F and rare V4+ doped cobalt hydroxide hybrid nanostructures: excellent OER activity with ultralow overpotential.
Highly efficient and stable Earth abundant transition metal electrocatalysts are in great demand for the oxygen evolution reaction (OER), a bottleneck process involved in the water splitting reaction and metal-air batteries. Herein, we have demonstrated a single step direct fabrication of cobalt hydroxide (Co(OH)2) nanowires doped with vanadium(V) in a less stable +4 oxidation state and fluoride (F) ions (V-Co(OH)2) on a carbon cloth electrode that showed highly enhanced OER activity under alkaline conditions. V-Co(OH)2 nanowires synthesized under the optimized conditions produced excellent OER activity with an ultralow overpotential of 136 mV at 10 mA cm-2 (scan rate 1 mV s-1), a small Tafel slope (51.6 mV dec-1) and good stability over 72 h. To the best of our knowledge, this is the lowest overpotential reported for cobalt-based electrocatalysts to achieve a geometric current density of 10 mA cm-2. The controlled synthesis and HR-TEM studies revealed the formation of hybrid nanostructures (nanowires along with spherical assembly of nanoparticles) and codoping of V and F ions played an important role in enhancing the OER activity. The detailed chemical composition and oxidation state analysis by X-ray photoelectron spectroscopy (XPS) confirmed the doping of V4+ and ionic F in V-Co(OH)2 with mixed valence states of Co2+/Co3+ and a higher Co2+ ratio. The outstanding OER activity of V-Co(OH)2 is attributed to the formation of a spherical assembly of nanoparticles with nanowires, which provided a high number of catalytically active sites with enhanced charge transport, and doping of higher valence V4+ and strongly electronegative F in V-Co(OH)2 with a higher ratio of Co2+/Co3+ promoted OOH* intermediate generation and significantly boosted the OER activity. Overall, the present work highlights the possibility of achieving highly active Earth abundant OER electrocatalysts by controlling the mixed oxidation state of Co with a judicious choice of dopants along with maintaining optimal nanostructure morphologies.


Thermal Stability of Platinum-Cobalt Bimetallic Nanoparticles: Chemically Disordered Alloys, Ordered Intermetallics, and Core-Shell Structures.
Pt-Co bimetallic nanoparticles are promising candidates for Pt-based nanocatalysts and magnetic-storage materials. By using molecular dynamics simulations, we here present a detailed examination on the thermal stabilities of Pt-Co bimetallic nanoparticles with three configurations including chemically disordered alloy, ordered intermetallics, and core-shell structures. It has been revealed that ordered intermetallic nanoparticles possess better structural and thermal stability than disordered alloyed ones for both Pt3Co and PtCo systems, and Pt3Co-Pt core-shell nanoparticles exhibit the highest melting points and the best thermal stability among Pt-Co bimetallic nanoparticles, although their meltings all initiate at the surface and evolve inward with increasing temperatures. In contrast, Co-Pt core-shell nanoparticles display the worst thermal stability compared with the aforementioned nanoparticles. Furthermore, their melting initiates in the core and extends outward surface, showing a typical two-stage melting mode. The solid-solid phase transition is discovered in Co core before its melting. This work demonstrates the importance of composition distribution to tuning the properties of binary nanoparticles.


Acute exercise inhibits gastric emptying of liquids in rats: influence of the NO-cGMP pathway.
We previously found that acute exercise inhibited the gastric emptying of liquid in awake rats by causing an acid-base imbalance. In the present study, we investigated the involvement of the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, vasoactive intestinal peptide (VIP), and corticotropin-releasing factor (CRF) peptide in this phenomenon. Male rats were divided into exercise or sedentary group and were subjected to a 15-min swim session against a load (2.5 or 5% b.w.). The rate of gastric emptying was evaluated after 5, 10, or 20 min postprandially. Separate groups of rats were treated with vehicle (0.9% NaCl, 0.1 mL/100 g, ip) or one of the following agents: atropine (1.0 mg/kg, ip), the NO non-selective inhibitor Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; 10.0 mg/kg, ip), or the selective cGMP inhibitor 1H-(1,2,4)oxadiazole[4,3-a]quinoxalin-1-one (ODQ; 5.0 mg/kg, ip), the i-NOS non-specific inhibitor (aminoguanidine; 10.0 mg/kg, ip), the corticotropin-releasing factor receptor antagonist (astressin; 100 µg/kg, ip), or the vasoactive intestinal peptide (VIP) receptor antagonist Lys1, Pro2,5, Arg3,4, Tyr6 (100 µg/kg, ip). Compared to sedentary rats, both the 2.5 and 5% exercise groups exhibited higher (P<0.05) values of blood lactate and fractional gastric dye recovery. Corticosterone and NO levels increased (P<0.05) in the 5% exercised rats. Pretreatment with astressin, VIP antagonist, atropine, L-NAME, and ODQ prevented the increase in gastric retention caused by exercise in rats. Acute exercise increased gastric retention, a phenomenon that appears to be mediated by the NO-cGMP pathway, CRF, and VIP receptors.


[Alpha 1-antitrypsin deficiency and emphysema. Replacement therapy?].
We present three patients with homozygous alpha-1-antitrypsin deficiency and pulmonary emphysema. They demonstrate the typical patterns of this syndrome: panlobular emphysema, early age of onset, serum alpha-1-antitrypsin below 35% of normal and phenotype PiZZ. We discuss epidemiology, pathogenesis and clinical manifestations, and review the experience concerning replacement therapy using alpha-1-antitrypsin derived from human plasma. We strongly point out the importance of stopping cigarette smoking in such patients.


Acceptance and efficacy of interventions for family caregivers of elderly persons with a mental disorder: a meta-analysis.
The aim of the present study was to conduct an extended meta-analysis of the efficacy and acceptance of supportive interventions for alleviating depressive symptoms in family caregivers of elderly relatives with a mental disorder, including dementia. The second aim was to analyze intervention characteristics as potential moderators of the efficacy and acceptance of these interventions. We searched electronic databases for randomized controlled trials (RCTs) published between 2005 and 2014. Thirty-three studies were included in the meta-analysis with a total of 5,980 participants. No RCTs that tested interventions for caregivers of elderly patients with mental disorders other than dementia were found. The weighted pooled effect size of the interventions for caregivers of dementia patients was positive but small (standardized mean difference = 0.13; CI0.95 [0.03; 0.23], p = 0.01). Meta-regression analysis revealed higher effect sizes for interventions that were individually customized. Intervention discontinuation rates were low (mean 11%, SD = 6.3) and independent of most intervention characteristics. If the intervention was delivered via telecommunication intervention discontinuation rates tended to be higher (r = -0.39, p = 0.07). Comparative research for caregivers of elderly patients with mental disorders other than dementia is lacking. RCTs of interventions for family caregivers of dementia patients of the last decade show good acceptance among intervention participants, but there is still a need to improve the efficacy of these interventions. Individual customization of intervention components might enhance efficacy. More research is needed on the acceptance of telecommunication interventions for family caregivers.


Assessing consciousness with auditory event-related potential during coma recovery: a case study.
To observe changes in mismatch negativity (MMN) and P300 in a patient transitioning from a vegetative state (VS) to a minimally conscious state (MCS). One patient with intracerebral hemorrhage and an 8-month disease course was evaluated as being in the VS using the Coma Recovery Scale-Revised. Two weeks after the patient was admitted to the hospital, another evaluation was performed, and the patient was determined to be in an MCS. Using the Oddball paradigm, pure tone and name stimuli were presented to the patient to study event-related potentials (ERPs). A 15-week clinical follow-up was carried out, and four ERP examinations were performed at 2 days and 2, 6, and 15 weeks after admission. One healthy individual was assessed as a control participant. MMN and P300 were elicited in all four ERP examinations. MMN and P300 may occur earlier than believed in patients in persistent VS and MCS; their predictive values for prognosis need to be further confirmed by follow-up studies on a large clinical sample.


Echocardiography in chronic thromboembolic pulmonary hypertension.
Chronic thromboembolic pulmonary hypertension (CTEPH) is a significant complication of venous thromboembolism and is caused by incomplete resolution of pulmonary emboli. The persistent chronic pulmonary hypertension leads to right-ventricle pressure overload. As a result, there is often significant functional and morphological alteration of both the right and the left ventricle. Transthoracic echocardiography, which allows for the estimation of pulmonary arterial pressures, not only plays an important role in the diagnosis of pulmonary hypertension but also provides insights in the pathophysiology of CTEPH. This article reviews the echocardiographic techniques and findings in CTEPH patients.


Histochemical identification of glycoproteins in pig bronchial epithelium: (a) normal and (b) hypertrophied from enzootic pneumonia.
The glycoproteins in the normal pig bronchial gland are identified by the combined Alcian Blue (AB)-periodic acid Schiff (PAS) technique, with the use of sialidase digestion and AB staining either at pH 2-6 or at pH 1-0. In enzootic pneumonia (produced experimentally by infection with Mycoplasma hyorhinis) the bronchial gland hypertrophies, mucous and serous cells both increase, in number and size; hence the total glycoprotein content of the gland increases. The distribution of glycoproteins in the hypertrophied gland differs from that in the normal. Quantitative analysis of the mucous cells shows that in the hypertrophied gland the acid glycoprotein is increased relative to the neutral. There is also a relative change in the amounts of sialidase-sensitive sialomucin and sulphomucin; both are significantly increased at the expense of the sialidase-resistant sialomucin. Qualitative analysis of the serous cells shows that in the normal gland most of the glycoprotein is neutral and that the small amount of acid glycoprotein is sialidase-resistant sialomucin. In the hypertrophied gland there is relatively more acid glycoprotein which is either sialidase-resistant sialomucin or sulphomucin; in addition, in pigs with enzootic pneumonia there is an increase in the height of the bronchial epithelium and a depletion in both goblet cell number and glycoprotein content, which latter has more neutral glycoprotein and less acid glycoprotein.


Fabrication of fluorescent SiO2@zeolitic imidazolate framework-8 nanosensor for Cu(2+) detection.
A simple strategy to fabricate a fluorescent SiO2@zeolitic imidazolate framework-8 (ZIF-8) core-shell nanosensor for Cu(2+) detection was demonstrated in this work. The nanosensor was synthesized using carboxyl-functionalized SiO2 nanoparticles (SiO2 NPs) as a template to induce the growth of ZIF-8 on its surface. The porous SiO2@ZIF-8 exhibited extremely good adsorption properties and a large specific surface area to accumulate Cu(2+), and the pyridyl nitrogen sites in imidazole played vital roles in the recognition of Cu(2+). The fluorescent intensity decreased linearly with the increasing of Cu(2+) concentration in the range of 10-500 nM and the detection limit was estimated to be 3.8 nM. The SiO2@ZIF-8 nanosensor could be further used to determine trace amounts of Cu(2+) in real water samples, while some previous sensors had to be dispersed in organic solution for use, such as DMSO and MeCN. The core-shell nanostructures of SiO2@ZIF-8 made it possible for it to be dispersed directly in aqueous solution and prevented ZIF-8 from aggregation, which enhanced the sensing performance of the SiO2@ZIF-8 nanosensor.


