Diverse biological functions of vitamin K: from coagulation to ferroptosis.
Vitamin K is essential for several physiological processes, such as blood coagulation, in which it serves as a cofactor for the conversion of peptide-bound glutamate to γ-carboxyglutamate in vitamin K-dependent proteins. This process is driven by the vitamin K cycle facilitated by γ-carboxyglutamyl carboxylase, vitamin K epoxide reductase and ferroptosis suppressor protein-1, the latter of which was recently identified as the long-sought-after warfarin-resistant vitamin K reductase. In addition, vitamin K has carboxylation-independent functions. Akin to ubiquinone, vitamin K acts as an electron carrier for ATP production in some organisms and prevents ferroptosis, a type of cell death hallmarked by lipid peroxidation. In this Perspective, we provide an overview of the diverse functions of vitamin K in physiology and metabolism and, at the same time, offer a perspective on its role in ferroptosis together with ferroptosis suppressor protein-1. A comparison between vitamin K and ubiquinone, from an evolutionary perspective, may offer further insights into the manifold roles of vitamin K in biology.


Cationic covalent organic nanosheets for rapid and effective detection of phenoxy carboxylic acid herbicides residue emitted from water and rice samples.
Development of efficient and sensitive adsorbent for capturing phenoxy carboxylic acids (PCAs) from environmental and food samples is necessary because PCAs could threaten human health. Designing nanoparticle with multiple functional groups is beneficial to achieve the strong adsorption interaction and the specific recognition for target compound. In this paper, TpTGCl as an ionic covalent organic framework (ICOF), that could offer plenty of positive charges and hydrogen-bonding sites, was fabricated. TpTGCl achieved quicker, more sensitive enrichment for anionic PCAs. The analysis of binding affinity by density functional theory (DFT) demonstrated that PCAs bonded to TpTGCl primarily via electrostatic attraction, N H···O and O H···O, and C H···π interaction. The quantitative approach indicated low limits of detection (0.016-0.036 ng·g-1 for rice and 0.43-0.78 ng·L-1 for water). Furthermore, successfully determining PCAs emitted from real samples indicated the applicability of TpTGCl.


Statistical-mechanical theory of passive transport through semipermeable membranes.
The first general multicomponent equations for transport through semipermeable membranes are derived from basic statistical-mechanical principles. The procedure follows that used earlier for open membranes, but semipermeability is modelled mathematically by the introduction of external forces on the impermeant species. Gases are treated first in order to clarify the problems involved, but the final results apply to general nonideal solutions of any concentration. The mixed-solvent effect is treated rigorously, and a mixed-solvent osmotic pressure is defined. A useful specific identification of so-called osmotic flow is given, along with a demonstration that such an identification cannot be unique. Results are obtained both for discontinuous membrane models, and for a continuous model.


Safety assessment of newly marketed herbal medicines--methodological approach (Ginkgo biloba example in Bulgaria).
This study presents a proposal for the methodological approach for postmarketing safety profile assessment based on sales data and information for adverse drug reactions of newly introduced herbal medicinal products in the market. The study covers all herbal medicinal products containing dry extract of Ginkgo biloba leaves allowed for sale in Bulgaria. The methodological approach we create should be used for the establishment of the national herbal drugs policy complying with the recent European regulatory changes and specificity of the therapeutic practice in the country.


High-resolution kinetic characterization of the RIG-I-signaling pathway and the antiviral response.
RIG-I recognizes viral dsRNA and activates a cell-autonomous antiviral response. Upon stimulation, it triggers a signaling cascade leading to the production of type I and III IFNs. IFNs are secreted and signal to elicit the expression of IFN-stimulated genes, establishing an antiviral state of the cell. The topology of this pathway has been studied intensively, however, its exact dynamics are less understood. Here, we employed electroporation to synchronously activate RIG-I, enabling us to characterize cell-intrinsic innate immune signaling at a high temporal resolution. Employing IFNAR1/IFNLR-deficient cells, we could differentiate primary RIG-I signaling from secondary signaling downstream of the IFN receptors. Based on these data, we developed a comprehensive mathematical model capable of simulating signaling downstream of dsRNA recognition by RIG-I and the feedback and signal amplification by IFN. We further investigated the impact of viral antagonists on signaling dynamics. Our work provides a comprehensive insight into the signaling events that occur early upon virus infection and opens new avenues to study and disentangle the complexity of the host-virus interface.


A Novel Phylogenetic Negative Binomial Regression Model for Count-Dependent Variables.
Regression models are extensively used to explore the relationship between a dependent variable and its covariates. These models work well when the dependent variable is categorical and the data are supposedly independent, as is the case with generalized linear models (GLMs). However, trait data from related species do not operate under these conditions due to their shared common ancestry, leading to dependence that can be illustrated through a phylogenetic tree. In response to the analytical challenges of count-dependent variables in phylogenetically related species, we have developed a novel phylogenetic negative binomial regression model that allows for overdispersion, a limitation present in the phylogenetic Poisson regression model in the literature. This model overcomes limitations of conventional GLMs, which overlook the inherent dependence arising from shared lineage. Instead, our proposed model acknowledges this factor and uses the generalized estimating equation (GEE) framework for precise parameter estimation. The effectiveness of the proposed model was corroborated by a rigorous simulation study, which, despite the need for careful convergence monitoring, demonstrated its reasonable efficacy. The empirical application of the model to lizard egg-laying count and mammalian litter size data further highlighted its practical relevance. In particular, our results identified negative correlations between increases in egg mass, litter size, ovulation rate, and gestation length with respective yearly counts, while a positive correlation was observed with species lifespan. This study underscores the importance of our proposed model in providing nuanced and accurate analyses of count-dependent variables in related species, highlighting the often overlooked impact of shared ancestry. The model represents a critical advance in research methodologies, opening new avenues for interpretation of related species data in the field.


Prospective study of a panfungal PCR assay followed by sequencing, for the detection of fungal DNA in normally sterile specimens in a clinical setting: a complementary tool in the diagnosis of invasive fungal disease?
We prospectively analyzed 34 clinical biopsy samples from 23 patients with a suspected invasive fungal infection by fungal culture, histology and a panfungal PCR followed by sequencing. Results were compared to the composite diagnosis according the European Organization for Research and Treatment of Cancer (EORTC) criteria. In 34 samples, culture, histology and panfungal PCR were positive in 35%, 38% and 62%, respectively. On the sample level the panfungal PCR revealed a sensitivity of 69% and a specificity of 62.5% compared to proven IFI according postoperative EORTC criteria. On patient level, the sensitivity of the PCR approach was 100%, specificity 62.5%.


Splenic abscess.
Abscess of the spleen is a rare entity. It may develop after generalized infection, hematologic disorders and trauma. The authors report the case of a 7-year-old boy who presented with a 2-month history of spiking fever, anorexia, fatigue and weight loss. He had left subcostal tenderness and a palpable spleen. He had a history of trauma to the left flank 5 months before admission but a splenic scan obtained at that time appeared normal. A splenic abscess was diagnosed by gallium scanning, computerized tomography and ultrasonography. Although splenectomy has been advocated as the treatment of choice for splenic abscess, this patient was treated successfully with appropriate antibiotics and simple drainage, preserving the spleen. Cultures grew Staphylococcus aureus. Of all the diagnostic methods available, ultrasonography is the least invasive study that will make the diagnosis and is less expensive than some methods.


Cilomilast, tacrolimus and rapamycin modulate dendritic cell function in the elicitation phase of allergic contact dermatitis.
Cilomilast and tacrolimus as well as rapamycin are potential drugs for the treatment of allergic skin diseases like atopic dermatitis and allergic contact dermatitis. To compare the in vitro and in vivo immunomodulatory effects of the phosphodiesterase 4 inhibitor cilomilast with those of tacrolimus and rapamycin. The in vitro action of cilomilast, tacrolimus and rapamycin were tested in a mixed leucocyte reaction (MLR). In vivo, the inhibitory action of the immunomodulatory drugs was compared in the toluene-2,4-diisocyanate (TDI)-induced allergic inflammatory response with particular focus on dendritic cell (DC) function. Cilomilast, tacrolimus and rapamycin were all able to inhibit DC-mediated T-cell activation in a MLR. But it was demonstrated for cilomilast that the target cells are T cells rather than DC. In vivo, a combination of systemic and topical administration of each of these three substances significantly inhibited swelling in the murine ear 16 h after TDI challenge. There was also a reduction in the weight of the draining auricular lymph node, in lymphocyte cell count, and in the number of emigrated DC. The density of Langerhans cells in the epidermis was correspondingly higher in mice treated with cilomilast, tacrolimus and rapamycin than in those treated with vehicle. All three substances were found to inhibit DC migration ex vivo in a skin DC migration assay performed on ear tissue after TDI challenge. DC migration into the draining lymph node also takes place in the elicitation phase of allergic contact dermatitis and this migration can be influenced by tacrolimus and rapamycin, and, to a lesser extent, by cilomilast.


Determination of fuel ethers in water by membrane extraction ion mobility spectrometry.
Fuel oxygenates are environmentally detrimental compounds due to their rapid migration to groundwater. Fuel oxygenates have been reported to cause taste and odour problems in drinking water, and they also have long-term health effects. Feasible analytical methods are required to observe the presence of fuel oxygenates in drinking and natural water. The authors studied ion mobility spectrometry (IMS) to determinate isomeric fuel ether oxygenates; ethyl tert-butyl ether (ETBE), diisopropyl ether (DIPE), and tert-amyl methyl ether (TAME), separated from aqueous matrices with a pervaporation membrane module. Methyl tert-butyl ether (MTBE) was also membrane extracted and detected with IMS. The authors demonstrated that fuel ethers (MTBE, ETBE, DIPE, and TAME) can be quantified at μg/L level with membrane extraction IMS. A membrane extraction module coupled to IMS is a time and cost effective analysis method because sampling can be performed in a single procedure and from different natural water matrices within a few minutes. Consequently, IMS combined with membrane extraction is suitable not only for waterworks and other online applications but also in the field monitoring the quality of drinking and natural water.


