm muscle size, a finding which is compatible with Frost's hypothesis that the mechanostat setpoint is increased in osteogenesis imperfecta.


Crystal structures of cephaibols.
The crystal structures of the peptaibol antibiotics cephaibol A, cephaibol B and cephaibol C have been determined at ca. 0.9 A resolution. All three adopt a helical conformation with a sharp bend (of about 55 degrees) at the central hydroxyproline. All isovalines were found to possess the D configuration, superposition of all four models (there are two independent molecules in the cephaibol B structure) shows that the N-terminal helix is rigid and the C-terminus is flexible. There are differences in the hydrogen bonding patterns for the three structures that crystallize in different space groups despite relatively similar unit cell dimensions, but only in the case of cephaibol C does the packing emulate the formation of a membrane channel believed to be important for their biological function.


Atrial Fibrillation in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.
To examine the incidence and risk factors for de novo atrial fibrillation (AF) after allogeneic hematopoietic cell transplantation (HCT) and to describe the impact of AF on HCT-related outcomes. A retrospective cohort study design was used to examine AF and associated outcomes in 487 patients who underwent allogeneic HCT from 2014 to 2016 and to characterize patient- and HCT-related risk factors. A nested case-control study design was used to describe the association between pre-HCT echocardiographic measures and future AF events. The median age at HCT was 52.4 years (18.1-78.6); the median time to AF was 117.5 days (4.0-1,405.0). The 5-year cumulative incidence of AF was 10.6%. Older (≥ 50 years) age (hazard ratio [HR], 2.76; 95% CI, 1.37 to 5.58), HLA-unrelated donor (HR, 2.20; 95% CI, 1.18 to 4.12), dyslipidemia (HR, 2.40; 95% CI, 1.23 to 4.68), and pre-HCT prolonged QTc interval (HR, 2.55; 95% CI, 1.38 to 4.72) were independent risk factors for AF. Despite having comparable left ventricular systolic function, patients who developed AF were significantly more likely to have lower left atrial ejection fraction, left atrial reservoir function, and elevated tricuspid regurgitant jet velocity prior to HCT, compared with patients who did not. The incidence rate of stroke after AF was 143 per 1,000 person-years. In adjusted analyses, AF was associated with a 12.8-fold (HR, 12.76; 95% CI, 8.76 to 18.57) risk of all-cause mortality and 15.8-fold (HR, 15.78; 95% CI, 8.70 to 28.62) risk of nonrelapse mortality. The burden of AF after allogeneic HCT population is substantial, and the development of AF is associated with poor survival. We identified important associations between patient demographics, pre-HCT cardiac parameters, HCT-related exposures, and risk of AF, setting the stage for targeted prevention strategies during and after HCT.


Progesterone receptors (PR) mediate STAT actions: PR and prolactin receptor signaling crosstalk in breast cancer models.
Estrogen is the major mitogenic stimulus of mammary gland development during puberty wherein ER signaling acts to induce abundant PR expression. PR signaling, in contrast, is the primary driver of mammary epithelial cell proliferation in adulthood. The high circulating levels of progesterone during pregnancy signal through PR, inducing expression of the prolactin receptor (PRLR). Cooperation between PR and prolactin (PRL) signaling, via regulation of downstream components in the PRL signaling pathway including JAKs and STATs, facilitates the alveolar morphogenesis observed during pregnancy. Indeed, these pathways are fully integrated via activation of shared signaling pathways (i.e. JAKs, MAPKs) as well as by the convergence of PRs and STATs at target genes relevant to both mammary gland biology and breast cancer progression (i.e. proliferation, stem cell outgrowth, tissue cell type heterogeneity). Thus, rather than a single mediator such as ER, transcription factor cascades (ER>PR>STATs) are responsible for rapid proliferative and developmental programming in the normal mammary gland. It is not surprising that these same mediators typify uncontrolled proliferation in a majority of breast cancers, where ER and PR are most often co-expressed and may cooperate to drive malignant tumor progression. This review will primarily focus on the integration of PR and PRL signaling in breast cancer models and the importance of this cross-talk in cancer progression in the context of mammographic density. Components of these PR/PRL signaling pathways could offer alternative drug targets and logical complements to anti-ER or anti-estrogen-based endocrine therapies.