Severe head trauma. Review of the factors influencing the prognosis.
A series of 72 severely head injured patients are reported, 24 (33%) with surgical intracranial hematomas. All patients were intensively cared for under the same therapeutic regime; intracranial pressure (ICP) was monitored and treated if increased. The series mortality was 39%. Uncontrollable increase of ICP (UI-ICP), always fatal, was observed in 18% of patients and in 13 of 28 deaths (46%); the incidence of UI-ICP among deaths was higher in patients less than in those more than 40 years old (55% vs 25%). Patients with UI-ICP were frequently deeply comatose and with arterial hypotension on admission; almost all died in the first days. Patients directly admitted from the scene with well staffed Life Flight Helicopter Emergency Care compared with those directly admitted from the scene with different type of ambulance service (paramedics, police, firemen and private) had a mortality rate significantly less (20% vs 54%) and an incidence of UI-ICP strongly lower both among patients (5% vs 29%) and among deaths (25% vs 54%). Thus in this small series intensive care after admission was not effective to obtain good results if patients had received poor preadmission emergency care. Review of the literature on main clinical predictors of outcome in severe head injury, have made possible some observations. Ischemic and intracranial hypertension brain lesions were generally present in patients killed by head trauma; while diffuse axonal injury, frequently responsible for vegetative, severe disability survival and late deaths, was observed only in 20-30% of postmortem examinations. Old age, poor neurological status and cardiocirculatory and respiratory disturbances prior to and upon admission positively worsened the outcome, while intracranial hematomas had a more variable predictive value. Intracranial hypertension was a definitively ominous predictor only if very high when the risk to be or become uncontrollable seems to be much elevated. UI-ICP, often fatal despite any aggressive therapy, was the single most frequent killer after severe head injury, responsible for about half of all deaths after admission. The different outcome among severe head injury series could be conceivably related to a different frequency of UI-ICP. Besides the severity of head injury and delay and mode of admission, we suggest that preadmission respiratory and cardiocirculatory and the quality of emergency medical system could strongly affect the incidence of uncontrollable increase of ICP in admitted patients and thus the mortality rate and favorable recovery of the series. The advanced preadmission emergency care service with intensive care after admission could significantly explain the better results often observed in severe head injury series.


The use of patient pictures and verification screens to reduce computerized provider order entry errors.
To determine whether an order verification screen, including a patient photograph, is an effective strategy for reducing the risk that providers will place orders in an unintended patient's electronic medical record (EMR). We describe several changes to the EMR/provider interface and ordering workflow that were implemented as one part of a hospital-wide quality improvement effort to improve patient identification and verification practices. We measured the impact by comparing the number of reported incidents of care being provided to any patient other than for whom it was intended before the intervention, and directly after the intervention. For the year before the interventions described herein, placement of orders in the incorrect patient's chart was the second most common cause of care being provided to the wrong patient, comprising 24% of the reported errors. In the 15 months after the implementation of an order verification screen with the patient's photo centrally placed on the screen, no patient whose picture was in the EMR was reported to have received unintended care based on erroneous order placement in his or her chart. The incorporation of patient pictures within a computerized order entry verification process is an effective strategy for reducing the risk that erroneous placement of orders in a patient's EMR will result in unintended care being provided to an incorrect patient.


Long-term kidney isografts develop functional and morphologic changes that mimic those of chronic allograft rejection.
This study examined antigen-independent factors in the pathogenesis of chronic rejection of organ transplants. In addition to alloantigen-dependent events, antigen-independent factors can influence chronic rejection of organ allografts. Initial injury, including early ischemia and acute rejection, may contribute. Kidney isografts were transplanted orthotopically into bilaterally nephrectomized rat recipients and studied functionally, morphologically and immunohistologically, at serial intervals up to 72 weeks after transplantation. Controls included chronically rejecting kidney allografts using a well-established model, non-nephrectomized and uninephrectomized animals with a native kidney that had undergone initial ischemia and uninephrectomized rats whose remaining kidney had been manipulated operatively. Allograft recipients developed progressive proteinuria after 12 weeks, with gradual renal failure ultimately leading to death. At the same time, morphologic changes, including progressive arteriosclerosis and glomerulosclerosis, tubular atrophy, and interstitial fibrosis, developed. Immunohistologically, macrophages infiltrated glomeruli during this period and cytokines became upregulated. Comparable changes occurred in isografts, but later, beginning after week 24 and progressing thereafter. The single ischemic kidney in uninephrectomized controls also developed the same lesions; no comparable changes were noted in other control kidneys. Antigen-independent functional and morphologic changes occur in long-term kidney isografts that resemble those appearing considerably earlier in allografts that reject chronically. Initial injury and extent of functioning renal mass may be important factors for such late changes.


J wave and ST segment elevation in the inferior leads: a latent type of variant Brugada syndrome?
In a patient referred for the evaluation of non-sustained monomorphic ventricular tachycardia on Holter recordings, ventricular fibrillation was electrically induced during electrophysiologic study. Despite the absence of structural heart diseases, his ECG revealed J wave and ST segment elevation in the inferior leads, which showed circadian variation and were augmented by the sodium channel blocker, pilsicainide. This case might lead us to notice a new concept, a 'latent' type of variant Brugada syndrome, and these ECG findings and changes might serve as its diagnostic sign.


Advances in MRI biomarkers for the diagnosis of Alzheimer's disease.
With the prevalence of Alzheimer's disease (AD) predicted to increase substantially over the coming decades, the development of effective biomarkers for the early detection of the disease is paramount. In this short review, the main neuroimaging techniques which have shown potential as biomarkers for AD are introduced, with a focus on MRI. Structural MRI measures of the hippocampus and medial temporal lobe are still the most clinically validated biomarkers for AD, but newer techniques such as functional MRI and diffusion tensor imaging offer great scope in tracking changes in the brain, particularly in functional and structural connectivity, which may precede gray matter atrophy. These new advances in neuroimaging methods require further development and crucially, standardization; however, before they are used as biomarkers to aid in the diagnosis of AD.


Sulfur cycling in freshwater sediments: A cryptic driving force of iron deposition and phosphorus mobilization.
Sulfur cycling in freshwater ecosystems has been previously considered minor, and the direct evidence of its impacts on iron and phosphorus cycles in freshwater sediments remains unclear. In this study, mesocosms with amended acetate and various sulfate concentrations (1.5-3.0 mmol L-1) were set up to investigate sulfur cycling and its influences on iron-rich freshwater sediments. Acetate addition induced hypoxia and provided substrates, which stimulated the sulfur cycling with evidence of SO42- decline, ΣS2-, S0 increase and corresponding variations of sulfate-reducing bacteria (SRB) and sulfur-oxidizing bacteria. Meanwhile, the growth of iron-reducing bacteria (IRB) was suppressed, and lower Fe(II) release was correspondingly related to larger SRB abundance at higher sulfate level, indicating that microbial iron reduction might be blocked by SRB activities. However, continuous dissolution of Fe(III) oxides and generation of iron sulfides were observed, suggesting that sulfide-mediated chemical iron reduction (SCIR) became the dominant iron-reducing pathway, and Fe(II) was buried as iron sulfides instead of released to water column, which resulted in a transition of iron cycling into unidirectional SCIR. Consequently, continuous dissolution of Fe(III) oxides led to significant increase of PO43- concentration in the water column and sediment pore-water, revealing the phosphorus mobility in sediments derived from the SCIR process. To note, sustained accumulation of iron sulfides was observed even without ΣS2- presence, suggesting that ΣS2- precipitation occurred prior to diffusion. Thus, ΣS2--missing sulfur cycling seemed "cryptic" in this study. To highlight, the transition of the iron-reducing pathway and resulting PO43- release can be induced even under current sulfate level of Lake Taihu, and elevated sulfate levels could significantly intensify SCIR and phosphorus mineralization. Thus, the stimulated iron deposition and the resulting phosphorus release derived from the sulfur cycling should be paid more attention to in the treatment of eutrophic freshwater ecosystems.


Synergistic Reinforcing Mechanisms in Cellulose Nanofibrils Composite Hydrogels: Interfacial Dynamics, Energy Dissipation, and Damage Resistance.
Engineering reversible cross-links between nanoparticles and polymer matrix is a promising avenue to reinforce the mechanical properties of elastomers and in particular soft hydrogels. In this work, we study a model system of composite hydrogel reinforced with cellulose nanofibrils (CNFs), where the integration of reversible hydrogen bonds into a lightly covalently cross-linked polyacrylamide (PAAm) matrix. This approach yields the dual cross-linked networks with synergistically improved strength, modulus, and toughness. The reversible nature of the hydrogen-bonded cross-links manifests a strong strain rate (έ) dependent dynamics properties. The CNF-PAAm interaction among physically adsorbed chains on the surface of CNF is examined as a function of CNF fraction by sum frequency generation spectroscopy. The results indicate a decrease of the number of free -OH groups on the CNF surface. Moreover, the deformation-resting experiments show a unique interface stiffening mechanism where the polymer chains desorbed from the CNF surface under oscillatory shear become entangled during resting time. The bending micromechanics test reveals that the CNF interfacial slip imparts the capability to strengthen the composites during deformation. The fibril pull-out process activates a series of dissipation mechanisms that increase the crack propagation resistance. These findings advance our understanding the role of interfacial layer in microscopic reinforcement mechanism and provide a constitutive foundation for exploring the deformation behaviors of the cellulosic hydrogels.


miR-506-3p alleviates uncontrolled osteoclastogenesis via repression of RANKL/NFATc1 signaling pathway.
Bone erosion is the major cause of deformities in autoimmune disease conditions such as osteoporosis and rheumatoid arthritis. Aberrant receptor activator of nuclear factor kappa B ligand (RANKL) secretion in bone disorders have been implicated to promote uncontrolled osteoclast differentiation through the regulation of nuclear factor of activated T cells 1 (NFATc1) transcription factor. This phenomenon is governed by several molecular factors including microRNAs, which are under-expressed during disease progression. This report focuses on elucidating the molecular mechanism of miR-506-3p towards the RANKL/NFATc1 pathway. miR-506-3p showed high binding affinity towards NFATc1 (ΔG = -22.4 kcal/mol). Bone marrow-derived macrophages (BMMs) isolated from rats stimulated with RANKL (100 ng/ml) showed active expression of NFATc1 which differentiated into mature osteoclasts. Moreover, NFATc1 activation resulted in downstream secretion of various bone resorptive enzymes (cathepsin K, carbonic anhydrase II, tartarate acid phosphatase, and matrix metalloproteinase 9) which lead to active bone resorption. However, transfection of miR-506-3p resulted in selective repression of NFATc1 inside the cells. This further resulted in the diminished release of bone resorptive enzymes that were essential for the degradation of the bone. Overall, we predict that miR-506-3p can be used as a molecular intervention for RANKL/NFATc1 mediated osteoclastogenesis.