Reversion of human prostate tumorigenic growth by azatyrosine.
Azatyrosine, an antibiotic isolated from a Streptomyces species, has been previously shown to have antitumor activity against ras- and neu-transformed fibroblasts and human epithelial cells. In this study, we investigated the effect of azatyrosine on human prostate cancer cell growth and the reversion potential of this antibiotic on prostate tumorigenic cell lines. Three androgen-independent human prostate cancer cell lines (TSU-Prl, DU-145, and PC-3) were cultured in the presence of azatyrosine and their growth rates were determined over a 7-day period. Following exhaustive treatment with azatyrosine for 5 weeks, three azatyrosine-resistant colonies were cloned from the PC-3 cell line and were subsequently established as stable cell lines. The growth characteristics of these azatyrosine-resistant clones were examined both in vitro and in vivo to establish their "potentially revertant" profiles. Incubation with azatyrosine (for 7 days) resulted in greater than 95% in vitro growth inhibition of the three parental prostate cancer cell lines. Analysis of the biologic properties of these azatyrosine-resistant cell lines revealed: (1) a significant reduction in in vitro growth rates; (2) a decreased rate of DNA synthesis as measured by thymidine uptake; and (3) a decreased ability for colony formation in soft agar. Moreover all three azatyrosine-resistant clones exhibited suppressed tumorigenicity in severe combined immunodeficient (SCID) mice when compared with the parental cell line. An important observation was that one revertant clone demonstrated complete loss of tumorigenicity. On the basis of this biologic behavior, these cell lines were characterized as revertants. Cytogenetic analysis revealed gross chromosomal differences between the revertant clones and the parental cell line. Northern hybridization analysis demonstrated elevated expression of the K-rev-1 and bcl-2 but not the rrg mRNA transcripts in the revertant cell lines. These results suggest that azatyrosine inhibits prostate tumorigenic growth; it has a high reversion efficiency on human prostate cancer cells; and the K-rev-1 suppressor gene and the bcl-2 proto-oncogene could be potentially involved in the reversion mechanism mediated by azatyrosine. This reversion of prostate cancer cells to an apparently nontumorigenic phenotype points to a potentially significant therapeutic role for azatyrosine in the treatment of advanced prostate cancer.


Kaposi's sarcoma-associated herpesvirus load in asymptomatic contacts of Cuban epidemic KS patients.
To evaluate the pathogenic mechanisms and transmission routes involved in KSHV infection in 22 Cuban individuals who maintained close contact with epidemic KS patients, real-time PCR was used to quantify KSHV-DNA in clinical samples of plasma, saliva and peripheral blood mononuclear cells (PBMC). KSHV-DNA was detected in 72.7% (16/22) of the contacts. The highest levels of KSHV load were detected in saliva, followed by PBMC (average log copies/100 ng DNA = 1.28 and 1.12), while significantly lower levels were detected in plasma (average log copies/ml = 0.37). Two of three intra-domiciliary and two serodiscordant sexual contacts of AIDS-KS patients were infected with KSHV. The rate of KSHV-DNA detection in saliva and PBMC samples in men who have sex with men (MSM) was significantly higher than in heterosexuals (HT) (p = 0.014). MSM were more likely to harbor KSHV-DNA in saliva when compared with HT individuals (OR 4.33; 95% CI 1.117-16.8). These results emphasize that, in Cuba, KSHV horizontal transmission through saliva may occur, although homosexual behavior may predispose an individual to KSHV acquisition. Even in the absence of disease, KSHV could cause an asymptomatic systemic infection in individuals who maintain close contact with AIDS-KS patients.


Current perspectives on diffuse midline glioma and a different role for the immune microenvironment compared to glioblastoma.
Diffuse midline glioma (DMG), formerly called diffuse intrinsic pontine glioma (DIPG), is a high-grade malignant pediatric brain tumor with a near-zero survival rate. To date, only radiation therapy provides marginal survival benefit; however, the median survival time remains less than a year. Historically, the infiltrative nature and sensitive location of the tumor rendered surgical removal and biopsies difficult and subsequently resulted in limited knowledge of the disease, as only post-mortem tissue was available. Therefore, clinical decision-making was based upon experience with the more frequent and histologically similar adult glioblastoma (GBM). Recent advances in tissue acquisition and molecular profiling revealed that DMG and GBM are distinct disease entities, with separate tissue characteristics and genetic profiles. DMG is characterized by heterogeneous tumor tissue often paired with an intact blood-brain barrier, possibly explaining its resistance to chemotherapy. Additional profiling shed a light on the origin of the disease and the influence of several mutations such as a highly recurring K27M mutation in histone H3 on its tumorigenesis. Furthermore, early evidence suggests that DMG has a unique immune microenvironment, characterized by low levels of immune cell infiltration, inflammation, and immunosuppression that may impact disease development and outcome. Within the tumor microenvironment of GBM, tumor-associated microglia/macrophages (TAMs) play a large role in tumor development. Interestingly, TAMs in DMG display distinct features and have low immune activation in comparison to other pediatric gliomas. Although TAMs have been investigated substantially in GBM over the last years, this has not been the case for DMG due to the lack of tissue for research. Bit by bit, studies are exploring the TAM-glioma crosstalk to identify what factors within the DMG microenvironment play a role in the recruitment and polarization of TAMs. Although more research into the immune microenvironment is warranted, there is evidence that targeting or stimulating TAMs and their factors provide a potential treatment option for DMG. In this review, we provide insight into the current status of DMG research, assess the knowledge of the immune microenvironment in DMG and GBM, and present recent findings and therapeutic opportunities surrounding the TAM-glioma crosstalk.


Longitudinal effects of lipid indices on incident cardiovascular diseases adjusting for time-varying confounding using marginal structural models: 25 years follow-up of two US cohort studies.
This study assesses the effect of blood lipid indices and lipid ratios on cardiovascular diseases (CVDs) using inverse probability-of-exposure weighted estimation of marginal structural models (MSMs). A pooled dataset of two US representative cohort studies, including 16736 participants aged 42-84 years with complete information at baseline, was used. The effect of each lipid index, including low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), ratios of TC/HDL-C, LDL-C/HDL-C, and TG/HDL-C on coronary heart disease (CHD) and stroke were estimated using weighted Cox regression. There were 1638 cases of CHD and 1017 cases of stroke during a median follow-up of 17.1 years (interquartile range: 8.5 to 25.7). Compared to optimal levels, the risk of CVD outcomes increased substantially in high levels of TC, LDL-C, TC/HDL-C, and LDL-C/HDL-C. If everyone had always had high levels of TC (≥240 mg/dL), risk of CHD would have been 2.15 times higher, and risk of stroke 1.35 times higher than if they had always had optimal levels (<200 mg/dL). Moreover, if all participants had been kept at very high (≥190 mg/dL) levels of LDL-C, risk of CHD would have been 2.62 times higher and risk of stroke would have been 1.92 times higher than if all participants had been kept at optimal levels, respectively. Our results suggest that high levels of HDL-C may be protective for CHD, but not for stroke. There was also no evidence of an adverse effect of high triglyceride levels on stroke. Using MSM, this study highlights the effect of TC and LDL-C on CVD, with a stronger effect on CHD than on stroke. There was no evidence for a protective effect of high levels of HDL-C on stroke. Besides, triglyceride was not found to affect stroke.


Genomic characterization and antimicrobial resistance profiles of Salmonella enterica serovar Infantis isolated from food, humans and veterinary-related sources in Brazil.
To characterize the genetic relatedness, phenotypic and genotypic antimicrobial resistance and plasmid content of 80 Salmonella Infantis strains isolated from food, humans and veterinary sources from 2013 to 2018 in Brazil. Pulsed-field gel electrophoresis and single-nucleotide polymorphism analysis showed major clusters containing 50% and 38.8% of the strains studied respectively. Multilocus sequence typing assigned all strains to ST32. Disk-diffusion revealed that 90% of the strains presented resistant or intermediate resistant profiles and 38.8% displayed multidrug resistance. Resistance genes for aminoglycosides (aac(6')-Iaa; aadA12; aph(3″-Ib; aph(6)-Id), β-lactams (blaTEM-1 ; blaCTX-M-8 ; blaCMY-2 ), trimethoprim (dfrA8), tetracycline (tet(A)), amphenicols (floR), sulfonamide (sul2), efflux pumps (mdsA; mdsB), chromosomal point mutations in gyrB, parC, acrB and pmrA were detected. Strains harboured IncI, IncF, IncX, IncQ, IncN and IncR plasmids. The presence of a prevalent S. Infantis subtype in Brazil and the high antimicrobial resistance rates reinforced the potential hazard of this serovar for the public health and food safety fields. This is the first study characterizing a large set of S. Infantis from Brazil by whole-genome sequencing, which provided a better local and global comprehension about the distribution and characteristics of this serovar of importance in the food, human and veterinary fields.


The effects of timing of prophylaxis, type of anesthesia, and use of mechanical methods on outcome in major orthopedic surgery - subgroup analyses from 17,701 patients in the XAMOS study.
Real-world data on the use of rivaroxaban in the perioperative period in patients undergoing major orthopedic surgery are limited. Subsets of data from the Phase IV, non-interventional XAMOS study were analyzed to explore the potential influence of timing of the first thrombo prophylactic dose, type of anesthesia, and concomitant mechanical prophylaxis on clinical outcomes in patients undergoing major orthopedic surgery in routine clinical practice. In XAMOS, 8,778 patients received rivaroxaban (10 mg once daily) and 8,635 received standard-of-care (SOC) pharmacological prophylaxis (safety population). Crude incidences of symptomatic thromboembolic and treatment-emergent bleeding events were analyzed according to timing of the first postoperative thromboprophylactic dose, use of general or neuraxial anesthesia, and use of mechanical prophylaxis with pharmacological thromboprophylaxis. In the rivaroxaban group, the incidences of symptomatic thromboembolic events were 0.7%, 1.0%, and 0.7% in patients receiving the first thromboprophylactic dose at ≤6 hours, >6 hours to ≤10 hours, and >10 hours to ≤24 hours after surgery, respectively. In the SOC group, the incidence of symptomatic thromboembolic events was slightly higher when the postoperative dose was given at >10 hours to ≤24 hours (1.8% vs 1.1% at ≤6 hours and 1.3% at >6 hours to ≤10 hours). The antithrombotic effect of rivaroxaban was maintained in comparison to the SOC group. The incidence of major bleeding (RECORD trial definition) was low and similar between the two treatment groups and was not influenced by timing of the first thromboprophylactic dose. Neuraxial anesthesia was used more than any other form of anesthesia for both hip and knee surgery; the effectiveness of rivaroxaban was not influenced by the type of anesthesia used. No spinal hematomas were reported in patients receiving neuraxial anesthesia in either treatment group. Use of mechanical thromboprophylaxis in addition to rivaroxaban or SOC pharmacological prophylaxis did not reduce the risk of thromboembolic events further. The effectiveness and safety of rivaroxaban in patients undergoing major orthopedic surgery in routine clinical practice were maintained irrespective of timing of the first postoperative dose within 24 hours after surgery, the type of anesthesia, and the additional use of mechanical thromboprophylaxis.


