Systemic immune-inflammation index, thymidine phosphorylase and survival of localized gastric cancer patients after curative resection.
Systemic immune-inflammation index (SII), based on lymphocyte (L), neutrophil (N), and platelet (P) counts, was recently developed and reflects comprehensively the balance of host inflammatory and immune status. We explored its prognostic value in localized gastric cancer (GC) after R0 resection and the potential associations with Thymidine phosphorylase (TYMP), which was reported to increase the migration and invasion of gastric cancer cells. A total of 455 GC patients who received D2 gastrectomy were enrolled. Blood samples were obtained within 1 week before surgery to measure SII (SII = P × N/L). TYMP expression was measured on tumor sections by immunohistochemical analysis. Preoperative high SII indicated worse prognosis (HR: 1.799; 95% CI: 1.174-2.757; p = 0.007) in multivariate analysis and was associated with higher pathological TNM stage, deeper local invasion of tumor and lymph node metastasis (all p < 0.001). SII predicted poor overall survival in pathological TNM stage I subgroup also (p < 0.001). Furthermore we found that in high SII group, positive rate of TYMP expression increased (53.7% vs 42.7%, p = 0.046) and TYMP positive patients had higher SII score (median 405.9 vs. 351.9, p = 0.026). SII, as a noninvasive and low cost prognostic marker, may be helpful to identify higher-risk patients after R0 resection, even for stage I GC patients.


Cytochrome P-450 and FAD-monooxygenase mediated S- and N-oxygenations.
S- and N-Oxygenations are mostly mediated by either the cytochrome P-450 group of enzymes (haemoproteins), or the FAD-containing monooxygenases (flavoproteins). The nucleophilicity of the heteroatom may be an important determinant of which of these microsomal enzymes is utilised for specific oxygenations. This article describes the approaches that could be used for assessing the relative contribution of these microsomal oxidases to a particular reaction, with reference to studies with N,N-dimethylaniline, diethylsulphide, tetrahydrothiophen and dibenzothiophen.


Discrete water hexamers and template-assisted molecular recognition in an elastic zincophosphate lattice.
Water molecules and terephthalic acid, respectively, exist as a self-assembled monolayer of cyclic (H2O)6 clusters and (TA)infinity chiral chains between the zincophosphate sheets (in blue wires); the irremovable template H3tren3+ ions (in purple wires) are dynamic and could translate back and forth on the sheets during the conversion of the supramolecule contained in one another.


Intravascular Cutaneous Disorders. A Clinicopathologic Review.
Intravascular proliferations of the skin are clinically heterogeneous and may present with a wide range of clinical features, including violaceous papules, nodules, plaques, or other unspecific cutaneous lesions. Histopathologically, these conditions are characterized by proliferation of different cell types within the lumina of dermal vessels and endothelial cell hyperplasia. Immunohistochemistry is the best tool to identify the nature of the intravascular proliferating cells and the type of involved vessel. In this review, we analyzed the clinicopathologic and immunohistochemical characteristics of intravascular large cell lymphoma, T-cell and natural killer-cell intravascular large cell lymphoma, intralymphatic variant of CD30+ cutaneous lymphoproliferative disorders, benign atypical intralymphatic CD30+ T-cell proliferation, reactive angioendotheliomatosis, intralymphatic histiocytosis, papillary intralymphatic angioendothelioma or Dabska tumor, glomeruloid hemangioma, papillary hemangioma, intravascular papillary endothelial hyperplasia or Masson phenomenon, and the intralymphatic involvement of Merkel cell carcinoma, cutaneous metastases, and cutaneous angiosarcoma.


[Constriction of the femoral vein after McVay hernioplasty].
Constriction of the femoral vein is a well known complication to the Cooper ligament repair of inguinal hernia. This may occur as the transversalis fascia and aponeurosis are sutured to Copper's ligament, either because a suture is passed through the vein or the vein is compressed by tissue. Clinical presentation is usually signs of deep venous thrombosis or pulmonary embolism. Venography verifies the diagnosis by showing a characteristic constriction of the femoral vein.