PLGA nanometer surface features manipulate fibronectin interactions for improved vascular cell adhesion.
The largest cause of mortality in the Western world is atherosclerotic vascular disease. Many of these diseases require synthetic vascular grafts; however, their patency rate is only 30% in small (<6 mm) diameter vascular grafts after 5 years of implantation. In an effort to increase small diameter vascular graft success, researchers have been designing random nanostructured surface features which enhance vascular cell functions. However, for the present study, highly-controllable, nanostructured features on poly(lactic-co-glycolic acid) (PLGA) surfaces were formulated. To create ordered nanostructured roughness on PLGA surfaces, either 500, 200, or 100 nm polystyrene nanospheres were separately placed onto mica. These were then used as a template for creating an inverse poly(dimethylsiloxane) mold which was utilized to cast PLGA. Compared to all other PLGA films formulated, AFM results demonstrated greater initial fibronectin spreading on PLGA which possessed spherical 200 nm features. Compared to smooth PLGA, PLGA with 500 or 100 nm surface features, results further showed that PLGA with 200 nm spherical features promoted vascular cell (specifically, endothelial, and smooth muscle cell) adhesion. In this manner, the present study demonstrated a specific nanometer surface feature size that promoted fibronectin spreading and subsequent vascular cell adhesion; criteria critical to vascular graft success.


Giant and tunable electric field enhancement in the terahertz regime.
A novel array of slits design combining the nano-slit grating and dielectric-metal is proposed to obtain giant and tunable electric field enhancement in the terahertz regime. The maximum amplitude of electric field is more than 6000 times larger than that of the incident electric field. It is found that the enhancement depends primarily on the stripe and nano-slits width of grating, as well as the thickness of spacer layer. This property is particularly beneficial for the realization of ultra-sensitive nanoparticles detection and nonlinear optics in the terahertz range, such as the second harmonic generation (SHG).


Protein synthesis inhibitors attenuate seizures induced in rats by lithium plus pilocarpine.
The effects of two protein synthesis inhibitors, cycloheximide and anisomycin, were tested on seizures induced by coadministration of lithium and pilocarpine to rats. Systemic cycloheximide (2 mg/kg, s.c.) and centrally administered anisomycin (300 micrograms/10 microliters, i.c.v.) doubled the latency to initiation of seizures and to status epilepticus, while peripherally administered anisomycin (50 mg/kg, s.c.) completely blocked lithium-pilocarpine seizures. These results indicate that protein synthesis is required for initiation of seizures.


3-Allyl-1-{[3-(4-nitro-phen-yl)-4,5-dihydro-1,3-oxazol-5-yl]meth-yl}-1H-anthra[1,2-d]imidazole-2,6,11(3H)-trione.
The mol-ecular structure of the title compound, C(28)H(20)N(4)O(6), consists of three fused six-membered rings (A,B,C) and one five-membered ring (D). The latter is linked to an isoxazole ring (E) via a methyl-ene unit. A 4-nitro-phenyl substituent (F) is attached to the isoxazole. The fused five and six-membered rings (C,D) are almost coplanar with an r.m.s. deviation of 0.0345 Å and make a dihedral angle of 9.40 (8)° with ring A. The isoxazole and 4-nitro-phenyl rings (E,F) are also almost coplanar with the imidazole and the fused adjacent ring (C,D), forming a dihedral angle of 11.4 (6)°. The crystal packing displays inter-molecular C-H⋯O hydrogen bonding. An intra-molecular C-H⋯O inter-action also occurs.


Effect of Papaverine on Left Internal Mammary Artery Flow: Topical Spraying versus Perivascular Injection Method.
To analyze two techniques of papaverine application, topical spray on the harvested left internal mammary artery (LIMA) and perivascular injection, to find out their ability to improve LIMA flow. Forty patients were randomized into two groups. In Group 1, papaverine was sprayed on the harvested pedunculated LIMA. In Group 2, papaverine was delivered into the perivascular plane. Drug dosage was the same for both groups. LIMA flow was measured 20 minutes after applying papaverine. Blood flow was recorded for 20 seconds and flow per minute was calculated. The systemic mean pressures were maintained at 70 mmHg during blood collection. The data collected was statistically evaluated and interpreted. The LIMA blood flow before papaverine application in the Group 1 was 51.9±13.40 ml/min and in Group 2 it was 55.1±15.70 ml/min. Statistically, LIMA flows were identical in both groups before papaverine application. The LIMA blood flow, post papaverine application, in Group 1 was 87.20±13.46 ml/min and in Group 2 it was 104.7±20.19 ml/min. The Group 2 flows were statistically higher than Group 1 flows. Papaverine delivery to LIMA by the perivascular injection method provided statistically significant higher flows when compared to the topical spray method. Hence, the perivascular delivery of papaverine is more efficient than the spray method in improving LIMA blood flow.


Effect of individual differences on the jamming transition in traffic flow.
The individual difference, particularly in drivers' distance perception, is introduced in the microscopic one-dimensional optimal velocity model to investigate its effect on the onset of the jamming instability seen in traffic systems. We show analytically and numerically that the individual difference helps to inhibit the traffic jam at high vehicle densities while it promotes jamming transition at low vehicle densities. In addition, the jamming mechanism is further investigated by tracking how the spatial disturbance travels through traffics. We find that the jamming instability is uniquely determined by the overall distribution of drivers' distance perception rather than the spatial ordering of vehicles. Finally, a generalized form of the optimal velocity function is considered to show the universality of the effect of the individual difference.


Ultraviolet rays induced expression of lectins on the surface of a squamous carcinoma keratinocyte cell line.
Human keratinocytic cells from squamous carcinoma (SCL-1) present, under resting conditions, relatively low amounts of endogenous lectins (sugar-binding proteins). Upon uv irradiation, they express on their cell surface large amounts of endogenous lectin molecules able to bind neoglycoproteins bearing either alpha-L-rhamnosyl or alpha-D-glucosyl residues. A similar binding specificity was found with normal human keratinocytes under the same culture conditions. At sunlike doses, uv.A (365 nm) was more efficient than uv.B (312 nm) in the expression of such receptors on the surface of SCL-1 cells. The increased presentation of lectins by SCL-1 cells was transient and reached a maximum 4 h after irradiation. Such a specific modulation of receptor expression upon uv irradiation might be biologically significant, considering the numerous intercellular recognition phenomena in skin biology. alpha-L-Rhamnose-specific receptor on SCL-1 could not be distinguished from alpha-D-glucose-specific receptor on the basis of neoglycoproteins binding, uptake, and related inhibitions. Lectin expression was mainly detected on the cell surface, and its overexpression due to uv rays required a de novo protein synthesis process.


Plasma estrogen levels during pregnancy in the western spotted skunk.
The present study was undertaken to obtain an estrogen profile throughout gestation in the western spotted skunk with special emphasis on relating changes in estrogen levels to blastocyst development. Blood samples were collected from 130 pregnant animals by cardiac puncture and plasma estrogen levels were determined by radioimmunoassay (RIA). Estrogen levels varied throughout the period of embryonic diapause, with mean levels ranging between 3 to 18 pg/ml. There was a tendency for estrogen levels to be less variable and somewhat lower during the 15 days immediately prior to blastocyst implantation than during the preceding period. Plasma estrogen levels in skunks with delayed implanting blastocysts (diameters of 1.1 mm or less) were significantly higher (P less than 0.05) than those in females with activating blastocysts (i.e., diameters of 1.2 mm or greater), again suggesting that estrogen levels were reduced during the period immediately preceding implantation. However, the exact physiological significance, if any, of this modest reduction in estrogen levels remains to be determined.


Neural substrates of levodopa-responsive gait disorders and freezing in advanced Parkinson's disease: a kinesthetic imagery approach.
Gait disturbances, including freezing of gait, are frequent and disabling symptoms of Parkinson's disease. They often respond poorly to dopaminergic treatments. Although recent studies have shed some light on their neural correlates, their modulation by dopaminergic treatment remains quite unknown. Specifically, the influence of levodopa on the networks involved in motor imagery (MI) of parkinsonian gait has not been directly studied, comparing the off and on medication states in the same patients. We therefore conducted an [H2 (15) 0] Positron emission tomography study in eight advanced parkinsonian patients (mean disease duration: 12.3 ± 3.8 years) presenting with levodopa-responsive gait disorders and FoG, and eight age-matched healthy subjects. All participants performed three tasks (MI of gait, visual imagery and a control task). Patients were tested off, after an overnight withdrawal of all antiparkinsonian treatment, and on medication, during consecutive mornings. The order of conditions was counterbalanced between subjects and sessions. Results showed that imagined gait elicited activations within motor and frontal associative areas, thalamus, basal ganglia and cerebellum in controls. Off medication, patients mainly activated premotor-parietal and pontomesencephalic regions. Levodopa increased activation in motor regions, putamen, thalamus, and cerebellum, and reduced premotor-parietal and brainstem involvement. Areas activated when patients are off medication may represent compensatory mechanisms. The recruitment of these accessory circuits has also been reported for upper-limb movements in Parkinson's disease, suggesting a partly overlapping pathophysiology between imagined levodopa-responsive gait disorders and appendicular signs. Our results also highlight a possible cerebellar contribution in the pathophysiology of parkinsonian gait disorders through kinesthetic imagery.


The effects of acetylsalicylic acid on the human gastric mucosa as revealed by gastrocamera.
The influence on the gastric mucosa of acetylsalicylic acid (ASA) given as a buffered solution (Bamyl-SR, AB Hässle, Sweden) and as a conventional disintegrating tablet (MagnecylR, ACO, Sweden) has been compared in 7 healthy volunteers, using the gastrocamera technique. The study was performed crossover with randomized treatment periods. The dosage of ASA was 1 g 3 times daily for 3 days. Before and after each treatment period gastrocamera examinations were performed. The evaluation of the gastro-camera films was made blindly. It was found that after the ASA-tablets all subjects had multiple and prominent erosions. However, in all subjects the erosive effects on the gastric mucosa were less pronounced with the buffered solution. It was concluded that any person taking conventional ASA-tablets in a dose of 1 g 3 times daily for 3 days runs the risk of developing lesions of the gastric mucosa. This risk is less when ASA is taken in the form of a buffered solution.