Preclinical ocular changes in systemic lupus erythematosus patients by optical coherence tomography.
The aim of the present study was to detect preclinical changes in SLE patients in retinal microvascularization or retinal and optical nerve structure by optical coherence tomography. This cross-sectional, single-centre study aimed to describe structural changes [macular and retinal nerve fibre layer (RNFL) thickness] by structural spectral-domain optical coherence tomography (SD-OCT) and perifoveal vascular [vessel density (VD) and vascular perfusion (VP) and foveal avascular zone (FAZ) structural parameters] findings by OCT angiography (OCTA) in 78 SLE patients and 80 healthy volunteers. In addition, we analysed their association with clinical and laboratory parameters, medications received, disease duration, and SLE activity and damage. Structural parameters by SD-OCT and perifoveal vascular parameters by OCTA were decreased in SLE patients compared with controls. OCTA parameters (VD, VP and FAZ circularity) and macular thickness were also decreased in patients with longer disease duration (>10 years). The presence of aPLs was associated with a decreased RNFL thickness, mainly in the inferior quadrants. Patients developing APS also showed decreased RNFL thickness and OCTA flow changes. SD-OCT and OCTA results were not associated with disease activity. Foveal structural parameters were lower in patients with higher damage score. SD-OCT and OCTA can detect preclinical structural and microcirculatory changes in SLE patients. Structural and perifoveal vascular macular changes in SLE patients are related to disease duration. Macular structural parameters were impaired in patients with higher disease damage. APS seems to be associated with preclinical damage to the optic nerve and impairment of the perifoveal microvasculature.


Effect of deep-fat frying on ascorbic acid, carotenoids and potassium contents of plantain cylinders.
The influence of thermal treatment (frying of plantain) on the micronutrients ascorbic acid, potassium and carotenoids is evaluated. Cylinders (diameter 30 mm, thickness 10 mm) of plantain (Musa AAB 'barraganete') were fried at four thermal treatments (120-180 degrees C and from 24 to 4 min) to obtain products with approximately the same water content (approximately 0.8+/-0.02 kg/kg1) and fat content (approximately 0.15+/-0.06 kg/kg). The thermal study used the cook value and the mean cook value as indicators of the effect of several different treatment temperatures and times on quality. Deep-fat frying had no significant effect on carotenoid contents at any frying conditions, and on potassium content, except at 120 degrees C and 24 min (loss <or= 11%). There was a significant, but not complete, loss (<or=45%) of ascorbic acid. The process with the greatest effect was low temperature and long time (120 degrees C/24 min), as observed for potassium and ascorbic acid. These results are in agreement with other studies that demonstrated short thermal treatments at high temperatures protect food nutritional quality, as shown by the cook value and the mean cook value. In our work, deep-fat frying of plantain preserved most of the micronutrient contents that were evaluated.


Tuning anion binding properties of Bis(indolyl)methane Receptors: Effect of substitutions on optical responses.
Chromogenic probes based onoxidizedbis(indolyl)methanes have been synthesized with varying substituents (R = -Me [1], -OMe [2], -OH, [3]) on the central aryl ring. In addition to electronic influence, the involvement of substituents in ion-dipole and charge-assisted hydrogen bonding interactions significantly alters the solvatochromic response and pH-sensitive behavior. In polar aprotic solvents, like CH3CN, a concentration-dependent stepwise color change was observed with F- ions. In the case of2, a reversible hydrogen bonding interaction between the deprotonated probe and HF2- dimer might be responsible for that, while step-wise deprotonation caused by F- ions could be the probable reason with3. Since the formation of HF2- is energetically unfavorable in a polar protic solvent, the response of 2 with F- ions appears to be very different in EtOH medium. Interestingly, no such alteration in anion sensing behavior was noticed with3going from an aprotic to a protic solvent.


[Electrochemical etching of alloys as a method for extension of the surfaces of the fixing elements of the AET constructions].
Electrochemical etching of metal alloys is one of the method for obtaining of micromechanical retention on the surface of the fixing elements of AET constructions. On the basis of literature survey and own experiences the author describes the nature of the electrolytic etching of metal alloys for obtaining of retention surface. The effect is described also of etching on the binding force of various metal alloys and resin cements.


Functional analogs of bleomycin: sequence-specific DNA cleavage with porphyrin (Fe) intercalators.
Synthetic porphyrin (Fe) intercalators cleave DNA at guanine-cytosine and guanine-thymine sequences. The specificity for cleavage of base sequences of DNA is quite similar to that of bleomycin.


Low and dysregulated BDNF secretion from immune cells of MS patients is related to reduced neuroprotection.
Multiple sclerosis (MS) is characterized by lesions with inflammatory infiltration, demyelination and axonal damage in the CNS white matter that correlates with the extent of disease disability. Knowledge of up-regulatory triggers of neuroprotective pathways in the CNS is essential for the development of the next generation of disease therapies. Recent studies have suggested a neuroprotective activity of the lesion-infiltrating immune cells. We studied the secretion of brain-derived neurotrophic factor (BDNF) from the immune cells of untreated patients with relapsing remitting (RR) MS with mild to moderate disability and sought immune factors that regulate the BDNF levels and affect the survival of neuronal cells in vitro. We found lower than normal secreted levels of BDNF from the immune cells of these patients. The normal effect of CD40 stimulation that up-regulates BDNF secretion levels and induces neuroprotection was absent in the MS patients, while the expression of CD40 on their monocytes was elevated. The failure of BDNF availability from immune cells in patients with RR-MS and the loss of a neuroprotective effect by these cells may be related to a more widespread phenomenon of deviated immunity in MS, and may be linked to the continuous CNS neuronal tissue loss during the course of this disease.


Characterization of capacitive electromyography biomedical sensor insulated with porous medical bandages.
A capacitive electromyography (cEMG) biomedical sensor measures the EMG signal from human body through capacitive coupling methodology. It has the flexibility to be insulated by different types of materials. Each type of insulator will yield a unique skin-electrode capacitance which determine the performance of a cEMG biomedical sensor. Most of the insulator being explored are solid and non-breathable which cause perspiration in a long-term EMG measurement process. This research aims to explore the porous medical bandages such as micropore, gauze, and crepe bandage to be used as an insulator of a cEMG biomedical sensor. These materials are breathable and hypoallergenic. Their unique properties and characteristics have been reviewed respectively. A 50 Hz digital notch filter was developed and implemented in the EMG measurement system design to further enhance the performance of these porous medical bandage insulated cEMG biomedical sensors. A series of experimental verifications such as noise floor characterization, EMG signals measurement, and performance correlation were done on all these sensors. The micropore insulated cEMG biomedical sensor yielded the lowest noise floor amplitude of 2.44 mV and achieved the highest correlation coefficient result in comparison with the EMG signals captured by the conventional wet contact electrode.


Prenatal exposure to ethanol stimulates hypothalamic CCR2 chemokine receptor system: Possible relation to increased density of orexigenic peptide neurons and ethanol drinking in adolescent offspring.
Clinical and animal studies indicate that maternal consumption of ethanol during pregnancy increases alcohol drinking in the offspring. Possible underlying mechanisms may involve orexigenic peptides, which are stimulated by prenatal ethanol exposure and themselves promote drinking. Building on evidence that ethanol stimulates neuroimmune factors such as the chemokine CCL2 that in adult rats is shown to colocalize with the orexigenic peptide, melanin-concentrating hormone (MCH) in the lateral hypothalamus (LH), the present study sought to investigate the possibility that CCL2 or its receptor CCR2 in LH is stimulated by prenatal ethanol exposure, perhaps specifically within MCH neurons. Our paradigm of intraoral administration of ethanol to pregnant rats, at low-to-moderate doses (1 or 3g/kg/day) during peak hypothalamic neurogenesis, caused in adolescent male offspring twofold increase in drinking of and preference for ethanol and reinstatement of ethanol drinking in a two-bottle choice paradigm under an intermittent access schedule. This effect of prenatal ethanol exposure was associated with an increased expression of MCH and density of MCH(+) neurons in LH of preadolescent offspring. Whereas CCL2(+) cells at this age were low in density and unaffected by ethanol, CCR2(+) cells were dense in LH and increased by prenatal ethanol, with a large percentage (83-87%) identified as neurons and found to colocalize MCH. Prenatal ethanol also stimulated the genesis of CCR2(+) and MCH(+) neurons in the embryo, which co-labeled the proliferation marker, BrdU. Ethanol also increased the genesis and density of neurons that co-expressed CCR2 and MCH in LH, with triple-labeled CCR2(+)/MCH(+)/BrdU(+) neurons that were absent in control rats accounting for 35% of newly generated neurons in ethanol-exposed rats. With both the chemokine and MCH systems believed to promote ethanol consumption, this greater density of CCR2(+)/MCH(+) neurons in the LH of preadolescent rats suggests that these systems function together in promoting alcohol drinking during adolescence.


Induced magnetic field gradients and forces in the human head in MRI.
To map the induced magnetic field gradients and estimate the magnetic force in the human head during magnetic resonance imaging at 4 Tesla (T). The magnetic field distribution in the human head was measured using two gradient-echo experiments with different echo times. The phase of the complex image ratio removed the wrapping artifact, characteristic of phase images, and was used to map the magnetic field distribution and calculate the accurate maps of the magnetic field gradients in the human head. The time-independent gradient fields induced by air/tissue interfaces in the head can be 50 times larger than those resulting from the magnetic field inhomogeneity of the MRI magnet. However, the associated magnetic force in the brain is by far smaller than the gravitational force. The induced gradient fields increase the magnetic force on tissues. However, even for tissue components with large magnetic susceptibility such as iron-containing proteins, this force is negligible compared with the gravitational force. Therefore, this study suggests that static and uniform magnetic fields do not have a significant risk for the tissues in the head.