Conversion of 5-(1,2-epoxy-2,6,6-trimethylcyclohexyl)-3-methylpenta-cis-2-trans-4-dienoic acid into abscisic acid in plants.
(+/-)-5-(1,2-Epoxy-2,6,6-trimethylcyclohexyl) -3-methyl[2-(14)C]penta-cis-2-trans-4-dienoic acid is converted into abscisic acid by tomato fruit in 1.8% yield (or 3.6% of one enantiomer if only one is utilized) and 15% of the abscisic acid is derived from the precursor. The 2-trans-isomer is not converted. The amounts of [2-(3)H]mevalonate incorporated into abscisic acid have shown that the 40-times higher concentration of (+)-abscisic acid in wilted wheat leaves in comparison with unwilted ones reported by Wright & Hiron (1969) arises by synthesis. The conversion of (+/-)-5-(1,2-epoxy-2,6,6-trimethylcyclohexyl) -3-methyl-[2-(14)C]penta-cis-2-trans-4-dienoic acid into abscisic acid by wheat leaves is also affected in the same way by wilting and it is concluded from this that the epoxide or a closely related compound derived from it is on the biosynthetic pathway leading to abscisic acid. The oxygen of the epoxy group was shown, by (18)O-labelling, to become the oxygen of the tertiary hydroxyl group of abscisic acid.


Current US neurosurgical resident involvement, interest, and barriers in global neurosurgery.
It is estimated that nearly 47 million preventable deaths occur annually due the current worldwide deficit in surgical care; subsequently, the World Health Organization resolved unanimously to endorse a decree to address this deficit. Neurosurgeons from industrialized nations can help address the needs of underserved regions. Exposure during training is critical for young neurosurgeons to gain experience in international work and to cultivate career-long interest. Here, the authors explore the opinions of current residents and interest in global neurosurgery as well as the current state of international involvement, opportunities, and barriers in North American residency training. An internet-based questionnaire was developed using the authors' university's REDCap database and distributed to neurosurgical residents from US ACGME (Accreditation Council for Graduate Medical Education)-approved programs. Questions focused on the resident's program's involvement and logistics regarding international rotations and the resident's interest level in pursuing these opportunities. A 15% response rate was obtained from a broad range of training locations. Twenty-nine percent of respondents reported that their residency program offered elective training opportunities in developing countries, and 7.6% reported having participated in these programs. This cohort unanimously felt that the international rotation was a beneficial experience and agreed that they would do it again. Of those who had not participated, 81.3% reported interest or strong interest in international rotations. The authors' results indicate that, despite a high level of desire for involvement in international rotations, there is limited opportunity for residents to become involved. Barriers such as funding and rotation approval were recognized. It is the authors' hope that governing organizations and residency programs will work to break down these barriers and help establish rotations for trainees to learn abroad and begin to join the cause of meeting global surgical needs. To meet overarching international neurosurgical needs, neurosurgeons of the future must be trained in global neurosurgery.