Modeling Occurrence of Urban Mosquitos Based on Land Use Types and Meteorological Factors in Korea.
Mosquitoes are a public health concern because they are vectors of pathogen, which cause human-related diseases. It is well known that the occurrence of mosquitoes is highly influenced by meteorological conditions (e.g., temperature and precipitation) and land use, but there are insufficient studies quantifying their impacts. Therefore, three analytical methods were applied to determine the relationships between urban mosquito occurrence, land use type, and meteorological factors: cluster analysis based on land use types; principal component analysis (PCA) based on mosquito occurrence; and three prediction models, support vector machine (SVM), classification and regression tree (CART), and random forest (RF). We used mosquito data collected at 12 sites from 2011 to 2012. Mosquito abundance was highest from August to September in both years. The monitoring sites were differentiated into three clusters based on differences in land use type such as culture and sport areas, inland water, artificial grasslands, and traffic areas. These clusters were well reflected in PCA ordinations, indicating that mosquito occurrence was highly influenced by land use types. Lastly, the RF represented the highest predictive power for mosquito occurrence and temperature-related factors were the most influential. Our study will contribute to effective control and management of mosquito occurrences.


Prenatal morphine administration alters behavioral development in the rat.
Female rats were administered increasing doses of morphine sulfate 5 days prior to mating and during gestation until 4-6 days before the birth of their litters. Prenatal morphine exposure altered the normal during the 3rd and 4th postnatal weeks. This disruption in behavioral ontogeny did not coincide with changes in physical parameters. Decreased body weight ant postnatal week. The appearance of behavioral disturbances in the absence of physical abnormalities stresses the need for follow-up studies of infants born to narcotic-dependent mothers after signs of physical withdrawal or retarded growth have disappeared.


Are the C-reactive protein values and erythrocyte sedimentation rate equivalent when estimating the 28-joint disease activity score in rheumatoid arthritis?
A formula for calculating disease activity score with 28 joint counts (DAS28) with C-reactive protein (CRP) instead of the erythrocyte sedimentation rate (ESR) has been proposed. Here we analyze the factors that contribute to the differences in the DAS28 when calculated using either the ESR (DAS28-ESR) or the CRP values (DAS28-CRP). We analyzed the data from 587 visits made by 220 patients with early arthritis. The age at the onset of the disease was 51+/-16 years old and 76.3% of the patients were women. The disease evolution at the first visit was 5 months and at each visit information related to several variables was collected, including that necessary to calculate the DAS28-ESR and DAS28-CRP. We defined a new variable DIFDAS=DAS28-ESR-DAS28-CRP to analyze which independent variables account for differences between the two indexes. There was a correlation between the two indexes of 0.91 (p<0.0001), although the DAS28-ESR value obtained was higher than that of DAS28-CRP at approximately 90% of the visits. Significantly, the difference between both indexes was higher than 0.6 in 44% of the visits studied. A multivariate analysis showed that female gender and disease duration were associated with the higher values obtained for DAS28-ESR when compared to those of DAS28-CRP. Our data show that DAS28-ESR and DAS28-CRP are not fully equivalent, because the former usually produces higher values. This finding is particularly relevant in females and patients with a long disease duration.


A theoretical study of substitution effect on an electrocyclization reaction.
A theoretical study of substitution effect on an electrocyclization reaction was performed using DFT method at B3LYP level of theory with 6-311G* basis sets. Equilibrium molecular geometries and harmonic vibrational frequencies of the reactant, transition state (TS), and product were calculated. The considered rate constants and activation thermodynamic parameters were calculated. The results indicated the reaction is low dependent to the temperature. These calculations showed that the reaction proceeds through an asynchronous non concerted mechanism and functional group has a major effect on the reaction.