Perched Anteromedial Radial Head Dislocation.
Perched anteromedial radial head dislocation is a rare injury pattern that is yet to be reported in the literature. This article describes a case report of an isolated radial head dislocation that was perched on the coronoid process. The images in this study show this rare injury pattern, which did not include a fracture of the coronoid or true elbow dislocation. The patient was successfully treated with a closed reduction. The patient regained full ROM and function. Previously described literature has failed to report this injury pattern or successful closed treatment. The success of this case demonstrates the difficulty of closed reductions even under proper anesthesia and the importance of performing them in the setting where the surgeon has the option to convert to open reduction in unsuccessful cases.


The multiple effects of fecal microbiota transplantation on diarrhea-predominant irritable bowel syndrome (IBS-D) patients with anxiety and depression behaviors.
Anxiety and depression are complications in Irritable bowel syndrome (IBS) patients. In this study, we recruited 18 IBS patients with mild-modest anxiety and depression behaviors, and after the screening, we defined the FMT treatment group (n = 9) and the control group (n = 9). The IBS symptom severity scale (IBS-SSS), Hamilton Anxiety Rating Scale (HAM-A), Hamilton Depression Rating Scale (HAM-D), Irritable Bowel Syndrome Quality of Life (IBS-QOL) and Bristol stool scale (BSS) were evaluated one week before FMT (baseline), one-week-, one-month-, two-month-, and three-month-following FMT. Meanwhile, we determined the SCFAs in the patient's feces and serum and continued the metagenomic analysis of the microorganisms in the patient's feces. The results showed that the patient's anxiety and depression behavior gradually improved with FMT treatment. Moreover, the illness and quality of life had also been relieved significantly. The content of isovaleric acid and valeric acid was significantly reduced in the FMT group compared to the Col group. Metagenomic analysis showed that FMT treatment decreased the abundance of Faecalibacterium, Eubacterium and Escherichia. From KEGG functional analysis, we confirmed that the top five abundant pathways were "bacterial chemotaxis, "flagellar assembly", "glycine, serine and threonine metabolism", "apoptosis", and "bacterial invasion of epithelial cells". FMT treatment can effectively alleviate the anxiety and depression behaviors of IBS-D patients and reduce the IBS-SSS score, indicating that FMT can improve patients' symptoms. The high throughput sequencing results show that Bifidobacterium and Escherichia play the most critical role in the formation and recovery of IBS-D patients. The GC/MS data indicated that faeces isovaleric acid and valeric acid might be more suitable as a metabolic indicator of IBS-D remission. Trial registration ChiCTR, ChiCTR1900024924, Registered 3 August 2019, https://www.chictr.org.cn/showproj.aspx?proj=41676 .


Changes of MRI in inter-spinal distraction fusion for lumbar degenerative disease: A retrospective analysis covering 3 years.
To assess the preoperative and postoperative changes in MRI image and the short-term efficacy of the ISDF with BacFuse covering 3 years. 32 patients who underwent ISDF were involved in this retrospective study. The symptoms assessment including VAS, ODI, and SF-12 were evaluated preoperative and postoperative at 1 year and 3 years. The X-ray was used to measure posterior disk height (PDH), foramina height (FH), foramina width (FW), and MRI was taken to assess the cross-sectional area of dura sac (CSADS), cross-sectional area of canal (CSAC), herniated disc area, ligamentum flavum area. The preoperative ratio of herniated disc area and ligamentum flavum area to CSAC were compared with post-operative ratio. The modified Pfirrmann grade system was used to assess the surgical lumbar disc. The symptom indexes were significantly improved after surgery. PDH and FH increased significantly (P < 0.05) after surgery compared with that before surgery, but there was no statistical difference in FW (P > 0.05). CSADS and CSAC increased obviously (P < 0.05), while the area of herniated disc and ligamentum flavum decreased significantly (P < 0.05). The ratio changes showed a significant difference between last follow-up and pre-operation (P < 0.05), but there was no statistical significance in grade changes of surgical disc. ISDF with BacFuse could relieve clinical symptoms and expanse the spinal canal area in MRI. During 3-year observation, it could provide continuous traction and maintain the area of spinal canal, so as to partially retract the herniated disc and make it possible to repair the disc.


Children's Environmental Health: Beyond National Boundaries.
Children are especially vulnerable to environmental pollution, a major cause of disease, death, and disability in countries at every level of development. This article reviews threats to children, including air and water pollution, toxic industrial chemicals, pesticides, heavy metals, and hazardous wastes. Global climate change is expected to exacerbate many of these issues. Examples of innovative nongovernmental organizations and governmental programs that address the impacts of environmental hazards on children are included. International travel, adoption, migration, and movement of goods and pollutants worldwide make these conditions concerns for all pediatricians.


Maternal early-pregnancy ferritin and offspring neurodevelopment: A prospective cohort study from gestation to school age.
Iron plays a role in many key processes in the developing brain. During pregnancy, iron supplementation is widely recommended to prevent and treat iron deficiency; however, the prevalence of iron deficiency and the risk of iron overload vary greatly between populations. Evidence on the role of high levels of maternal ferritin, a storage iron marker during pregnancy in relation to offspring neurodevelopment is lacking. Our main objective was to examine if maternal ferritin levels during pregnancy are associated with child cognitive and motor abilities. We included Dutch mother-child dyads from the prospective population-based Generation R Study, born in 2002-2006. We compared children whose mothers had high (standard deviation score >+1) or low (standard deviation score <-1) early-pregnancy ferritin to children whose mothers had intermediate ferritin (reference group) using linear regression. Children underwent non-verbal intelligence and language tests at 4-9 years (cognitive abilities), finger-tapping and balancing tests at 8-12 years (motor abilities), and structural magnetic resonance imaging at 8-12 years (brain morphology). Covariates were child age, sex, maternal intelligence quotient estimate, age, body-mass-index, education, parity, smoking and alcohol use. Of the 2479 mother-child dyads with data on maternal ferritin and at least one child neurodevelopmental outcome, 387 mothers had low (mean = 20.6 µg/L), 1700 intermediate (mean = 64.6 µg/L) and 392 high (mean = 170.3 µg/L) early-pregnancy ferritin. High maternal ferritin was associated with 2.54 points (95% confidence interval -4.16, -0.92) lower child intelligence quotient and 16.02 cm3 (95% confidence interval -30.57, -1.48) smaller brain volume. Results remained similar after excluding mothers with high C-reactive protein. Low maternal ferritin was not associated with child cognitive abilities. Maternal ferritin was unrelated to child motor outcomes. High maternal ferritin during pregnancy was associated with poorer child cognitive abilities and smaller brain volume. Maternal iron status during pregnancy may be associated with offspring neurodevelopment.


Using proteomic analysis to investigate uniconazole-induced phytohormone variation and starch accumulation in duckweed (Landoltia punctata).
Duckweed (Landoltia punctata) has the potential to remediate wastewater and accumulate enormous amounts of starch for bioethanol production. Using systematical screening, we determined that the highest biomass and starch percentage of duckweed was obtained after uniconazole application. Uniconazole contributes to starch accumulation of duckweed, but the molecular mechanism is still unclear. To elucidate the mechanisms of high starch accumulation, in the study, the responses of L. punctata to uniconazole were investigated using a quantitative proteomic approach combined with physiological and biochemical analysis. A total of 3327 proteins were identified. Among these identified proteins, a large number of enzymes involved in endogenous hormone synthetic and starch metabolic pathways were affected. Notably, most of the enzymes involved in abscisic acid (ABA) biosynthesis showed up-regulated expression, which was consistent with the content variation. The increased endogenous ABA may up-regulate expression of ADP-glucose pyrophosphorylase to promote starch biosynthesis. Importantly, the expression levels of several key enzymes in the starch biosynthetic pathway were up-regulated, which supported the enzymatic assay results and may explain why there is increased starch accumulation. These generated data linked uniconazole with changes in expression of enzymes involved in hormone biosynthesis and starch metabolic pathways and elucidated the effect of hormones on starch accumulation. Thus, this study not only provided insights into the molecular mechanisms of uniconazole-induced hormone variation and starch accumulation but also highlighted the potential for duckweed to be feedstock for biofuel as well as for sewage treatment.


Thermodynamic studies of the interaction of alpha-chymotrypsin with water. I. Determination of the isosteric enthalpies and entropies of water binding to the native enzyme.
The enthalpies (deltaH) and entropies (deltaS) of the interaction of water with alpha-chymotrypsin were evaluated from multitemperature sorption isotherms in the temperature range 283--313 K, determined in a fully automatized, computer controlled sorption apparatus. The temperature dependence of deltaH and deltaS shows a marked anomaly in the temperature range 295--298 K. The experimental results are interpreted by a phase transition of the enzyme protein, and by the existence of a low- and high-temperature conformer of alpha-chymotrypsin below and above the transition region. The two conformers differ significantly in their water binding energetics, as proved by two F-tests based on analyses of variance. The deltaH and deltaS versus water content functions of the high and low temperature conformer show markedly different anomalies at and below 70 mol H2O per mol protein. This water content corresponds closely to the monolayer volume vm, (as defined by Brunauer, Emmett and Teller). The protein surface covered by one water-monolayer, agrees well with the polar and charged surface area of chymotrypsin, computed from X-ray data. The experimental results suggest that the interaction of the first water-monolayer with the protein surface induces major conformational changes. The energetic contributions of these structural changes dominate the deltaH and deltaS terms below vm, giving rise to the anomalies observed. Above this water content, their influence is drastically reduced, and the isosteric quantities are predominantly determined by the water binding process per se. This process is possibly related to the pronounced enthalphy-entropy compensation pattern exhibited by the deltaH and deltaS terms. A more detailed analysis and discussion of this compensation effect will be given.


Ileal biopsy: Clinical indications, endoscopic and histopathologic findings in 10,000 patients.
Ileal biopsies are often reported as having a low yield. Data from endoscopy practices in the private setting are lacking. To correlate the frequency of histologic abnormalities in ileal biopsies with clinical indications and ileoscopic appearances. Retrospective analysis of clinical, endoscopic, and histopathologic data from a large database. We studied 9785 unique adult patients (median age 46 years, 61.4% women) with ileal biopsies. The most common symptoms were diarrhoea (52.2%) and abdominal pain (37.1%). Ileoscopy was reported as being normal in 75.1% patients. Subjects screened for cancer had the highest prevalence of abnormal endoscopic findings (63.3%); patients with known or suspected Crohn's had the highest prevalence abnormal ileal histology (36.4%). Overall, 5.0% of ileal biopsies obtained from patients with normal endoscopy and 47.4% of biopsies from patients with an endoscopically abnormal ileum had significant histopathologic findings. In adults, biopsies from the endoscopically normal ileum rarely provide clinically relevant information and cannot be recommended. In contrast, half of the adult patients with an endoscopically abnormal ileum have significant histopathologic findings in ileal biopsies. Therefore, ileoscopy associated with a sensible use of the ileal biopsy is a valuable complement to the colonoscopy.