Molecularly imprinted fluorescent and colorimetric sensor based on TiO2@Cu(OH)2 nanoparticle autocatalysis for protein recognition.
A novel molecular imprinting sensor based on TiO2 sol-gel layers embedding Cu(OH)2 was developed for protein recognition. Protein-imprinted TiO2 layers were prepared by liquid phase deposition (LPD) using lysozyme (Lys) as a template protein. The synthetic molecularly imprinted nanoparticles (MIPs) can catalyze o-phenylenediamine (OPDA) oxidation to produce fluorescence and color. Cu(OH)2 played a catalytic role in this reaction. The fluorescence intensity was related to the amount of MIPs, but has nothing to do with the imprinted protein. Taking advantage of this phenomenon, the imprinted protein can be detected using ELISA plates to fixed MIPs by OPDA oxidation. The fluorescence intensity at 568 nm (ex: 350 nm) was found to increase with increasing concentration of Lys. It was found that the limit of detection was 0.001 mg mL-1 with the fluorescent sensor and 0.04 mg mL-1 with the colorimetric sensor under optimized conditions. The results show that the MIPs reached saturated adsorption at 0.2 mg mL-1. Furthermore, the MIPs showed high selectivity compared to other tested proteins. In contrast, the fluorescence change of the non-imprinted TiO2@Cu(OH)2 was only small. The proposed method will be a useful platform for recognition of protein with high sensitivity and specificity.


Redox Pioneer: Professor Hideo Kimura.
Dr. Hideo Kimura is recognized as a redox pioneer because he has published an article in the field of antioxidant and redox biology that has been cited >1000 times, and 29 articles that have been cited >100 times. Since the first description of hydrogen sulfide (H2S) as a toxic gas 300 years ago, most studies have been devoted to its toxicity. In 1996, Dr. Kimura demonstrated a physiological role of H2S as a mediator of cognitive function and cystathionine β-synthase as an H2S-producing enzyme. In the following year, he showed H2S as a vascular smooth muscle relaxant in synergy with nitric oxide and its production by cystathionine γ-lyase in vasculature. Subsequently he reported the cytoprotective effect of H2S on neurons against oxidative stress. Since then, studies on H2S have unveiled numerous physiological roles such as the regulation of inflammation, cell growth, oxygen sensing, and senescence. He also discovered polysulfides (H2Sn), which have a higher number of sulfur atoms than H2S and are one of the active forms of H2S, as potent signaling molecules produced by 3-mercaptopyruvate sulfurtransferase. H2Sn regulate ion channels and transcription factors to upregulate antioxidant genes, tumor suppressors, and protein kinases to, in turn, regulate blood pressure. These findings led to the re-evaluation of other persulfurated molecules such as cysteine persulfide and glutathione persulfide. Dr. Kimura is a pioneer of studies on H2S and H2Sn as signaling molecules. It is fortunate to come across a secret of nature and pick it up. -Prof. Hideo Kimura.


Silencing hsa_circ_0032449 inhibits the pancreatic differentiation of human embryonic stem cells via the hsa_miR-195-5p/CCND1/PI3K/AKT signaling pathway.
Stem cell-derived β cells (SC-β cells) differentiated from stem cell-derived pancreatic progenitor (PP) cells are promising tools for enabling normal glucose control of islet transplants and have therapeutic potential for type 1 diabetes treatment. Pancreatic specification is essential for SC-β cell induction in vitro and low-quality PP cells may convert into derivatives of non-pancreatic lineages both in vivo and in vitro, impeding PP-derived β cell safety and differentiation efficiency. Circular RNA (circRNA) commonly determines the fate of stem cells by acting as competing endogenous RNA (ceRNA). Currently, the relationships between endogenous circRNA and pancreatic specification remain elusive. Herein, we used whole transcriptome sequencing analysis and functional experiments to reveal that deficiency of hsa_circ_0032449 resulted in posterior foregut-derived PP cells with a weakened the progenitor state with decreased expression of PDX1, NKX6.1 and CCND1. As differentiation processed into maturation, silencing of hsa_circ_0032449 suppressed PP cell development into functionally mature and glucose-responsive SC-β cells. These SC-β cells exhibited lower serum C-peptide levels compared with those of control groups in nude mice and had difficulties in reversing hyperglycemia in STZ-induced diabetic nude mice. Mechanistically, loss of hsa_circ_0032449 participated in PI3K-AKT signaling transduction by acting as a ceRNA to sponge miR-195-5p and by influencing the expression of the downstream target CCND1 at transcription and translation levels. Overall, our findings identified hsa_circ_0032449 as an essential PP cell-fate specification regulator, indicating a promising potential in clinical applications and basic research.