Age and feeding system (supplemental feeding versus grazing) modulates colonic bacterial succession and host mucosal immune maturation in goats.
The gut microbiome plays important roles in the regulation of gastrointestinal tract functional development and host mucosal immune maturation. This study was conducted to test the hypothesis that age and feeding system (supplemental feeding [Sup] vs. grazing [G]) could alter colonic bacterial diversity and host mucosal immune maturation. Thirty Liuyang black goat kids ( = 4) were slaughtered on d 0, d 7 (nonrumination), d 28, d 42 (transition), and d 70 (rumination). The colonic microbiota was profiled by Miseq sequencing of the 16S rRNA gene. Host colonic mucosal immune maturation was examined using mRNA level expression of Toll-like receptors (TLR), proinflammatory cytokines, and the Toll-IL-1R (TIR) domain-containing adaptor. A correlation analysis was conducted to elucidate the relationship between bacterial diversity and fermentation parameters and host immune maturation variables. The results showed that α diversity indexes ( < 0.05), abundances of genera ( = 0.003) and ( = 0.024), ( = 0.004), and ( = 0.046) mRNA expressions were lower for Sup than for G, whereas the abundance of genera and ( < 0.05) was greater for Sup than for G. Regardless of the feeding system, bacterial 16S rRNA gene copy number and α diversity indexes increased ( < 0.05), whereas Proteobacteria abundance decreased linearly from d 0 to 70 after birth ( = 0.026). At the genus level, dominated the first week and declined sharply afterward, whereas abundance was greatest on d 7. abundance decreased linearly ( = 0.021), whereas abundances of , , , , and increased with age ( < 0.05). These findings coincided with increased , , and myeloid differentiation factor 88 () mRNA expressions with age ( < 0.05). Finally, correlation analysis revealed that different genera participated in different roles in fermentation capacity and host mucosal immune maturation. Collectively, colonic bacterial diversity and host mucosal immune maturation are age related, and concentrate supplement could alter bacterial diversity and alleviate overinflammation responses.


Future Research in Health Information Technology: A Review.
Currently, information technology is considered an important tool to improve healthcare services. To adopt the right technologies, policy makers should have adequate information about present and future advances. This study aimed to review and compare studies with a focus on the future of health information technology. This review study was completed in 2015. The databases used were Scopus, Web of Science, ProQuest, Ovid Medline, and PubMed. Keyword searches were used to identify papers and materials published between 2000 and 2015. Initially, 407 papers were obtained, and they were reduced to 11 papers at the final stage. The selected papers were described and compared in terms of the country of origin, objective, methodology, and time horizon. The papers were divided into two groups: those forecasting the future of health information technology (seven papers) and those providing health information technology foresight (four papers). The results showed that papers related to forecasting the future of health information technology were mostly a literature review, and the time horizon was up to 10 years in most of these studies. In the health information technology foresight group, most of the studies used a combination of techniques, such as scenario building and Delphi methods, and had long-term objectives. To make the most of an investment and to improve planning and successful implementation of health information technology, a strategic plan for the future needs to be set. To achieve this aim, methods such as forecasting the future of health information technology and offering health information technology foresight can be applied. The forecasting method is used when the objectives are not very large, and the foresight approach is recommended when large-scale objectives are set to be achieved. In the field of health information technology, the results of foresight studies can help to establish realistic long-term expectations of the future of health information technology.


Passive respiratory mechanics measured during natural sleep in healthy term neonates and infants up to 8 weeks of life.
The single occlusion technique (SOT) is a simple and noninvasive technique for measurement of passive respiratory mechanics in infants. Reference values based on measurements of a large population of healthy infants performed outside specialized research laboratories are lacking. The aim of this study was to present reference values for passive respiratory mechanics based on a large population of healthy term neonates and infants measured during natural sleep in routine care. As part of the ongoing Wheezing Illnesses Study Leidsche Rijn (WHISTLER), the compliance (C(rs)) and resistance (R(rs)) of the respiratory system were measured in 450 healthy unsedated neonates and infants with a mean age of 4.6 +/- 1.3 weeks. Multivariable regression analysis, with gestational age, age at measurement, body size, sex, and ethnicity as possible predictors, was carried out to estimate prediction equations for mean C(rs) and R(rs) values. Technically acceptable lung function measurements could be performed in 328 (73%) neonates and infants. Median C(rs) was 39.5 (range 14.8-79.1) ml/kPa and median R(rs) was 7.4 (range 3.8-19.5) kPa/L/sec. The following regression equations for C(rs) and R(rs) were obtained: ln C(rs) = 1.677 + 1.3 x 10(-4) x birth weight (g) + 0.030 x birth length (cm) and ln R(rs) = 2.496-3.1 x 10(-6) x birth length(3) (cm(3)) - 0.114 x sex. We provided reference values for passive respiratory mechanics using the SOT in a large population of healthy term neonates and infants measured during natural sleep. These data provide a frame of reference for assessing the normality of SOT measurements performed in routine care.