Impact of neutrophil-to-lymphocyte ratio on periprocedural myocardial infarction in patients undergoing non-urgent percutaneous coronary revascularisation.
Pro-thrombotic conditions importantly influence myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). The neutrophil-to-lymphocyte ratio (NLR) has emerged as a predictor of cardiovascular events and of long-term prognosis, especially in ST-elevation myocardial infarction patients undergoing primary PCI. The aim of our study was to evaluate the role of NLR on periprocedural myocardial infarction (MI) in patients undergoing non-urgent PCI. In a consecutive cohort of 1542 patients undergoing PCI, myonecrosis biomarkers were determined at 6, 12, 24 and 48 hours post-procedure. Patients were divided into quintiles according to NLR values. Periprocedural myonecrosis was defined as a troponin I increase of 3 times the upper limit of normal or as 50 % of an elevated baseline value, whereas periprocedural MI was defined as a CK-MB increase of 3 times the upper limit of normal or 50 % of baseline. Higher NLR was related to age, established risk factors and cardiovascular history. NLR was associated with severe coronary artery disease (p = 0.009), tighter stenosis (p < 0.001), coronary calcifications (p = 0.005), intracoronary thrombus or thrombectomy use (p < 0.001), TIMI flow pre- and post-PCI (p < 0.001), and inversely to restenosis (p = 0.04) and use of a drug-eluting stent (p = 0.001). NLR did not influence the occurrence of myonecrosis (p = 0.75; adjusted OR (95 % CI) = 0.99 (0.63-1.54), p = 0.96), but was associated with a higher occurrence of periprocedural MI, even after correction for baseline differences (p = 0.03; adjusted OR (95 % CI) = 1.33 (1.02-2.3), p = 0.02), with NLR ≥ 3 best predicting the risk of periprocedural MI at the receiver operating characteristic curve analysis. In patients undergoing non-urgent PCI, a higher NLR increases the risk of periprocedural MI, especially for values ≥ 3.


Prenatal exposure to particulate matter and placental gene expression.
While strong evidence supports adverse maternal and offspring consequences of air pollution, mechanisms that involve the placenta, a key part of the intrauterine environment, are largely unknown. Previous studies of air pollution and placental gene expression were small candidate gene studies that rarely considered prenatal windows of exposure or the potential role of offspring sex. We examined overall and sex-specific associations of prenatal exposure to fine particulate matter (PM2.5) with genome-wide placental gene expression. Participants with placenta samples, collected at birth, and childhood health outcomes from CANDLE (Memphis, TN) (n = 776) and GAPPS (Seattle, WA) (n = 205) cohorts of the ECHO-PATHWAYS Consortium were included in this study. PM2.5 exposures during trimesters 1, 2, 3, and the first and last months of pregnancy, were estimated using a spatiotemporal model. Cohort-specific linear adjusted models were fit for each exposure window and expression of >11,000 protein coding genes from paired end RNA sequencing data. Models with interaction terms were used to examine PM2.5-offspring sex interactions. False discovery rate (FDR < 0.10) was used to correct for multiple testing. Mean PM2.5 estimate was 10.5-10.7 μg/m3 for CANDLE and 6.0-6.3 μg/m3 for GAPPS participants. In CANDLE, expression of 13 (11 upregulated and 2 downregulated), 20 (11 upregulated and 9 downregulated) and 3 (2 upregulated and 1 downregulated) genes was associated with PM2.5 in the first trimester, second trimester, and first month, respectively. While we did not find any statistically significant association, overall, between PM2.5 and gene expression in GAPPS, we found offspring sex and first month PM2.5 interaction for DDHD1 expression (positive association among males and inverse association among females). We did not observe PM2.5 and offspring sex interactions in CANDLE. In CANDLE, but not GAPPS, we found that prenatal PM2.5 exposure during the first half of pregnancy is associated with placental gene expression.


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Four groups of 16 cyclic sows were fed with 50, 100, 500 or 1000 μg zearalenone per kg feed for 10 days. Afterwards the genital organs were examined routine histologically and lectinhistochemically. Alterations of the lectin binding pattern of the glandular and surface epithelial cells was seen in all four groups, while the routine histology often showed normal results by the two lower concentrations. Macroscopically detectable organ alterations were seen only in the two groups with the highest concentration steps, but not constantly. Clinical symptoms of hyperestrogenismen were very seldom seen.


Spatiotemporal regulation of Rho GTPase signaling during endothelial barrier remodeling.
The vasculature is characterized by a thin cell layer that comprises the inner wall of all blood vessels, the continuous endothelium. Endothelial cells can also be found in the eye's cornea. And even though cornea and vascular endothelial (VE) cells differ from each other in structure, they both function as barriers and express similar junctional proteins such as the adherens junction VE-cadherin and tight-junction member claudin-5. How these barriers are controlled to maintain the barrier and thereby its integrity is of major interest in the development of potential therapeutic targets. An important target of endothelial barrier remodeling is the actin cytoskeleton, which is centrally coordinated by Rho GTPases that are in turn regulated by Rho-regulatory proteins. In this review, we give a brief overview of how Rho-regulatory proteins themselves are spatiotemporally regulated during the process of endothelial barrier remodeling. Additionally, we propose a roadmap for the comprehensive dissection of the Rho GTPase signaling network in its entirety.


Public awareness of One Health in China.
One Health is recognized as an increasingly important approach to global health. It has the potential to inform interventions and governance approaches to prevent future pandemics. Successfully implementing the One Health approach in policy will require active engagement from the public, which begs the question: how aware is the public of One Health? In this study, we examine the level and distribution of One Health awareness among the general public in China using a survey conducted in Beijing (n = 1820). We distinguish between awareness of the term of "One Health" versus awareness of the core set of ideas - the interconnection between the health of people, animals, and the environment. Our analysis shows that 40% of respondents reported that they have heard of the term, but more than double the number indicated that they recognize the core idea of interconnection between people, animals, and the environment. Specifically, about 83% of the respondents said that they believe people's health is closely connected to animal health and 86% believe people's health is closely connected to plant and environmental health. Multiple regression analysis indicates that women, younger people, and individuals with a higher level of education show higher levels of One Health awareness than their counterparts. Being aware of the term is associated with higher recognition of the core ideas. Policymakers and health practitioners should consider these findings when designing public awareness campaigns and educational initiatives to promote One Health principles.


Relative humidity and qualities of hygroscopic medications stored in different one-dose packaging papers.
The one-dose package is useful for patients who are prescribed multiple medications. However, the one-dose packaging of hygroscopic medications is difficult because the quality of the medication is reduced by moisture absorption. Cellophane polyethylene laminating paper at 20 μm or 30 μm thickness and glassine papers are widely used for one-dose packaging. The basic characteristics, such as water permeability, of these packaging papers have been demonstrated by companies; however, the quality changes of hygroscopic medications stored in these packaging papers are poorly understood. In this study, we compared the relative humidity in packaging papers and the qualities of the stored hygroscopic medications among 20 μm and 30 μm thick cellophane polyethylene laminating paper and glassine paper. Glucobay® 50 mg, Magmitt® 330 mg, and Phosblock® 250 mg tablets were used as hygroscopic medications to be packaged and the relative humidity, weight change, and hardness of tablets were measured. The relative humidity decreased in the order of glassine paper, 20 μm thick cellophane polyethylene laminating paper, and 30 μm thick cellophane polyethylene laminating paper. Additionally, tablets inside the 30 μm thick cellophane polyethylene laminating paper gained the least weight. Therefore, tablets in a 30 μm thick polyethylene laminating paper absorb less moisture than those in other papers. However, the effect was less pronounced at high temperature, even if the relative humidity remained the same. We expect that the results will be used by hospitals and clinical pharmacies to understand the characteristics of packaging papers and ensure appropriate usage.


Determination of pressure resistance of a partially stoppered vial by using a coupled CFD-0D model of lyophilization.
Modeling lyophilization in a vial is frequently done on a single vial level. When setting up a numerical model, the main focus is on heat and mass transfer inside the lyophilizate, whereas the vapor dynamics in the headspace of the vial is taken into account simply through imposing the system pressure as a pressure boundary condition. The present paper offers a deeper insight into the interaction of the sublimated vapor flow and the corresponding vapor pressure conditions inside the headspace of a partially stoppered vial. This is achieved through a coupled numerical solution of the heat and mass transfer inside the product by means of a 0D model describing the frozen domain (ice) and the 3D fluid flow inside the vial geometry with the partially opened stopper, computed by means of Computational Fluid Dynamics. Due to low pressures, the slip flow regime within the continuum hypothesis has to be considered, leading to imposing velocity slip conditions at the solid walls. The 0D model is used for the computation of sublimation mass flow rate as well as heat transfer rate to the vial, with the results of the water vapor mass flow rate and the temperature communicated to the 3D CFD model as a new inlet boundary conditions for computation of compressible fluid flow dynamics inside the vial. The obtained CFD pressure field solution allows derivation of a pressure resistance model for a targeted vial stopper combination, which is then used in calculating the corresponding pressure drop in the headspace of the partially stoppered vial. The coupled CFD-0D model results are validated based on the results of dedicated experimental water runs on several vial and stopper geometries and show, that the vial geometry, but especially the installed stopper, alter the pressure field conditions inside the vial. The increased in-vial local vapor pressure values lead to a decrease of the mass flow rates and an increase of temperatures at the bottom of the product, which range from 0.6 K for the highest system pressure and up to 5.4 K for the lowest system pressure tested. The presented coupled model is suitable for the use in further studies of the impact of various vial forms as well as stoppers on the lyophilization dynamics in a vial.