Apelin stimulates glucose utilization in normal and obese insulin-resistant mice.
Adipose tissue (AT) secretes several adipokines that influence insulin sensitivity and potentially link obesity to insulin resistance. Apelin, a peptide present in different tissues, is also secreted by adipocytes. Apelin is upregulated in obese and hyperinsulinemic humans and mice. Although a tight relation exists between the regulation of apelin and insulin, it remains largely unknown whether apelin affects whole-body glucose utilization. Herein, we show that in chow-fed mice, acute intravenous injection of apelin has a powerful glucose-lowering effect associated with enhanced glucose utilization in skeletal muscle and AT. Through in vivo and in vitro pharmacological and genetic approaches, we demonstrate the involvement of endothelial NO synthase, AMP-activated protein kinase, and Akt in apelin-stimulated glucose uptake in soleus muscle. Remarkably, in obese and insulin-resistant mice, apelin restored glucose tolerance and increased glucose utilization. Apelin could thus represent a promising target in the management of insulin resistance.


Delivery of an miR155 inhibitor by anti-CD20 single-chain antibody into B cells reduces the acetylcholine receptor-specific autoantibodies and ameliorates experimental autoimmune myasthenia gravis.
MicroRNA-155 (miR155) is required for antibody production after vaccination with attenuated Salmonella. miR155-deficient B cells generated reduced germinal centre responses and failed to produce high-affinity immunoglobulin (Ig)G1 antibodies. In this study, we observed up-regulation of miR155 in the peripheral blood mononuclear cells (PBMCs) of patients with myasthenia gravis (MG), and miR155 was also up-regulated in torpedo acetylcholine receptor (T-AChR)-stimulated B cells. We used an inhibitor of miR155 conjugated to anti-CD20 single-chain antibody to treat both the cultured B cells and the experimental autoimmune MG (EAMG) mice. Our results demonstrated that silencing of miR155 by its inhibitor impaired the B cell-activating factor (BAFF)-R-related signalling pathway and reduced the translocation of nuclear factor (NF)-κB into the nucleus. Additionally, AChR-specific autoantibodies were reduced, which may be related to the altered amounts of marginal zone B cells and memory B cells in the spleens of EAMG mice. Our study suggests that miR155 may be a promising target for the clinical therapy of MG.


The novel technique of microwave heating of infant formulas and human milk with direct temperature monitoring.
We discuss the physical mechanisms of microwave heating of milk and infant formulas, and possible causes of nutrient degradation and scalds of infants reported in a number of papers. We list the advantages of microwave heating, formulate criteria of safe heating, and discuss discrepancies between different papers. A novel technique of microwave heating which prevents scalds and saves nutrients is reported. It features an appropriate and stepless microwave power control with direct temperature monitoring under forced permanent mixing. The discussed heating method does not kill live lactobacilli, has no influence on pathogen growth and does not modify the content of nutrients. We conclude that guidelines, which prohibit milk heating in domestic microwave ovens, are quite correct. Nevertheless, specific techniques of microwave heating can be successfully used due to their usability, fast heating, guaranteed precise target temperature and overall automation.


Isolation and analysis of circulating tuberculous antigens in Mycobacterium tuberculosis.
Serological techniques like enzyme linked immunosorbent assay (ELISA) and immunoblotting are useful for detection of mycobacterial antigens of diagnostic importance in tuberculosis. To isolate and identify circulating tuberculous antigens reactive with sputum positive and sputum negative pulmonary tuberculosis (PTB) sera. Circulating tuberculous antigen was isolated by ammonium sulphate fractionation from the sera of sputum positive and sputum negative (clinically and radiologically diagnosed) PTB cases. The circulating antigen fractions and individual patients' serum samples were resolved by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting was performed using anti M.tb sonicate IgG as a probe to detect antigens. Anti M.tb sonicate IgG was found to be reactive with mycobacterial proteins 170 kDa, 140 kDa, 85 kDa, 55 kDa, 43 kDa, 20 kDa and 16 kDa in the antigen fraction isolated from sputum positive tuberculosis sera by immunoblotting. However only 85 kDa, 55kDa, 43 kDa and 20 kDa antigenic proteins were found to be recognized by anti sonicate IgG in the antigen isolated from sputum negative sera. These observations were further confirmed by analysis of individual S+ and S- PTB serum by immunoblotting. Seroreactive studies of circulating tuberculous antigens showed the presence of 170 kDa, 140 kDa, 85 kDa, 55 kDa, 43 kDa, 20 kDa and 16 kDa protein antigens in sputum positive sera, while 85 kDa, 55 kDa, 43 kDa and 20 kDa antigens were found to be present in sputum negative PTB which need further evaluation for their use in serological diagnosis of tuberculosis.


[Breech presentation at term: the caesarean section that is routinely advised is ultimately not safe for the child].
Recently, the results have become available on both the neonatal and the maternal outcome of deliveries after randomisation in the Term breech trial. At 2 years, in contrast to the original results in which perinatal death and serious neonatal morbidity were higher in the planned vaginal delivery group, no differences were evident in the combined outcdme variable, including death after delivery and neurodevelopmental delay. There were also no apparent differences between the two groups in neurodevelopmental abnormalities as screened by the ASQ postal enquiry. These are the most important findings that should be discussed with the parents during counselling regarding the mode of delivery of a foetus in breech presentation.


Vessel tortuousity and reduced vascularization in the fetoplacental arterial tree after maternal exposure to polycyclic aromatic hydrocarbons.
Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental pollutants and the main toxicants found in cigarettes. Women are often exposed to PAHs before pregnancy, typically via prepregnancy smoking. To determine how prepregnancy exposure affects the fetoplacental vasculature of the placenta, we exposed female mice to PAHs before conception, perfused the fetoplacental arterial trees with X-ray contrast agent, and imaged the vasculature ex vivo by microcomputed tomography (micro-CT) at embryonic day 15.5. Automated vascular segmentation and flow calculations revealed that in control trees, <40 chorionic plate vessels (diameter>180 μm) gave rise to ∼1,300 intraplacental arteries (50-180 μm), predicting an arterial vascular resistance of 0.37±0.04 mmHg·s·μl(-1). PAH exposure increased vessel curvature of chorionic plate vessels and significantly increased the tortuousity ratio of the tree. Intraplacental arteries were reduced by 17%, primarily due to a 27% decrease in the number of arteriole-sized (50-100 μm) vessels. There were no changes in the number of chorionic vessels, the depth or span of the tree, the diameter scaling coefficient, or the segment length-to-diameter ratio. PAH exposure resulted in a tree with a similar size and dichotomous branching structure, but one that was comparatively sparse so that arterial vascular resistance was increased by 30%. Assuming the same pressure gradient, blood flow would be 19% lower. Low flow may contribute to the 23% reduction observed in fetal weight. New insights into the specific effects of PAH exposure on a developing arterial tree were achieved using micro-CT imaging and automated vascular segmentation analysis.


Validation of in silico biomarkers for drug screening through ordinal logistic regression.
Since the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiation, many studies have suggested various in silico features based on ionic charges, action potentials (AP), or intracellular calcium (Ca) to assess proarrhythmic risk. These in silico features are computed through electrophysiological simulations using in vitro experimental datasets as input, therefore changing with the quality of in vitro experimental data; however, research to validate the robustness of in silico features for proarrhythmic risk assessment of drugs depending on in vitro datasets has not been conducted. This study aims to verify the availability of in silico features commonly used in assessing the cardiac toxicity of drugs through an ordinal logistic regression model and three in vitro datasets measured under different experimental environments and with different purposes. We performed in silico drug simulations using the Tomek-Ohara Rudy (ToR-ORD) ventricular myocyte model and computed 12 in silico features comprising six AP features, four Ca features, and two ion charge features, which reflected the effect and characteristics of each in vitro data for CiPA 28 drugs. We then compared the classific performances of ordinal logistic regressions according to these 12 in silico features and used in vitro datasets to validate which in silico feature is the best for assessing the proarrhythmic risk of drugs at high, intermediate, and low levels. All 12 in silico features helped determine high-risky torsadogenic drugs, regardless of the in vitro datasets used in the in silico simulation as input. In the three types of in silico features, AP features were the most reliable for determining the three Torsade de Pointes (TdP) risk standards. Among AP features, AP duration at 50% repolarization (APD50) was the best when individually using in silico features per in vitro dataset. In contrast, the AP repolarization velocity (dVm/dtMax_repol) was the best when merging all in silico features computed through three in vitro datasets.


Successful treatment of ST elevation myocardial infarction caused by septic embolus with the use of a thrombectomy catheter in infective endocarditis.
A 71-year-old patient suffered a transmural (ST elevation) myocardial infarction (MI) as a result of a septic embolus from an infected tissue aortic valve replacement. Following failed fibrinolysis, his MI was successfully treated with thrombectomy using an export catheter. He suffered bleeding complications following the administration of tenectaplase and required aortic valve and root replacement due to ongoing systemic embolisation.


Bringing health into transportation and land use scenario planning: Creating a National Public Health Assessment Model (N-PHAM).
There is mounting evidence linking land development and transportation investments to physical activity with resulting implications for chronic disease prevention. Links between the physical environment and health have traditionally focused on harmful exposures such as air pollution, noise, and traffic injury. Given limited funds and competition for how and where investments are made, there is a need to prioritize and target resources to maximize health benefits that can include activity related chronic disease prevention. The ability to apply this evidence to decision making has been limited by the complexity and inconsistency of research methods, and lack of a direct connection with the planning contexts in which decisions are made. Scenario planning tools provide a method to apply evidence with spatial planning decisions at a range of geographic scales. The US Environmental Protection Agency commissioned the development of a National Public Health Assessment Model (N-PHAM). This project utilized built and natural environment data at the block-group level and large population surveys to model the relationships of the environment with several health outcomes for a range of age and income groups. N-PHAM is the first health assessment tool that can connect to multiple existing scenario planning platforms utilizing nationally available data and can be consistently applied nationally. Such tools can empower communities to choose investments that have the greatest potential to improve public health and quality of life, reduce health care costs, and address environmental justice related disparities.