The representation of arm movements in postcentral and parietal cortex.
Considerable experimental evidence supports the hypothesis that the neocortical processes underlying kinesthetic sensation form a hierarchical series of cells signalling increasingly complex patterns of movement of the body. However, this view has been criticized and the data lack quantitative verification under controlled conditions. These studies have also typically used one-dimensional (reciprocal) movements, even of multiple degree-of-freedom joints such as the wrist or shoulder, and have been restricted to passive movements. This latter limitation is particularly critical, since the response of many muscle receptors is affected by fusimotor activity while that of many articular receptors is sensitive to the level of muscle contractile activity. Both factors introduce significant kinesthetic ambiguity to the signals arising from these receptors during active movement. This ambiguity is evident in the discharge of primary somatosensory cortex proprioceptive cells. Studies in area 5 show that single cells signal shoulder joint movements in the form of broad directional tuning curves. The pattern of activity of the entire population encodes movement direction. The cells appear to encode spatial aspects of movement unambiguously, since their discharge is relatively insensitive to the changes in muscle activity required to produce the same movements under different load conditions. It is not yet certain whether the somesthetic activity in area 5 is a kinesthetic representation that is sequential to and hierarchically superior to that in SI, or whether it is a parallel representation with separate and distinct function.


Severe and refractory peptic ulcer disease: the diagnostic dilemma: case report and comprehensive review.
The recognition of Helicobacter pylori infection as a cause of peptic ulcer disease, medical regimens to eradicate the organism, and the widespread use of proton pump inhibition to suppress gastric acid secretion have revolutionized the management of peptic ulcer disease. As a result, successful medical management of peptic ulcer disease has largely supplanted the need for gastric surgery by general surgeons. Surgery is reserved for complications of the disease, refractory disease, or rare causes of ulcer disease such as gastrinoma and Zollinger-Ellison syndrome. In this report, we describe a case of intractable peptic ulcer disease that progressed to gastric outlet obstruction despite maximal medical therapy. We review the diagnostic studies utilized to evaluate the potential etiologies of peptic ulcer disease and the difficulty in diagnosing gastrinoma and Zollinger-Ellison in the setting of potent medical acid suppression therapy.


The ER luminal binding protein (BiP) alleviates Cd(2+)-induced programmed cell death through endoplasmic reticulum stress-cell death signaling pathway in tobacco cells.
Cadmium (Cd) is very toxic to plant cells and Cd(2+) stress induces programmed cell death (PCD) in Nicotiana tabacum L. cv. bright yellow-2 (BY-2) cells. In plants, PCD can be regulated through the endoplasmic reticulum (ER) stress-cell death signaling pathway. However, the mechanism of Cd(2+)-induced PCD remains unclear. In this study, we found that Cd(2+) treatment induced ER stress in tobacco BY-2 cells. The expression of two ER stress markers NtBLP4 and NtPDI and an unfolded protein response related transcription factor NtbZIP60 were upregulated with Cd(2+) stress. Meanwhile, the PCD triggered by prolonged Cd(2+) stress could be relieved by two ER chemical chaperones, 4-phenylbutyric acid and tauroursodeoxycholic acid. These results demonstrate that the ER stress-cell death signaling pathway participates in the mediation of Cd(2+)-induced PCD. Furthermore, the ER chaperone AtBiP2 protein alleviated Cd(2+)-induced ER stress and PCD in BY-2 cells based on the fact that heterologous expression of AtBiP2 in tobacco BY-2 cells reduced the expression of NtBLP4 and a PCD-related gene NtHsr203J under Cd(2+) stress conditions. In summary, these results suggest that the ER stress-cell death signaling pathway regulates Cd(2+)-induced PCD in tobacco BY-2 cells, and that the AtBiP2 protein act as a negative regulator in this process.