Predictors of mortality among nursing home residents with a diagnosis of Parkinson's disease.
Little is known about predictors of mortality among Parkinson patients living in long term care. We conducted a 3-year follow-up study on 15,237 PD residents aged 65 years and older using the Systematic Assessment in Geriatric drug use via Epidemiology (SAGE) database. The SAGE database consists of the Minimum Data Set (MDS) data collected on over 400,000 nursing home residents in 5 U. S. states, including demographic characteristics, dementia severity, comorbidity and other clinical variables. Information on death was derived through linkage to Medicare files. Baseline characteristics were used to predict survival using univariate and multivariate Cox proportional hazard models. The overall 3-year mortality rate was 50%. Advanced age (relative rate (RR) 2.22; 95% confidence interval (CI) 1.99-2.47, for patients 85+ years), male gender (RR 1.73; 95% CI 1.60-1.87), severe functional (RR 1.81; 95% CI 1.53-2.13) and cognitive (RR 1.54; 95% CI 1.38-1.72) impairment, the presence of vision problems (RR 1.25; 95% CI 1.20-1.57), pressure ulcers (RR 1.25; 95% 1.14-1.37), and a diagnosis of congestive heart failure (RR 1.49; 95% CI 1.35-1.65), diabetes mellitus (RR 1.22; 95% 1.11-1.35) and pneumonia (RR 1.39; 95% CI 1.09-1.77) were independent predictors of death. The specific presence of aspiration pneumonia had the highest mortality risk ratio among all comorbidities (RR 1.58; CI 0.97-2.56). African-Americans and other minority groups were less likely to die relative to white PD residents. Age, sex, functional and cognitive impairment and the diagnosis of pneumonia or congestive heart failure were the strongest predictors of death. Minority groups have a reduced risk of death relative to white PD nursing home residents.


Peritoneal well-differentiated papillary mesothelioma coexisting with endometrial adenocarcinoma mimicking peritoneal carcinomatosis: A case report.
We present a rare case of well-differentiated papillary mesothelioma (WDPM) found incidentally in a 59-year-old woman with endometrial cancer. A 59-year-old nulliparous obese woman with a past history of hypertension and diabetes mellitus presented with postmenopausal bleeding for 11 months. Two months prior to this admission, an episode of massive vaginal bleeding lasting for a day was noticed by the patient. Hysteroscopy was performed after her visit to our outpatient department. Papillary tumors with active bleeding were found in the uterine cavity. Endometrial biopsy showed adenocarcinoma, endometrioid type characterized by papillary architecture lined by columnar cells with mild nuclear pleomorphism. The patient proceeded to magnetic resonance imaging (MRI), which demonstrated a 6.4 × 5.5 × 4.9 cm intrauterine mass. Her tumor marker levels were elevated (CA 125 87.8 IU/ml, CA19-9160.54 IU/ml). The patient then underwent a staging surgery and final pathology revealed stage IA endometrial cancer. During surgery, multiple nodules were found in the peritoneum, initially considered as tumor metastasis and eventually proved to be WDPM. In conclusion, the simultaneous occurrence of WDPM with endometrial cancer is a rare entity. Although no standardized treatment has been established, WDPMs have a relatively favorable prognosis compared to malignant mesotheliomas.


Intravitreal triamcinolone for the treatment of refractory macular edema in idiopathic intermediate or posterior uveitis.
Cystoid macular edema (CME) is the most significant cause of visual loss associated with idiopathic uveitis. The authors report on the use of intravitreal triamcinolone acetonide (IVTA) in a group of patients with macular edema due to idiopathic intermediate and posterior uveitis. Retrospective, noncomparative, interventional case series. Thirty-three eyes were included with uveitic CME that was refractory to topical steroids, oral prednisone, or a combination thereof. Previous steroid treatment did not result in elevated intraocular pressure (IOP). The eyes received an intravitreal injection with 10 mg triamcinolone acetonide, after best-corrected visual acuity (BCVA) and fluorescein angiography (FA) were assessed. Ophthalmologic examination including FA was regularly performed during a 1-year follow-up period. Within 12 weeks after injection of IVTA, 50% of the eyes responded with an improvement in vision of more than two lines and 30% of the eyes reached an IOP of > or = 21 mmHg (p<0.01). All eyes with an elevated IOP responded well on topical antiglaucoma medication. After 12 months follow-up 40% of the eyes responded with an improvement in vision of more than two lines and 28% of the affected eyes underwent phacoemulsification during the follow-up. No other complications occurred within a year after the treatment. In macular edema due to idiopathic intermediate or posterior uveitis IVTA improves the visual acuity within the first 3 months. However, thereafter the visual acuity decreases again. Cataract and elevated IOP are common side effects.


Common mental disorders in patients undergoing lower limb amputation: a population-based sample.
Amputations result in a variety of limitations that have emotional consequences for patients. The aim of the present study was evaluate non-psychotic disorders and their associated factors in a sample of people with lower limb amputations. A cross-sectional study was conducted that assessed the association of sociodemographic and clinical variables in relation to psychiatric disorders evaluated through the Self Reporting Questionnaire (SRQ-20) for patients undergoing lower limb amputation. The association between the outcome of the SRQ-20 and the other variables was assessed with the chi-square and Student's t test; to explore the magnitude of association adjusted for covariates, a logistic regression model was developed. One hundred-thirty eight (138) patients were interviewed, and a prevalence of 43% (60/138) was observed for patients with mental disorders assessed with the SRQ-20 questionnaire. We also observed that male patients (p = 0.017) and those who were married (p = 0.035) had a lower rate of psychological problems; those who were not considered independent (p = 0.036) and those with a greater number of morbid conditions (p = 0.036) showed a higher positivity in relation to psychological morbidity (p = 0.003). Logistic regression analysis showed that only the associated chronic diseases (p = 0.0328) and lack of independence (p = 0.0197) remained significant. Given the high prevalence of mental disorders related to the number of associated morbid conditions and to the situation of dependency among lower limb amputees, the psychological and social assessment of these people is recommended, in addition to encouraging their self-care and the return to their activities.


Multicountry Analysis of Spectrum of Clinical Manifestations of Children <5 Years of Age Hospitalized with Diarrhea.
After introduction of rotavirus vaccine, other pathogens might become leading causes of hospitalizations for severe diarrhea among children <5 years of age. Our study in 33 hospitals in 7 countries found acute gastroenteritis accounted for most (84%) reported hospitalizations of children with diarrhea. Bloody and persistent diarrhea each accounted for <1%.


Associations between food groups and liver cancer: a systematic review and meta-analysis of observational studies.
Diet is emerging as a modifiable component of lifestyle for influencing the incidence of liver cancer. To investigate and quantify the potential relationship between food groups and liver cancer. PubMed and Web of Science were searched for eligible observational studies until 31st March, 2023. The meta-analysis was conducted by pooling relative risk (RR), odds ratio (OR) or hazards ratio (HR) with 95% confidence intervals (CIs). Potential sources of heterogeneity were detected by subgroup analysis. Sensitivity analysis and publication bias test were also carried out. Through stepwise screening, a total of 27 studies were included. The pooled estimates of liver cancer for whole grains and legumes intake were 0.66 (95% CI: 0.54-0.82; I2 = 25.3%) and 0.86 (95% CI: 0.75-0.99; I2 = 14.3%), respectively. However, there were null associations of nuts, poultry, egg and sweetened beverages consumption with liver cancer and the association between refined grains and liver cancer was inconclusive. In dose-response meta-analysis, the pooled estimates of liver cancer were 0.77 (95% CI: 0.65-0.91) for every 50 g/day increment in whole grains intake. Non-linear dose-response relationship (P = 0.031) was observed in the association between the intake of legumes and liver cancer, and the protective effect occurred with the dose ranging from 8 g/day to 40 g/day. This meta-analysis shows that whole grains and legumes were inversely associated with liver cancer, whereas intake of nuts, poultry, egg and sweetened beverages may not be associated with liver cancer. Further quantitative research needs to be undertaken within a range of populations to investigate the relationship between food groups and liver cancer. PROSPERO registration no. CRD42021246142.


Combination of vertebral bone quality scores from different magnetic resonance imaging sequences improves prognostic value for the estimation of osteoporosis.
Recent findings revealed a correlation between vertebral bone quality based on T1-weighted (VBQT1) magnetic resonance imaging (MRI) and volumetric bone mass density (vBMD) measured using quantitative computerized tomography. The coherence of VBQ for other MRI sequences, such as T2 or short tau inversion recovery (STIR), has not been examined. The combination of different VBQs has not been studied. The aims of the study were to confirm the correlation between VBQT1 and vBMD and to examine VBQs from other MRI sequences and their combination with vBMD. This was a retrospective cross-sectional study. The sample consisted of patients older than 18 years, who received treatment at a level-one university spine center of the German Spine Society for degenerative or traumatic reasons in 2017-2021. The outcome measures were the correlation of VBQs from different MRI sequences with vBMD and the association of VBQs with osteopenia/osteoporosis. Patients' VBQ was calculated based on the signal intensities of the vertebral bodies L1-4 in T1-, T2-, and STIR-weighted MRI. The VBQ was standardized according to the signal intensity of the cerebrospinal fluid. The vBMD was determined using data from a calibrated scanner (SOMATOM Definition AS+) and processed with CliniQCT (Mindways Software, Inc., USA). Groups were divided according to vBMD into the following groups: (I) osteoporosis/osteopenia (< 120 mg/m3) and (II) healthy (≥120 mg/m3). An analysis of the correlation between various VBQs and vBMD as well as receiver operating characteristic (ROC) and binary regression analyses were performed for the prediction of osteoporosis/osteopenia. We included 136 patients (women: 56.6%) in the study (69.7 ± 15.0 years). According to vBMD, 108 patients (79.4%) had osteoporosis/osteopenia. Women were affected significantly more often than men (p = .045) and had significantly higher VBQT1 and VBQT2 values than men (VBQT1: p = .048; VBQT2: p = .013). VBQT1 and VBQT2 values were significantly higher in patients with osteoporosis/osteopenia than in healthy persons (VBQT1: p<.001; VBQT2: p = .025). VBQT1 and VBQT2 were significantly negatively correlated with vBMD with a moderate effect size (p<.001), while VBQSTIR was not significantly correlated with vBMD, although it showed a positive coherence. The combination of different VBQs in terms of VBQT1 × VBQT2 / VBQSTIR distinctly increased the effect size of the negative correlation with vBMD compared to VBQ alone. A cutoff value for VBQT1 × VBQT2 / VBQSTIR of 2.9179 achieved a sensitivity of 80.0%, a specificity of 75.0%, and an area under the curve (AUC) of 0.775 for the determination of osteoporosis. The mathematical model derived from the binary logistic regression showed an excellent AUC of 0.846. This study confirms a significant correlation between VBQT1 and vBMD. The combination of VBQs from different MRI sequences enhances the prognostic value of VBQ for the determination of osteoporosis. While safe clinical application of VBQ for the determination of osteoporosis requires further validation, VBQ might offer opportunistic estimation for further diagnostics.