Association between vitamin D supplementation and cancer incidence and mortality: A trial sequential meta-analysis of randomized controlled trials.
Observational studies and clinical trials have evaluated the associations between vitamin D supplementation and cancer incidence/mortality and obtained mixed results. Previous meta-analyses have also yielded inconsistent conclusions. In this paper, we conduct an updated meta-analysis by including current randomized clinical trials (RCTs) to assess the association between vitamin D supplementation and cancer incidence and mortality. The PubMed, Scopus and Embase databases were systematically searched from their inception to 6 February 2022. Fixed-effects meta-analyses were conducted. Trial sequential analyses were performed using a risk ratio reduction threshold of 10% for cancer incidence and mortality. Twenty-six RCTs were eligible, and pooled results indicated that vitamin D supplementation, compared to placebo with/without calcium, was not associated with a reduction in total cancer incidence (risk ratio: 0.98, 95% CI: 0.94, 1.02; I2 = 0%). In contrast, vitamin D supplementation significantly reduced total cancer mortality (risk ratio: 0.88, 95% CI: 0.8, 0.96; I2 = 0%). Moreover, trial sequential analysis provided reliable evidence that supplementation with vitamin D lowered the relative risk of total cancer mortality by 10%. Our updated meta-analysis suggested that vitamin D supplementation did not reduce total cancer incidence but significantly lowered total cancer mortality.Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2022.2056574 .


Effect of pre-treatment on in vitro gastric digestion of quinoa protein (Chenopodium quinoa Willd.) obtained by wet and dry fractionation.
Quinoa protein was isolated from quinoa seeds using wet fractionation that resulted in a protein isolate (QPI) with a high protein purity of 87.1% (w/dw) and a protein yield of around 54%, and a dry fractionation method delivered a quinoa protein concentrate (QPC) with a purity of 27.8% (w/dw) and yield of around 47%. The dry fractionation process only involves milling and sieving and keeps the protein in its natural, native state. The aim was to study the in vitro gastric digestibility of both protein. Attention was paid to thermal pre-treatment of QPI and QPC. QPC showed significantly higher (p < .05) digestibility than QPI samples. The results were interpreted with a simple double exponential model. The fraction of easily digested protein in QPC is higher than for QPI. The better digestibility of the QPC was explained by the prevention of the formation of large aggregates during pre-heating of the protein.


Diagnostic Inefficiency of Nonselective Spinal Angiography (Flush Aortography) in the Evaluation of the Normal and Pathological Spinal Vasculature.
Selective spinal angiography was introduced in the 1960s to palliate the poor sensitivity of nonselective techniques for the evaluation of the spinal cord vasculature. Recent advances made in the field of angiography seem to have prompted a renewed interest for nonselective spinal angiography, or flush aortograms. This pictorial essay, illustrated with 2 cases of presurgical evaluation of the spinal cord supply and 2 cases of spinal vascular malformation, suggests that nonselective techniques remain insufficient to properly document the normal or pathological spinal vasculature. While flush aortography can play a role as a complement to spinal angiography, for example, to locate vessels eluding selective catheterization, relying on nonselective studies to rule out the presence of a spinal vascular malformation or to identify the normal spinal cord supply before surgical interventions may lead to false-negative investigations with potentially devastating consequences.


A neural network model for transference and repetition compulsion based on pattern completion.
In recent years because of the fascinating growth of the body of neuroscientific knowledge, psychoanalytic scientists have worked on models for the neurological substrates of key psychoanalytic concepts. Transference is an important example. In this article, the psychological process of transference is described, employing the neurological function of pattern completion in hippocampal and thalamo-cortical pathways. Similarly, repetition compulsion is seen as another type of such neurological function; however, it is understood as an attempt for mastery of the unknown, rather than simply for mastery of past experiences and perceptions. Based on this suggested model of neurological function, the myth of the psychoanalyst as blank screen is seen as impossible and ineffective, based on neurofunctional understandings of neuropsychological process. The mutative effect of psychoanalytic therapy, correcting patterns of pathological relatedness, is described briefly from conscious and unconscious perspectives. While cognitive understanding (insight) helps to modify transferentially restored, maladaptive patterns of relatedness, the development of more adaptive patterns is also contingent upon an affective experience (working through), which alters the neurological substrates of unconscious, pathological affective patterns and their neurological functional correlates.


Enantioselective Friedel-Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids.
The first direct asymmetric synthetic preparation of trifluoro-1-(indol-3-yl)ethanols (TFIEs) is described by an enantioselective organocatalytic method from indoles and inexpensive trifluoroacetaldehyde methyl hemiacetal. The reaction is catalyzed by hydroquinine to produce TFIEs in an almost quantitative yield and with enantioselectivities up to 75% at room temperature. The enantioselectivity is strongly dependent on the concentration of substrates and catalyst due to the competitive noncatalyzed reaction.


Sub-County Life Expectancy: A Tool to Improve Community Health and Advance Health Equity.
Compared with people in other developed countries, Americans live shorter lives, have more disease and disability, and lag on most population health measures. Recent research suggests that this poor comparative performance is primarily driven by profound local place-based disparities. Several initiatives successfully used sub-county life expectancy estimates to identify geographic disparities, generate widespread interest, and catalyze multisector actions. To explore the feasibility of scaling these efforts, the Centers for Disease Control and Prevention and the Council of State and Territorial Epidemiologists initiated a multiphase project - the Sub-County Assessment of Life Expectancy. Phase I participants reviewed the literature, assessed and identified appropriate tools, calculated locally relevant estimates, and developed methodological guidance. Phase I results suggest that most state and local health departments will be able to calculate actionable sub-county life expectancy estimates despite varying resources, expertise, and population sizes, densities, and geographies. To accelerate widespread scaling, we describe several successful case examples, identify user-friendly validated tools, and provide practical tips that resulted from lessons learned.


Translaminar Cortical Membrane Potential Synchrony in Behaving Mice.
The synchronized activity of six layers of cortical neurons is critical for sensory perception and the control of voluntary behavior, but little is known about the synaptic mechanisms of cortical synchrony across layers in behaving animals. We made single and dual whole-cell recordings from the primary somatosensory forepaw cortex in awake mice and show that L2/3 and L5 excitatory neurons have layer-specific intrinsic properties and membrane potential dynamics that shape laminar-specific firing rates and subthreshold synchrony. First, while sensory and movement-evoked synaptic input was tightly correlated across layers, spontaneous action potentials and slow spontaneous subthreshold fluctuations had laminar-specific timing; second, longer duration forepaw movement was associated with a decorrelation of subthreshold activity; third, spontaneous and sensory-evoked forepaw movements were signaled more strongly by L5 than L2/3 neurons. Together, our data suggest that the degree of translaminar synchrony is dependent upon the origin (sensory, spontaneous, and movement) of the synaptic input.


Concurrent Medullary Carcinoma and Hashimoto's Thyroiditis: A Case Report with an Emphasis on US Features.
Medullary thyroid carcinoma (MTC) is a rare malignancy that originates from the parafollicular cells of the thyroid gland. Hashimoto's thyroiditis (HT) is an autoimmune thyroid disease and is the most common cause of hypothyroidism. Previous studies have frequently discussed the association among HT, papillary thyroid carcinoma, and thyroid lymphoma. However, there have been few reports on the ultrasonographic findings of concomitant HT and MTC. In the present case, a heterogeneous hypoechoic background parenchymal echogenicity, with intraglandular echogenic strands, and increased vascularity were observed. A concurrent, ill-defined, parallel-oriented, heterogeneous hypoechoic mass with central microcalcifications was located at the left thyroid gland, consistent with reported US findings of medullary thyroid carcinoma except for an ill-defined margin in our case.


Effect of electrochemical redox reaction on biochemical ammonium oxidation and chemical nitrite oxidation.
A modified graphite felt electrode with neutral red (NRelectrode) was shown to catalyze the chemical oxidation of nitrite to nitrate under aerobic conditions. The electrochemically oxidized NR-electrode (EO-NR-electrode) and reduced NR-electrode (ER-NR-electrode) catalyzed the oxidation of 1,094+/-39 mg/l and 382+/-45 mg/l of nitrite, respectively, for 24 h. The electrically uncharged NRelectrode (EU-NR-electrode) catalyzed the oxidation of 345+/-47 mg/l of nitrite for 24 h. The aerobic bacterial community immobilized in the EO-NR-electrode did not oxidize ammonium to nitrite; however, the aerobic bacterial community immobilized in the ER-NR-electrode bioelectrochemically oxidized 1,412+/-39 mg/l of ammonium for 48 h. Meanwhile, the aerobic bacterial community immobilized on the EU-NR-electrode biochemically oxidized 449+/-22 mg/l of ammonium for 48 h. In the continuous culture system, the aerobic bacterial community immobilized on the ER-NR-electrode bioelectrochemically oxidized a minimal 1,337+/-38 mg/l to a maximal 1,480+/-38 mg/l of ammonium to nitrate, and the community immobilized on the EU-NR-electrode biochemically oxidized a minimal 327+/-23 mg/l to a maximal 412+/-26 mg/l of ammonium to nitrate every two days. The bacterial communities cultivated in the ER-NR-electrode and EU-NR-electrode in the continuous culture system were analyzed by TGGE on the 20th and 50th days of incubation. Some ammoniumoxidizing bacteria were enriched on the ER-NR-electrode, but not on the EU-NR-electrode.


Human norovirus GII.4 Hong Kong variant shares common ancestry with GII.4 Osaka and emerged in Thailand in 2016.
Human norovirus is a leading cause of non-bacterial acute gastroenteritis, which affects all age groups and are found globally. Infections are highly contagious and often occur as outbreaks. Periodic emergence of new strains are not uncommon and novel variants are named after the place of first reported nucleotide sequence. Here, we identified human norovirus GII.4 Hong Kong variant in stool samples from Thai patients presented with acute gastroenteritis. Comparison of amino acid residues deduced from the viral nucleotide sequence with those of historical and contemporary norovirus GII.4 strains revealed notable differences, which mapped to the defined antigenic sites of the viral major capsid protein. Time-scaled phylogenetic analysis suggests that GII.4 Hong Kong shared common ancestry with GII.4 Osaka first reported in 2007, and more importantly, did not evolve from the now-prevalent GII.4 Sydney lineage. As circulation of norovirus minor variants can lead to eventual widespread transmission in susceptible population, this study underscores the potential emergence of the GII.4 Hong Kong variant, which warrants vigilant molecular epidemiological surveillance.