A Safe and Healthful Work Environment: Development and Testing of an Undergraduate Occupational Health Nursing Curriculum.
Occupational health nursing focuses on promotion and restoration of health, prevention of illness and injury, protection from work-related and environmental hazards, and corporate profitability. Quality education about the relationship between work and health is critical for nurses' success regardless of work setting, and is consistent with Healthy People 2020 goals, but is lacking or limited in some programs. This report introduces an innovative occupational health nursing curriculum for students enrolled in baccalaureate nursing programs. The process of designing and pilot testing this novel curriculum, its alignment with nursing competencies, and its format and learning activities are described. Preparing professional nurses to understand the role of the occupational health nurse and the relationship between work and health is an essential curricular consideration for contemporary nursing education.


PD-1 Inhibitor Therapy: Consensus Statement From the Faculty of the Melanoma Nursing Initiative on Managing Adverse Events .
Programmed cell death protein 1 (PD-1) inhibitor therapies are now a standard treatment for advanced melanoma and other tumor types. The immune-related adverse events (irAEs) associated with PD-1 inhibitor therapy are drastically different from the AEs associated with chemotherapy. Because these irAEs reflect immune system activation rather than side effects of therapy, nurses should be cognizant of the range of organ systems potentially affected as well as likely clinical presentations. . This article presents consensus statements to guide nurses in the recognition and management of irAEs associated with PD-1 inhibitor monotherapy for advanced melanoma. . Members of the Melanoma Nursing Initiative discussed the current literature and clinical experience regarding nursing interventions related to irAEs associated with PD-1 inhibitor therapy. . The care step pathways provided for select irAEs represent a proactive, comprehensive nursing care plan to support optimal outcomes for patients receiving PD-1 inhibitor therapy.


Safety and efficacy of the rSh28GST urinary schistosomiasis vaccine: A phase 3 randomized, controlled trial in Senegalese children.
Urinary schistosomiasis, the result of infection by Schistosoma haematobium (Sh), remains a major global health concern. A schistosome vaccine could represent a breakthrough in schistosomiasis control strategies, which are presently based on treatment with praziquantel (PZQ). We report the safety and efficacy of the vaccine candidate recombinant 28-kDa glutathione S-transferase of Sh (rSh28GST) designated as Bilhvax, in a phase 3 trial conducted in Senegal. After clearance of their ongoing schistosomiasis infection with two doses of PZQ, 250 children aged 6-9 years were randomized to receive three subcutaneous injections of either rSh28GST/Alhydrogel (Bilhvax group) or Alhydrogel alone (control group) at week 0 (W0), W4, and W8 and then a booster at W52 (one year after the first injection). PZQ treatment was given at W44, according to previous phase 2 results. The primary endpoint of the analysis was efficacy, evaluated as a delay of recurrence of urinary schistosomiasis, defined by a microhematuria associated with at least one living Sh egg in urine from baseline to W152. During the 152-week follow-up period, there was no difference between study arms in the incidence of serious adverse events. The median follow-up time for subjects without recurrence was 22.9 months for the Bilhvax group and 18.8 months for the control group (log-rank p = 0.27). At W152, 108 children had experienced at least one recurrence in the Bilhvax group versus 112 in the control group. Specific immunoglobulin (Ig)G1, IgG2, and IgG4, but not IgG3 or IgA titers, were increased in the vaccine group. While Bilhvax was immunogenic and well tolerated by infected children, a sufficient efficacy was not reached. The lack of effect may be the result of several factors, including interference by individual PZQ treatments administered each time a child was found infected, or the chosen vaccine-injection regimen favoring blocking IgG4 rather than protective IgG3 antibodies. These observations contrasting with results obtained in experimental models will help in the design of future trials. ClinicalTrials.gov NCT 00870649.