Milk-derived multi-fluorescent graphene quantum dot-based cancer theranostic system.
An economical green-chemistry approach was used for the synthesis of aqueous soluble graphene quantum dots (GQDs) from cow milk for simultaneous imaging and drug delivery in cancer. The GQDs synthesized using one-pot microwave-assisted heating were multi-fluorescent, spherical in shape having a lateral size of ca. 5nm. The role of processing parameters such as heating time and ionic strength showed a profound effect on photoluminescence properties of GQDs. The GQDs were N-doped and oxygen-rich as confirmed by X-ray photoelectron spectroscopy (XPS) analysis. Cysteamine hydrochloride (Cys) was used to attach an anti-cancer drug berberine hydrochloride (BHC) on GQDs forming GQDs@Cys-BHC complex with c.a. 88% drug loading efficiency. In vitro drug release was studied at the acidic-basic environment and drug kinetics was studied using pharmacokinetic statistical models. The GQDs were biocompatible on L929 cells whereas theranostic GQDs@Cys-BHC complex showed a potent cytotoxic effect on different cancerous cell line models: cervical cancer cell lines such as HeLa cells and breast cancer cells such as MDA-MB-231 confirmed by Trypan blue and MTT-based cytotoxic assays. Furthermore, multi-excitation based cellular bioimaging was demonstrated using confocal laser scanning microscopy (CLSM) and fluorescence microscopy using GQDs as well as GQDs@Cys-BHC complex. Thus, drug delivery (therapeutic) and bioimaging (diagnostic) properties of GQDs@Cys-BHC complex are thought to have a potential in vitro theranostic application in cancer therapy.


Resolution of hemiballism after carotid endarterectomy: case report.
A 74-year-old man presented with a 3-week history of involuntary left-sided upper and lower extremity shaking without any focal neurologic deficit. Bilateral carotid artery duplex demonstrated severe stenosis of the right internal carotid artery and moderate stenosis of the left internal carotid artery. A right carotid endarterectomy was performed without complications and resulted in elimination of the left-sided involuntary movements postoperatively.


Asymptotic Analysis of a Target-Mediated Drug Disposition Model: Algorithmic and Traditional Approaches.
A detailed analysis is reported on a multiscale pharmacokinetic model, simulating the interaction of a drug with its target, the binding of the compounds and the outcome of their interaction. The analysis is based on the algorithmic computational singular perturbation (CSP) methodology. Among others, the analysis concludes that the partial equilibrium approximation and the quasi-steady-state approximation (PEA and QSSA) are valid in two distinct stages in the evolution of the process. Similar conclusions are reached from the algorithmic criteria for the validity of the QSSA and PEA. The reactions in the pharmacokinetic model that (i) generate the fast time scales, (ii) generate the constraints in which the system evolves and (iii) drive the system at various phases are identified, with the use of algorithmic CSP tools. These identifications are very important for the improvement of the model and for the identification of ways to control the evolution of the process. Regarding the qualitative understanding of the process, the present analysis systematises the findings in the literature and provides some new insights.


Tailpipe emissions from gasoline direct injection (GDI) and port fuel injection (PFI) vehicles at both low and high ambient temperatures.
Vehicle emissions are greatly influenced by various factors that are related to engine technology and driving conditions. Only the fuel injection method and ambient temperature are investigated in this research. Regulated gaseous and particulate matter (PM) emissions from two advanced gasoline-fueled vehicles, one with direct fuel injection (GDI) and the other with port fuel injection (PFI), are tested with conventional gasoline and ethanol-blended gasoline (E10) at both -7 °C and 30 °C. The total particle number (PN) concentrations and size distributions are monitored with an Electrical Low Pressure Impactor (ELPI(+)). The solid PN concentrations are measured with a condensation particle counter (CPC) after removing volatile matters through the particle measurement program (PMP) system. The results indicate that decreasing the ambient temperature from 30 °C to -7 °C significantly increases the fuel consumption and all measured emissions except for NOx. The GDI vehicle exhibits lower fuel consumption than the PFI vehicle but emits more total hydrocarbons (THC), PM mass and solid PN emissions at 30 °C. The adaptability of GDI technology appears to be better than that of PFI technology at low ambient temperature. For example, the CO, THC and PM mass emission factors of the PFI vehicle are higher than those of the GDI vehicle and the solid PN emission factors are comparable in the cold-start tests at -7 °C. Specifically, during start-up the particulate matter emissions of the PFI are much higher than the GDI. In most cases, the geometric mean diameter (GMD) of the accumulation mode particles is 58-86 nm for both vehicles, and the GMD of the nucleation mode particles is 10-20 nm. The results suggest that the gaseous and particulate emissions from the PFI vehicle should not be neglected compared to those from the GDI vehicle especially in a cold environment.


Prediction of long-term unprovoked seizures after status epilepticus.
Possible long-term consequences of status epilepticus (SE) include cognitive and behavioral impairment and the development of chronic epilepsy. However, these aspects have not been systematically studied in clinical practice. We aimed to evaluate long-term seizure recurrence after SE and the potential risk factors for their development. Data were obtained from a prospective registry of all SE episodes occurring in adult patients who attended our center from February 2011 to April 2022. Clinical data, electroencephalographic findings, treatment, and long-term data were prospectively recorded. We performed a cross-sectional study of consecutive SE patients without previous epilepsy diagnosis, and analyzed the development of unprovoked remote seizures. A total of 849 patients were registered in the database. After excluding in-hospital mortality (198/849, 23.3%) and patients with prior epilepsy history (291/849, 44.7%), 360 patients (42.4%) with a first SE episode were included. The median age was 68 years (interquartile range [IQR] = 56-79), and 176 patients (48.9%) were women. The median time to first-line treatment initiation was 2 h (IQR = .7-7.4), and it was correlated with SE duration (R = .375, p < .001). One hundred nine patients (30.3%) presented unprovoked seizures during a median follow-up of 1.8 years (IQR = .5-4.3). After adjusting for identifiable confounders in a multivariable Cox regression analysis, progressive symptomatic etiology (hazard ratio [HR] = 1.97, 95% confidence interval [CI] = 1.17-3.33, p = .011), time to first-line treatment initiation > 1.5 h (HR = 1.89, 95% CI = 1.25-2.87, p = .003), and superrefractory SE (HR = 2.34, 95% CI = 1.26-4.33, p = .007) were independently associated with a greater risk of unprovoked seizure recurrence. In contrast, older patients (HR = .99, 95% CI = .97-.99, p = .021) and an acute symptomatic etiology (HR = .44, 95% CI .28-.68, p < .001) were at lower risk of unprovoked seizure recurrence. The etiology of SE, the delay in initiating SE treatment, and the presence of superrefractoriness have been identified as potentials factors associated with unprovoked remote seizures following a new onset SE. Therefore, prompt and appropriate management should be applied to avoid seizure recurrence.


Decision-making around antithrombotics for stroke prevention in atrial fibrillation: the health professionals' views.
Background For stroke prevention in patients with atrial fibrillation (AF), the decision-making around antithrombotic therapy has been complicated by older age, multiple comorbidities, polypharmacy and the different pharmacological properties of warfarin and the nonvitamin K antagonist oral anticoagulants (NOACs). The complexity of decision-making has been associated with a reluctance by health professionals to use antithrombotic therapy, leading to poor clinical outcomes. In order to improve stroke prevention in patients with AF, the contemporary perspectives of health professionals on the decision-making around antithrombotic therapy needs exploration. Objective To elicit emerging themes describing health professionals' perspectives on the decision-making around antithrombotic therapy for stroke prevention in patients with AF. Setting Sydney metropolitan area of New South Wales, Australia. Method A qualitative study based on face-to-face interviews was conducted from August to October 2014. Seven pharmacists, seven specialists, six general practitioners and six nurses practising in the Sydney metropolitan area and managing antithrombotic therapy for AF were interviewed until theme saturation was achieved in each subgroup. Interview transcripts were analysed using manual inductive coding. Main outcome measure Emerging themes describing health professionals' perspectives on the decision-making around antithrombotic therapy for stroke prevention in patients with AF. Results Three overarching themes emerged. (1) Comprehensive assessment is necessary for decision-making but is not always implemented. Health professionals mostly focused on stroke risk assessment, not on the bleeding risk and medication safety issues. (2) Health professionals from different disciplines have different preferences for antithrombotic therapies. Although the majority of health professionals considered warfarin as the first-line therapy, NOACs were preferred by neurologists and haematologists. (3) Health professionals focused on different aspects of the decision making process: GPs and specialists were concerned about the appropriate prescription of antithrombotics, while pharmacists and nurses focused on daily medication management by patients. Conclusion The decision-making process appears to be partially preference based rather than systematic, and health professionals from various disciplines focus on different parts of the decision-making process.


The Link Between Health Literacy and Three Conditions of Metabolic Syndrome: Obesity, Diabetes and Hypertension.
Health literacy (HL) intervention could be a potential prevention strategy to reduce the risk of metabolic syndrome (MS), but the association between low HL and MS is controversial. Therefore, the aim of this study was to investigate whether low HL is associated with obesity, diabetes, and hypertension, considering them as one cluster. We used data from the Hamburg Diabetes Prevention Survey, a population-based cross-sectional study in Germany. The 1349 eligible subjects were 18-60 years old. The European Health Literacy Questionnaire (HLS-EU-Q16) was used to assess HL. Depending on the reported number of metabolic syndrome conditions (CMS), four groups were categorized as follows: "0", any "1", any "2" and "3" CMS. Ordered logistic regression was used to analyze the relationship between HL level (independent variable) and the reported number of CMS (dependent variable) adjusted for age, gender and education. 63.9% of subjects (n=862) reported having "0", 25.7% (n=346) only "1", 8.2% (n=111) only "2" and 2.2% (n=30) "3" of the three CMS. In the group with sufficient HL, rates of "1," "2," or "3" CMS were lower than in the group with problematic or inadequate HL. Subjects with inadequate HL showed a 1.62-fold higher risk of having a higher number of CMS than subjects with sufficient HL (OR 1.62; 95% CI 1.13 to 2.31). The risk increased with each life year (OR 1.05; 95% CI 1.04 to 1.06), and was higher in persons with low education (OR 2.89; 95% CI 2.08 to 4.01) than in highly educated persons. Women showed lower risk (OR 0.73; 95% CI 0.58 to 0.91) than men. Lower HL was associated with a higher number of MS conditions. Our findings suggest that HL intervention on health-promoting behaviors could help reduce MS risk in people with limited HL.