External polyacrylate-coating as alternative material for preparation of photopolymerized sol-gel monolithic column.
Photopolymerized sol-gel monolithic columns for use in capillary electrochromatography were prepared in 125 microm i.d. polyacrylate-coated fused-silica capillaries. The polyacrylate-coating, unlike the polyimide one, is transparent to the radiation used (approximately 370 nm), and thus, no coating removal is necessary. This is a very important particularity since intrinsic capillary column characteristics, such as flexibility and mechanical resistance, are unchanged. A mixture containing metacryloxypropyltrimethoxysilane (MPTMS) as the polymeric precursor, hydrochloric acid as the catalyst, toluene as the porogen and bis(2,4,6-trimethylbenzoyl)-phenylphosphine oxide (Irgacure 819) as the photoinitiator was irradiated at 370 nm for 20 min inside the capillaries to prepare the columns through sol-gel approach. The versatility and viability of the use of polyacrilate as a new capillary external coating were shown through preparation of two columns under different conditions, which were tested in electrochromatography for separation of standard mixture containing thiourea (marker compound), propylbenzene, phenanthrene and pyrene.


A computational platform for robotized fluorescence microscopy (II): DNA damage, replication, checkpoint activation, and cell cycle progression by high-content high-resolution multiparameter image-cytometry.
Dissection of complex molecular-networks in rare cell populations is limited by current technologies that do not allow simultaneous quantification, high-resolution localization, and statistically robust analysis of multiple parameters. We have developed a novel computational platform (Automated Microscopy for Image CytOmetry, A.M.I.CO) for quantitative image-analysis of data from confocal or widefield robotized microscopes. We have applied this image-cytometry technology to the study of checkpoint activation in response to spontaneous DNA damage in nontransformed mammary cells. Cell-cycle profile and active DNA-replication were correlated to (i) Ki67, to monitor proliferation; (ii) phosphorylated histone H2AX (γH2AX) and 53BP1, as markers of DNA-damage response (DDR); and (iii) p53 and p21, as checkpoint-activation markers. Our data suggest the existence of cell-cycle modulated mechanisms involving different functions of γH2AX and 53BP1 in DDR, and of p53 and p21 in checkpoint activation and quiescence regulation during the cell-cycle. Quantitative analysis, event selection, and physical relocalization have been then employed to correlate protein expression at the population level with interactions between molecules, measured with Proximity Ligation Analysis, with unprecedented statistical relevance.


Association of serum lipid concentrations, insulin resistance index and catch-up growth with serum cortisol/cortisone ratio by liquid chromatography tandem mass spectrometry in children born small for gestational age.
Intrauterine growth restriction (IUGR) may influence adrenocortical function, lipid metabolism and glucose tolerance in later life. Both cortisol (F) synthesis and metabolism contribute to serum F concentrations. 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) enzyme converts F to biologically inactive cortisone (E). Decreased 11beta-HSD2 activity has been suggested for a reason to IUGR and to its metabolic consequences. Our aim was to develop a specific liquid chromatography - tandem mass spectrometry (LC-MS/MS) method for analysing serum F and E concentrations, to determine the F/E ratios, and to correlate them with serum lipid concentrations, insulin resistance index (HOMA-IR), and catch-up growth in children born small for gestational age (SGA). The mean serum F and E concentrations, and F/E ratios did not differ between the SGA and their control children at 12 y age. The SGA children in the highest F/E ratio quartile had poorer gain in height between 0-12 y, and higher serum total and LDL cholesterol levels than those with lower F/E ratios. In logistic regression analysis, high LDL cholesterol, high HOMA-IR, and early pubertal stage associated with high F/E ratio in the SGA children. In conclusion, our LC-MS/MS method enables a reliable measurement of both F and E concentrations from a single serum sample. High serum F/E ratio may be associated with IUGR, its metabolic consequences, and poor catch-up growth in a subset of SGA children.


Endotoxin fever in granulocytopenic rats: evidence that brain cyclooxygenase-2 is more important than circulating prostaglandin E(2).
PGE(2) is a recognized mediator of many fevers, and cyclooxygenase (COX) is the major therapeutic target for antipyretic therapy. The source, as well as the site of action of PGE(2), as an endogenous pyrogen, is widely accepted as being central, but PGE(2) in the circulation, possibly from leukocytes, may also contribute to the development of fever. However, bacterial infections are important causes of high fever in patients receiving myelosuppressive chemotherapy, and such fevers persist despite the use of COX inhibitors. In the study reported here, the febrile response to bacterial LPS was measured in rats made leukopenic by cyclophosphamide. A striking increase in LPS fever occurred in these granulocytopenic rats when compared with febrile responses in normal animals. Unlike LPS fever in normal rats, fever in granulocytopenic rats was neither accompanied by an increase in blood PGE(2) nor inhibited by ibuprofen. Both leukopenic and normal rats showed LPS-induced COX-2-immunoreactivity in cells associated with brain blood vessels. Furthermore, LPS induced an increase of PGE(2) in cerebrospinal fluid. Induction of COX-2-expression and PGE(2) production was inhibited by ibuprofen in normal but not in leukopenic rats. Although the results presented are, in part, confirmatory, they add new information to this field and open a number of important questions as yet unresolved. Overall, the present results indicate that, in contrast to immunocompetent rats, leukocytes and/or other mechanisms other than PGE(2) are implicated in the mechanisms restricting and reducing the enhanced febrile response to endotoxin in immunosuppressed hosts.


Factors related to the need for surgery after the diagnosis of bicuspid aortic valve: one center´s experience under a conservative approach.
Bicuspid aortic valve (BAV) increases the risk of aortic valve dysfunction and ascending aorta aneurysm and, consequently, the need for aortic valve replacement and/or aortic repair. However, there is no universal consensus about the surgical criteria and the predictors for surgery. The aim of this study was to investigate related factors to the need for surgery in the setting of a strict long-term follow-up with relatively conservative surgical criteria. We prospectively followed 120 patients after the diagnosis of BAV. Predisposing factors for a future need for aortic valve replacement and ascending aorta repair were assessed. Aortic surgery was indicated when the ascending aorta diameter was ≥ 55 mm and was recommended based on patient characteristics and in the presence of a severe aortic valve dysfunction with an aortic diameter ≥ 50 mm. During follow-up (mean, 86 months), 34 patients (28%) (mean age, 56 ± 12 years) were surgically treated. Aortic valve dysfunction (n=22; 64%) and ascending aorta dilatation (n=12; 36%) were the indications for surgery. Aortic regurgitation was the most frequent valve dysfunction at the time of diagnosis for BAV, but aortic stenosis was the most frequent indication for surgery. The presence at surgery of either aortic regurgitation or stenosis was clearly related to age, with regurgitation predominating in patients under 55 years, and aortic stenosis in older patients.Multivariate Cox analysis showed that aortic stenosis (hazard ratio 4.1, p=0.001), indexed ascending aorta dilatation (hazard ratio 3.0, p=0.03) and left ventricular end-diastolic diameter ≥ 60 mm (hazard ratio=4.0, p=0.01) at diagnosis were factors associated with future surgery. Aortic dissection was not observed in patients that did not undergo surgery. A relatively conservative approach for the indication of ascending aortic surgery in BAV is safe. In this setting, the presence of aortic or left ventricle dilatation and aortic stenosis at diagnosis of BAV were predictive of the need for surgery in the follow-up.


Protective Effects of Molsidomine Against Cisplatin-Induced Nephrotoxicity.
Cisplatin, an effective chemotherapeutic agent, is used for the treatment of several types of cancers. However, cisplatin has some severe side effects such as nephrotoxicity. On the other hand, molsidomine, a NO donor, has anti-oxidative and vasodilator effects. The aim of this study was to estimate the protective effects of molsidomine on cisplatin-induced nephrotoxicity. Thirty-two rats were randomly divided into 4 groups as follows: (1) control; (2) received a single-dose intraperitoneal (i.p.) injection of 5 mg/kg cisplatin; (3) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days before cisplatin treatment; (4) received single i.p. dose of molsidomine (4 mg/kg/day) for 3 consecutive days. The specific biochemical markers, including antioxidants, and the histopathological alterations were evaluated. Cisplatin significantly increased malondialdehyde (MDA) and myeloperoxidase (MPO) levels and decreased glutathione peroxidase (GPX) level. Molsidomine significantly decreased MPO level nearly to control level; however, its ameliorating effects on MDA, SOD, CAT and GPX did not reach to significant levels. Cisplatin-induced elevation of blood-urea-nitrogen and serum-creatinine were diminished after molsidomine administration. Cisplatin also induced severe tubular degeneration, nuclear condensation, apoptosis and scattered patchy inflammation in the histological examination. Molsidomine improved all of these histological damages. In this study, the beneficial effect of molsidomine against cisplatin nephrotoxicity has been evaluated for the first time.


Effect of a Single Application of CPP-ACPF Varnish on the Prevention of Erosive Tooth Wear: An AAS, AFM and SMH Study.
The aim of this study was to investigate the in vitro effect of casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) and fluoride-containing varnish on prevention enamel erosive tooth wear. A total of 28 enamel samples were prepared from human molars, divided into four groups: CPP-ACPF varnish, TCP-F varnish, NaF varnish, and deionised water. For the remineralisation process stimulated human pooled saliva was used. After treatment, all enamel samples were exposed to 10 ml of Coca Cola. Ca++ release was determined by atomic absorption spectroscopy (AAS). The surface topography was evaluated by atomic force microscopy (AFM). Surface microhardness of enamel was analysed and SMHR % (surface microhardness reduction ) was calculated. Data were analysed with repeated measures analysis of variance (ANOVA). Deionised water demonstrated a statistically significantly higher Ca+2 release compared to those of groups NaF > fTCP > CPP-ACPF, respectively (p <0.01). All groups measured for root-mean-square-roughness (Rrms) showed a statistically significantly difference of 6 × 6 μm2 and 12 × 12 μm2 enamel area (p <0.05) compared with a negative control group. CPP-ACPF varnish showed rougher surfaces than all remineralisation groups. SMHR % of enamels were as follows: CPP-ACPF < fTCP < NaF < deionised water (p <0.01). According to the findings of this study; CPP-ACP containing agents have a statistically statistically significant effect on preventing dental erosion. Among these, CPP-ACPF-containing remineralisation agents have the most effect on the remineralisation process.


Synthesis of Amphiphilic Poly(β-amino ester) for Efficiently Minicircle DNA Delivery in Vivo.
Minicircle DNA (mcDNA) is a kind of enhanced nonviral DNA vector with excellent profiles in biosafety and transgene expression. Herein, we reported a novel amphiphilic polymer comprising polyethylenimine(PEI) modified Poly(β-amino ester) PEI-PBAE(C16) for efficient mcDNA delivery in vivo. The synthesized polymer could condense mcDNA into nanoscaled structure and exhibited efficient gene transfection ability without detectable cytotoxicity. Importantly, when injected into mouse intraperitoneally, these PEI-PBAE(C16) nanocomplexes were able to result in high level of trangene expression which lasted at least 72 h. Overall, these results demonstrated the PEI-PBAE(C16) can mediate effective and safe gene delivery in vivo with clinical application potential.


Bone Morphogenetic Protein 10-A Novel Biomarker to Predict Adverse Outcomes in Patients With Atrial Fibrillation.
Background Patients with atrial fibrillation (AF) face an increased risk of death and major adverse cardiovascular events (MACE). We aimed to assess the predictive value of the novel atrial-specific biomarker BMP10 (bone morphogenetic protein 10) for death and MACE in patients with AF in comparison with NT-proBNP (N-terminal prohormone of B-type natriuretic peptide). Methods and Results BMP10 and NT-proBNP were measured in patients with AF enrolled in Swiss-AF (Swiss Atrial Fibrillation Study), a prospective multicenter cohort study. A total of 2219 patients were included (median follow-up 4.3 years [interquartile range 3.9, 5.1], mean age 73±9 years, 73% male). In multivariable Cox proportional hazard models, the adjusted hazard ratio (aHR) associated with 1 ng/mL increase of BMP10 was 1.60 (95% CI, 1.37-1.87) for all-cause death, and 1.54 (95% CI, 1.35-1.76) for MACE. For all-cause death, the concordance index was 0.783 (95% CI, 0.763-0.809) for BMP10, 0.784 (95% CI, 0.765-0.810) for NT-proBNP, and 0.789 (95% CI, 0.771-0.815) for both biomarkers combined. For MACE, the concordance index was 0.732 (95% CI, 0.715-0.754) for BMP10, 0.747 (95% CI, 0.731-0.768) for NT-proBNP, and 0.750 (95% CI, 0.734-0.771) for both biomarkers combined. When grouping patients according to NT-proBNP categories (<300, 300-900, >900 ng/L), higher aHRs were observed in patients with high BMP10 in the categories of low NT-proBNP (all-cause death aHR, 2.28 [95% CI, 1.15-4.52], MACE aHR, 1.88 [95% CI, 1.07-3.28]) and high NT-proBNP (all-cause death aHR, 1.61 [95% CI, 1.14-2.26], MACE aHR, 1.38 [95% CI, 1.07-1.80]). Conclusions BMP10 strongly predicted all-cause death and MACE in patients with AF. BMP10 provided additional prognostic information in low- and high-risk patients according to NT-proBNP stratification. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02105844.


Marked enhancement of antibody synthesis following immunization with antigen bound to host lymphocytes. A potential treatment of patients with allergy.
Immunization of rabbits with I ugm of the gammaglobulins in goat anti-rabbit immunoglobulin antiserum (GG-GARIG) immunologically bound to circulating rabbit lymphocytes results in a humoral immune response to normal goat gammaglobulin (NGGG) super to that induced following repeated immunization with 10 mg GG-GARIG or NGGG. This form of immunization can only be carried out with antigen bound to cells possessing receptors for the antigen. Such a situation exists with respect to the allergic individual who possesses circulating lymphocytes capable of interacting with the specific allergen. It is suggested that desensitization or immunotherapy of the allergic individual with the allergen immunologically bound to autologous lymphocytes will result in extensive formation of IgG blocking antibodies unaccompanied by an anaphylactic reaction in view of the very minute quantity of allergen administered.


The risk of eating disorders and academic performance in adolescents: DADOS study.
eating disorders (ED) are complex multifactorial chronic diseases with adverse consequences on cognition in adolescence. the main aim of the present study was to analyze the association between the risk of ED and academic performance in adolescents, considering the key role of weight status. a total of 261 adolescents (13.9 ± 0.3 years) from the DADOS (Deporte, Adolescencia y Salud) Study were included in the analysis. The risk of ED was assessed using the Sick Control on Fast Food (SCOFF) questionnaire. Weight status was assessed by body mass index (BMI) (kg/m2). Academic performance was assessed through final grades and through the Spanish version of the SRA Test of Educational Ability (TEA). the risk of ED was negatively associated with academic grades, and with verbal and numeric abilities measured through TEA. Adolescents with non-eating disorder risk showed higher scores in academic grades (but not in the TEA components). Overweight and obese adolescents reported higher risk of ED. the risk of ED is negatively associated with academic performance, being higher in overweight and obese adolescents. Interventional programs aimed to improve academic performance should take into account weight status and the risk of ED.


NAD binding induces conformational changes in Rho ADP-ribosylating clostridium botulinum C3 exoenzyme.
We have solved the crystal structures of Clostridium botulinum C3 exoenzyme free and complexed to NAD in the same crystal form, at 2.7 and 1.95 A, respectively. The asymmetric unit contains four molecules, which, in the free form, share the same conformation. Upon NAD binding, C3 underwent various conformational changes, whose amplitudes were differentially limited in the four molecules of the crystal unit. A major rearrangement concerns the loop that contains the functionally important ARTT motif (ADP-ribosyltransferase toxin turn-turn). The ARTT loop undergoes an ample swinging motion to adopt a conformation that covers the nicotinamide moiety of NAD. In particular, Gln-212, which belongs to the ARTT motif, flips over from a solvent-exposed environment to a buried conformation in the NAD binding pocket. Mutational experiments showed that Gln-212 is neither involved in NAD binding nor in the NAD-glycohydrolase activity of C3, whereas it plays a critical role in the ADP-ribosyl transfer to the substrate Rho. We observed additional NAD-induced movements, including a crab-claw motion of a subdomain that closes the NAD binding pocket. The data emphasized a remarkable NAD-induced plasticity of the C3 binding pocket and suggest that the NAD-induced ARTT loop conformation may be favored by the C3-NAD complex to bind to the substrate Rho. Our structural observations, together with a number of mutational experiments suggest that the mechanisms of Rho ADP-ribosylation by C3-NAD may be more complex than initially anticipated.


The parameters of electron cyclotron resonance/radio-frequency hybrid hydrogen plasma adjusted by substrate arrangements.
Hybrid hydrogen plasma was formed by biasing 13.56 MHz radio-frequency (rf) power on a substrate immersed in 2.45 GHz microwave electron cyclotron resonance (ECR) plasma. The influences of the substrate configuration on plasma characteristics were investigated. With increasing rf self-bias voltage, electron temperature, T(e), increases obviously in the case of the single-electrode substrate, whereas a slight change in T(e) was observed with the double-electrode substrate condition. Electron density rises almost with a same magnitude under both two substrate conditions. It exhibited that electron energy and density in ECR-rf hybrid mode could be adjusted independently by controlling rf discharge with favorable substrate configurations.


[The effect of antitumor polychemotherapy on the structural, metabolic, and functional status of erythrocytes in patients with head and neck tumors].
The structure, metabolic status, and functional properties of erythrocytes in patients with stage III-IV head and neck tumors in the course of antineoplastic cytostatic chemotherapy (platidiam, 5-fluorouracil, methotrexate) were studied. In the course of this treatment, disorders of the morphology and functional state of erythrocytes (reduced dry mass, decreased content of sulfohydryl grups and lipoproteins, increased number of transformed cells and the cells with violated ultrastructure, enhanced reversible aggregation of erythrocytes) were retained or became more pronounced.


Quantifying the time for accurate EEG decoding of single value-based decisions.
Recent neuroimaging studies suggest that value-based decision-making may rely on mechanisms of evidence accumulation. However no studies have explicitly investigated the time when single decisions are taken based on such an accumulation process. Here, we outline a novel electroencephalography (EEG) decoding technique which is based on accumulating the probability of appearance of prototypical voltage topographies and can be used for predicting subjects' decisions. We use this approach for studying the time-course of single decisions, during a task where subjects were asked to compare reward vs. loss points for accepting or rejecting offers. We show that based on this new method, we can accurately decode decisions for the majority of the subjects. The typical time-period for accurate decoding was modulated by task difficulty on a trial-by-trial basis. Typical latencies of when decisions are made were detected at ∼500 ms for 'easy' vs. ∼700 ms for 'hard' decisions, well before subjects' response (∼340 ms). Importantly, this decision time correlated with the drift rates of a diffusion model, evaluated independently at the behavioral level. We compare the performance of our algorithm with logistic regression and support vector machine and show that we obtain significant results for a higher number of subjects than with these two approaches. We also carry out analyses at the average event-related potential level, for comparison with previous studies on decision-making. We present a novel approach for studying the timing of value-based decision-making, by accumulating patterns of topographic EEG activity at single-trial level.


Who are parish nurses?
This article introduces parish nursing by describing seven areas, including: the varied professional background of nurses, their educational background, the nurse as a unique person, resources to which interdisciplinary professionals and parish nurses can turn, limitations of the practice, a brief history of the profession, and types of practices.


Potassium perylene-tetracarboxylate with two-electron redox behaviors as a highly stable organic anode for K-ion batteries.
Potassium perylene-3,4,9,10-tetracarboxylate was exploited as a new organic anode for potassium-ion batteries, exhibiting two-electron redox behavior and a theoretical capacity of 93 mA h g-1. After optimization, the K4PTC electrode showed an average of 50 mA h g-1 over 2500 cycles at a current density of 0.5 A g-1.


Vitamin K3 preferentially inhibits stimulation of phospholipase D-mediated hydrolysis of phosphatidylethanolamine by protein kinase C activators in NIH 3T3 fibroblasts.
Vitamin K3 (menadione), a synthetic vitamin K congener, inhibits the growth of tumor cells. Here, we examined possible effects of vitamin K3 on phospholipase D (PLD) activity, an enzyme which produces growth regulatory substances. In NIH 3T3 fibroblasts, vitamin K3 (50-100 microM) alone had no effect on PLD-catalyzed formation of phosphatidylethanol, a marker of PLD activity, but it slightly (10-21%) inhibited the stimulatory effect of phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC). Of the two major substrates of PLD, phosphatidylcholine (PtdCho) and phosphatidylethanolamine (PtdEtn), vitamin K3 (10-100 microM) preferentially inhibited PtdEtn hydrolysis when stimulated by PMA or platelet-derived growth factor, the latter being a hormonal activator of PKC. Vitamin K3 had no inhibitory effect on sphingosine- or staurosporine-induced hydrolysis of PtdEtn or PtdCho. Inhibition of PMA-induced PtdEtn hydrolysis by vitamin K3 was effectively reduced by both cysteine (1 mM) and reduced glutathione (1 mM) and was mimicked by the superoxide-generating xanthine/xanthine oxidase system. The results show that vitamin K3 preferentially inhibits the effects of PKC activators on PLD-mediated hydrolysis of PtdEtn by a mechanism which may involve oxidation of thiols in a critically important regulatory component.