Does a history of wound infection predict postoperative surgical site infection after ventral hernia repair?
Stratification of risks of postoperative wound/mesh infection after hernia repair remains a challenge. We aimed to determine the role of a previous wound infection on surgical site infection in patients undergoing open ventral hernia repair. All patients undergoing open ventral hernia repair in a clean setting were evaluated from a prospectively maintained database. The primary end point was the development of a postoperative surgical site infection. A total of 146 patients were included in the analysis, and 22 patients had a history of previous wound infection. The rate of surgical site infection did not differ between those with or without a history of wound infection (14% vs 9%; P = .444). Patients with a history of chronic obstructive pulmonary disease or smoking were at an increased risk of developing a surgical site infection. For patients undergoing open ventral hernia repair, a history of previous wound infection is not predictive of postoperative surgical site infection.


A Systematic Review Of Implicit Attitudes And Their Neural Correlates In Eating Behaviour.
An increasing number of studies suggests that implicit attitudes toward food and body shape predict eating behaviour and characterize patients with eating disorders (EDs). However, literature has not been previously analysed, thus differences between patients with EDs and healthy controls and the level of automaticity of the processes involved in implicit attitudes are still matters of debate. The present systematic review aimed to synthetize current evidence from papers investigating implicit attitudes towards food and body in healthy and EDs populations. PubMed, EMBASE (Ovid), PsycINFO, Web of Science and Scopus were systematically screened and 183 studies using different indirect paradigms were included in the qualitative analysis. The majority of studies reported negative attitudes towards overweight/obese body images in healthy and EDs samples and weight bias as a diffuse stereotypical evaluation. Implicit food attitudes are consistently reported as valid predictors of eating behaviour. Few studies on the neurobiological correlates showed neurostimulation effects on implicit attitudes, but the automaticity at brain level of implicit evaluations remains an open area of research. In conclusion, implicit attitudes are relevant measures of eating behaviour in healthy and clinical settings, although evidence about their neural correlates is limited.


Responder analyses and the assessment of a clinically relevant treatment effect.
Ideally, a clinical trial should be able to demonstrate not only a statistically significant improvement in the primary efficacy endpoint, but also that the magnitude of the effect is clinically relevant. One proposed approach to address this question is a responder analysis, in which a continuous primary efficacy measure is dichotomized into "responders" and "non-responders." In this paper we discuss various weaknesses with this approach, including a potentially large cost in statistical efficiency, as well as its failure to achieve its main goal. We propose an approach in which the assessments of statistical significance and clinical relevance are separated.


Limited Granulomatosis With Polyangiitis of Nose and Paranasal Sinuses - a Case Report.
Granulomatosis with polyangiitis is a rare disease with involvement of multiple organ system. It classically affects the upper respiratory tract, lower respiratory tract and kidneys. 90% of patients present with upper respiratory diseases like rhinosinusitis, nasal polyposis, nasal septal perforation, serous otitis media, impaired hearing and stridor due to subglottic stenosis. Disease manifests in two forms as limited disease i.e. without renal involvement and generalized disease i.e. with renal involvement. It needs to be differentiated from chronic granulomatous diseases like tuberculosis and delay in the treatment should be prevented. Here we present a case with disease limited to Nose and Paranasal sinuses.


A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.
Afatinib (systematic name: N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol-ecules (A and B) in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two mol-ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetra-hydro-furanyl substituents of the two independent mol-ecules. This can, in turn, be traced back to C-H⋯N and C-H⋯O inter-actions of the aceto-nitrile solvent mol-ecules with the tetra-hydro-furan oxygen and CH2 units. In the crystal, neighboring mol-ecules are connected via N-H⋯O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol-ecules, which are engaged in O-H⋯O and O-H⋯N hydrogen bonds connecting to the di-methyl-amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol-ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by aceto-nitrile solvent mol-ecules situated on that axis, and parallel channels which are not occupied by any solvent.


The grip pattern of the healthy hand during eating.
Thirty subjects with healthy hands have been studied in standardized meal experiments comprising serving, eating and drinking. The activities were filmed and the grips classified by means of a descriptive code system and analysed by automatic data processing. The investigation has resulted in new information about the grip pattern of the normal hand as well as detailed data on fingers and parts of fingers used. The study demonstrates the value of analysing hand function with reference to integrated activities.


Total knee arthroplasty for valgus osteoarthritis: the results of a standardized soft-tissue release technique.
The study reports the 2-year follow-up results of patients with valgus osteoarthritis undergoing total knee arthroplasty (TKA) with a standardized soft-tissue release. Between 2008 and 2013, 222 TKAs were performed for valgus osteoarthritis by a single surgeon. A total of 181 TKAs in 164 patients were available for a minimum 2-year follow-up (range 24-87 months). Preoperative and postoperative range of motion (ROM), mechanical alignment, the postoperative medial proximal tibial angle (MPTA), Western Ontario and McMaster Universities Arthritis Index (WOMAC), VF-12 score, visual analogue pain scale (VAS), and the actual UCLA activity score, desired UCLA score, ligamentous stability (medial collateral ligament) and complications and revision rates were recorded. The ROM increased from a preoperative flexion contracture of 4.7° (range 0-40) and flexion of 110° (range 35-135) to a postoperative mean flexion contracture of 0.1° (range -5 to 10) and flexion of 128° (range 100-140). The mean hip-knee-ankle alignment was changed from 8.4° of mechanical valgus (range 5.3-25.4) to 0.02° of varus alignment (range -2.9 to 4.1). Tibia component angle (MPTA) was 90.4° (range 86.1-93.7). The WOMAC score, VF-12, UCLA and VAS significantly improved after surgery (p < 0.05). Two patients (1.1 %) underwent revision surgery for instability. The described standardized soft-tissue release (release of the iliotibial band and posterolateral corner) provided excellent clinical results at a minimum 2-year follow-up and can be used safely for a "cook-book" approach to the valgus knee with up to 25° mechanical valgus alignment. IV.


Assignment of the imidazole ring nitrogen protons of histidine 48 in the proton NMR spectrum of ribonuclease A in water solution.
Several exchangeable resonances, designated a, b, c and d are observed in the 11-14 ppm (from 2,2-dimethyl-2-silapentane-5-sulfonate) region of the proton spectrum of ribonuclease A in water solution. We describe a number of lines of evidence suggesting the assignment of peaks b and c to the N1 and N3 protons of His 48, which occupies an interior position in the protein remote from the active site. This evidence includes the observation that the binding of Cu(II) and 3'-CMP (cytidine 3'-monophosphate) has no effect on these resonances. Further evidence includes pH titration data showing a pKa of approx. 2 for these protons, solvent exchange rates in the native state and with disulfide bridges IV-V and III-VIII cleaved, the observation of the carboxymethylated enzymes CM-His12-RNAase A and CM-His119-RNAase A, and of the modified enzymes Des(1-21)-RNAase A (S-protein) and Des(119-124)-RNAase A.


Proteomics, dietary intake, and changes in cardiometabolic health within a behavioral weight-loss intervention: A pilot study.
Identifying associations among circulating proteins, dietary intakes, and clinically relevant indicators of cardiometabolic health during weight loss may elucidate biologically relevant pathways affected by diet, allowing for an incorporation of precision nutrition approaches when designing future interventions. This study hypothesized that plasma proteins would be associated with diet and cardiometabolic health indicators within a behavioral weight-loss intervention. This secondary data analysis included participants (n = 20, mean [SD], age: 40.1 [9.5] years, BMI: 34.2 [4.0] kg/m2 ) who completed a 1-year behavioral weight-loss intervention. Cardiovascular disease-related plasma proteins, diet, and cardiometabolic health indicators were evaluated at baseline and 3 months. Associations were determined via linear regression and integrated networks created using Visualization Of LineAr Regression Elements (VOLARE). A total of 16 plasma proteins were associated with ≥1 diet or health indicator at baseline (p < 0.001); changes in 42 proteins were associated with changes in diet or health indicators from baseline to 3 months (p < 0.005). Baseline tumor necrosis factor receptor superfamily member 10C (TNFRSF10C) was associated with intakes of dark green vegetables (r = -0.712), and fatty acid-binding protein 4 (FABP4) was associated with intakes of unsweetened coffee (r = -0.689). Changes in refined-grain intakes were associated with changes in scavenger receptor cysteine-rich type 1 protein M130 (CD163; r = 0.725), interleukin-1 receptor type 1 (IL1R-T1; r = 0.624), insulin (r = 0.656), and triglycerides (r = 0.648). Circulating cardiovascular disease-related proteins were associated with diet and cardiometabolic health indicators prior to and in response to weight loss.


Detection of conformational changes in complex III of the respiratory chain by a maleimido spin label.
Changes in the conformation of Complex III (CoQH2-cytochrome c reductase) of the mitochondrial respiratory chain were detected upon oxidoreduction using the nitroxide spin label, 3-(maleimidomethyl)-2,2,5,5-tetramethyl-1-pyrrolidinyloxyl. EPR spectra of the spin label show a transition from a greater to a lesser degree of immobilization when the labeled enzyme, reduced either with ascorbate or sodium dithionite, is oxidized with potassium ferricyanide or ferricytochrome c. These observations are interpreted to indicate that Complex III is more compact in the reduced state at least in the locality of the spin label. An apparent increase in the concentration of total spins during oxidation of the complex suggests change in the interaction between the spin label and other paramagnetic centers and not an oxidation of spin label, itself, since reduced free spin label could not be reoxidized. Addition of antimycin A had no effect on the EPR spectrum of the spin-labeled enzyme, indicating that this inhibitor does not initiate a conformational change in the region of the spin label. Experiments in which N-ethyl-[2-3H] maleimide was bound to Complex III show that binding occurs primarily to a subunit with a molecular weight of 45,000. Although no qualitative differences were observed, it was found that less radioactivity appears in samples reduced with dithionite than in those reduced with ascorbate. This difference appears to be caused by decomposition products of dithionite.


Redox-Active Metallacarborane-Decorated Octasilsesquioxanes. Electrochemical and Thermal Properties.
Polyanionic and electroactive hybrids based on octasilsesquioxanes bearing metallacarborane units are developed. They show remarkable solubility in organic solvents and outstanding thermal stability. The metallacarboranes act as independent units simultaneously undergoing the reversible redox process.