Choosing the right strategy based on individualized treatment effect predictions: combination versus sequential chemotherapy in patients with metastatic colorectal cancer.
Translating results from randomized trials to individual patients is challenging, since treatment effects may vary due to heterogeneous prognostic characteristics. We aimed to demonstrate model development for individualized treatment effect predictions in cancer patients. We used data from two randomized trials that investigated sequential versus combination chemotherapy in unresectable metastatic colorectal cancer (mCRC) patients. We used data from 803 patients included in CAIRO for prediction model development and internal validation, and data from 1423 patients included in FOCUS for external validation. A Weibull model with pre-specified patient and tumour characteristics was developed for a prediction of gain in median overall survival (OS) by upfront combination versus sequential chemotherapy. Decision curve analysis with net benefit was used. A nomogram was built using logistic regression for estimating the probability of receiving second-line treatment after the first-line monochemotherapy. Median-predicted gain in OS for the combination versus sequential chemotherapy was 2.3 months (IQR: -1.1 to 3.7 months). A predicted gain in favour of sequential chemotherapy was found in 231 patients (29%) and a predicted gain of >3 months for combination chemotherapy in 294 patients (37%). Patients with benefit from sequential chemotherapy had metachronous metastatic disease and a left-sided primary tumour. Decision curve analyses showed improvement in a net benefit for treating all patients according to prediction-based treatment compared to treating all patients with combination chemotherapy. Multiple characteristics were identified as prognostic variables which identify patients at risk of never receiving second-line treatment if treated with initial monochemotherapy. External validation showed good calibration with moderate discrimination in both models (C-index 0.66 and 0.65, respectively). We successfully developed individualized prediction models including prognostic characteristics derived from randomized trials to estimate treatment effects in mCRC patients. In times where the heterogeneity of CRC becomes increasingly evident, such tools are an important step towards personalized treatment.


Utilisation of Traditional Pacific Healers by mothers and children of the Pacific Islands Families Study.
This research explores data on the mother's willingness to use, and children's use of Traditional Pacific Healers (TPH) from the first five waves of the Pacific Islands Families study (PIFS). Specific aims were: to report the prevalence of, and describe factors associated with, (1) the willingness of Pacific mothers to use the health services of Traditional Pacific Healers, (2) the use of Traditional Pacific Healers to treat children within the cohort and (3) to assess whether the use of Traditional Pacific Healers was a substitute or a supplement for western medicine. Mothers were asked whether they would use a Traditional Pacific Healer if sick (willingness) and how often their child had seen a Traditional Pacific healer in the previous 12 months (use). These questions were asked at multiple measurement waves consisting of 6 week, 4 and 6 year for mothers, and 6 weeks, 1, 2, 4, and 6 year measurement waves for children. At 6 weeks 48% of mothers were willing to use TPH and this decreased to 36% at year 4 and 24% at year 6. Pacific born mothers, Samoan and Tongan mothers, and religious mothers were significantly more willing to use a TPH. Varied patterns of use were observed by children based on ethnicity and measurement wave. Like mothers--use by children declined as they aged. At 6 weeks 18% of children saw a TPH whilst 8% saw a TPH at age 6 years. Mothers amenable to using traditional healers are using them as supplemental to western medicine, rather than as a substitute. There is a steady reduction observed in mother's willingness and children's use of TPH in the PIFS over time. This raises the question of the whether provision of TPH is sustainable in NZ. There are significant differences in use of TPH by ethnicity. Further research that assesses reasons for visits, treatments provided, and costs may help explain the observed variations shown in this study.


Analysis of survival of C-18 cells after irradiation in suspension with chelated and ionic bismuth-212 using microdosimetry.
A previous analysis of non-stochastic dose (Jostes et al., Radiat. Res. 127, 211-219, 1991; Schwartz et al., Health Phys. 62, 458-461, 1992) based on data obtained during irradiations of C-18 cells in suspension by alpha particles emitted from two forms (chelated and ionic) of 212Bi was made using survival curves. No appreciable difference in slope (1/D0) was found between the two forms. Such non-stochastic analyses do not account for the large differences in specific energies deposited in the individual cell nuclei. This microdosimetric (stochastic) analysis aims to determine the survival sensitivity (1/z0) of the individual C-18 cells using the distribution of specific energies deposited in the individual cell nuclei. The resulting sensitivity is greater for the alpha particles emitted from the chelated 212Bi than from the ionic 212Bi. An attempt to account for this greater sensitivity in terms of greater LET of alpha particles passing through the cell nuclei from the chelated 212Bi is unsuccessful. Instead the greater sensitivity disappears if the microdosimetric analysis uses average values for the radii of the cell and of its nucleus rather than the values (from the peak in the cell size distribution) used by the non-stochastic dose analysis.


Nocardia Arthritis: 3 Cases and Literature Review.
Nocardia are Gram-positive filamentous bacteria responsible for infections ranging from opportunistic life-threatening disseminated diseases to chronic skin and soft-tissue infections.Even if virtually all organs can be infected, articular involvement is rare. Therefore, we report 3 recent cases and performed a literature review of cases of Nocardia arthritis in order to describe clinical features, therapeutic challenges, and outcome of these patients.Among 34 patients (31 in the literature plus our 3 cases), 21 (62%) were due to hematogenous dissemination, 9 (26%) were due to direct bacterial inoculation through the skin, and in 4 cases, the mechanism of infection was unknown. Four out of these 34 cases occurred on prosthetic joints.Whereas hematogenous infections mostly occurred in immunocompromised hosts (17 of 21, 81%), direct inoculation was mostly seen in immunocompetent patients.Eighty-two percent of patients (28 out of 34) received trimethoprim-sulfamethoxazole-containing regimens and median antibiotic treatment duration was 24 weeks (range, 12-120) for hematogenous infections and 12 weeks (range, 6-24) for direct inoculations. Outcome was favorable in 27 cases despite unsystematic surgical management (17 cases) without sequelae in 70% of the cases.Nocardia arthritis is rare but its management is complex and should rely on a combined approach with rheumatologist, infectious diseases expert, and surgeon.


Fyn regulates the duration of TCR engagement needed for commitment to effector function.
In naive T cells, engagement of the TCR with agonist peptide:MHC molecules leads to phosphorylation of key intracellular signaling intermediates within seconds and this peaks within minutes. However, the cell does not commit to proliferation and IL-2 cytokine production unless receptor contact is sustained for several hours. The biochemical basis for this transition to full activation may underlie how T cells receive survival signals while maintaining tolerance, and is currently not well understood. We show here that for CD8 T cells commitment to proliferation and cytokine production requires sustained activation of the Src family kinase Lck and is opposed by the action of Fyn. Thus, in the absence of Fyn, commitment to activation occurs more rapidly, the cells produce more IL-2, and undergo more rounds of division. Our data demonstrate a role for Fyn in modulating the response to Ag in primary T cells.


The conformation of a large RNA fragment from the E.coli ribosomal 16S-RNA. An X-ray and neutron small-angle scattering study.
A large 12S RNA fragment which constitutes the 5' two-thirds of 16S-RNA from the E. coli 30S subunit has been investigated by small-angle X-ray and neutron scattering. The results indicate that in reconstitution buffer the 12S-RNA fragment has a molecular weight of 270,000 +/- 20,000 and a radius of gyration of 7.1 nm. The scattering data are compatible with the RNA being folded into two major domains with the shapes of two adjacent, quite similar cylinders.


Mercuric chloride poisoning due to ingestion of a stool fixative.
We present a case of ingestion of a commonly used stool fixative containing 675 mg of mercuric chloride per 15 mL vial. Early chelator therapy with dimercaprol and aggressive hydration were initiated and the patient remained asymptomatic. Safety packaging of this product is recommended.


Stapedectomy in residency training.
The number of new patients with otosclerosis seen by the average otolaryngologist has declined over the past several years. As a result, a controversy has arisen regarding the ability to train residents adequately in the technique of stapedectomy. In this regard, we have analyzed 44 consecutive stapedectomies performed by senior residents, under direct faculty supervision, at the University of California, San Francisco. All procedures were total stapedectomies, performed under local anesthesia, utilizing either wire-vein or wire-perichondrium technique. Four of the ears required footplate or promontory drilling. Closure to within 10 dB of the preoperative bone conduction, averaged over the speech frequencies of 500, 1000, and 2000 Hz, was achieved in 75% of ears, and closure to within 20 dB in 93% of ears. In no patient was hearing made worse. While there were no permanent complications, self-limited problems occurred in 9% of the procedures. Despite a declining caseload of otosclerotic ears in residency programs, it is possible to train residents safely in stapes surgery, given a program of consistent technique and close faculty supervision.


Predictive factors and oncological outcomes of pathological T3a upstaging in patients with clinical T1 renal cell carcinoma undergoing partial nephrectomy.
To investigate predictive factors and oncological outcomes of pathological T3a upstaging in renal cell carcinoma patients who were initially diagnosed as clinical T1 and treated with partial nephrectomy. The clinical records and survival data of 1617 patients, who had undergone partial nephrectomy for clinical T1 renal cell carcinoma at Tokyo Women's Medical University, Tokyo, Japan between January 2011 and December 2020, were analyzed retrospectively. Of 1617 clinical T1 renal cell carcinoma patients who underwent partial nephrectomy, 28 (1.73%) had pathological T3a upstaging. In the multivariable analysis for pathological T3a upstaging using logistic regression models, male sex and clinical T1b were significant factors associated with pathological T3a upstaging (male sex: odds ratio = 5.07, 95% confidence interval: 1.18-21.8, clinical T1b: odds ratio = 8.36, 95% confidence interval: 3.56-19.6). The Kaplan-Meier method of the recurrence-free survival showed shorter recurrence-free survival in patients with pathological T3a upstaging than in those with pathological T1 (P < 0.0001). In the multivariable analysis using Cox proportional hazards regression models, pathological T3a upstaging was no longer significantly associated with recurrence-free survival after adjustment for other pathological factors (hazard ratio = 1.59, 95% confidence interval: 0.58-4.36). In a sensitivity analysis that analyzed its components individually instead of whole pathological T3a, neither perinephric fat invasion, sinus fat invasion, nor renal vein invasion was associated with recurrence-free survival. Male sex and clinical T1b were significant predictors for pathological T3a upstaging after partial nephrectomy in clinical T1 renal cell carcinoma patients. Although patients with pathological T3a upstaging had worse recurrence-free survival compared with those without upstaging, multivariable analyses revealed that pathological T3a upstaging was not an independent predictor for poor recurrence-free survival.