[Evaluation of the application of hyaluronic acid in postoperative arthroscopy patients with grade II-III gonarthrosis using the WOMAC scale].
gonarthrosis is a degenerative disease, whose loss of cartilage causes changes in the adjacent bone and its response produces deformations and attempts at regeneration. In 1934 Meyer and Palmer isolated bovine vitreous humor, a polysaccharide called hyaluronic acid, which has the property of visco-elasticity. Today, multiple procedures performed in orthopedics are known, in order to limit the degenerative process that this entails. to know the use and efficacy of hyaluronic acid in the patient requiring knee arthroscopy, evaluating the evolution of the patient using the WOMAC scale; as well as the ideal time of application of hyaluronic acid in this study group. clinical, non-randomized, prospective, analytical trial. 48 patients from 45 to 60 years of age, divided into 3 groups with a diagnosis of gonarthrosis grade II-III, who underwent arthroscopy with subsequent hyaluronic acid application, were evaluated; in the postoperative period (group 1), one month after the postoperative period (group 2) and without application (group 3) in a period from September 2015 to June 2016 at the ISSSTE Hospital "Dr. Darío Fernández Fierro". the treatment showed differences in patients regarding reduction of pain and stiffness; and improvement in functional capacity. despite, there are no conclusive results if the treatment is better than the other, certain data suggests that using hyaluronic acid in the postoperative improves rigidity and function, however, it was not statistically significant.


Timing of critical genetic changes in human breast disease.
Breast cancer development has been characterized as a nonobligatory sequence of histological changes from normal epithelium through invasive malignancy. Although genetic alterations are thought to accumulate stochastically during tumorigenesis, little is known about the timing of critical mutations. This study examined allelic imbalance (AI) in tissue samples representing a continuum of breast cancer development to examine the evolution of genomic instability. Laser-microdissected DNA samples were collected from histologically normal breast specimens (n = 25), atypical ductal hyperplasia (ADH, n = 16), ductal carcinoma-in-situ (DCIS, n = 37), and stage I to III invasive carcinomas (n = 72). Fifty-two microsatellite markers representing 26 chromosomal regions commonly deleted in breast cancer were used to assess patterns of AI. AI frequencies were <5% in histologically normal and ADH specimens, 20% in DCIS lesions, and approximately 25% in invasive tumors. Mann-Whitney tests showed (1) that levels of AI in ADH samples did not differ significantly from those in histologically normal tissues and (2) that AI frequencies in DCIS lesions were not significantly different from those in invasive carcinomas. ADH and DCIS samples, however, differed significantly (P < .0001). DCIS lesions contain levels of genomic instability that are characteristic of advanced invasive tumors, and this suggests that the biology of a developing carcinoma may already be predetermined by the in situ stage. Observations that levels of AI in ADH lesions are similar to those in disease-free tissues provide a genomic rationale for why prevention strategies at the ADH level are successful and why cases with ADH involving surgical margins do not require further resection.


Predicting β-lactam susceptibility from the genome of Streptococcus pneumoniae and other mitis group streptococci.
For Streptococcus pneumoniae, β-lactam susceptibility can be predicted from the amino acid sequence of the penicillin-binding proteins PBP1a, PBP2b, and PBP2x. The combination of PBP-subtypes provides a PBP-profile, which correlates to a phenotypic minimal inhibitory concentration (MIC). The non-S. pneumoniae Mitis-group streptococci (MGS) have similar PBPs and exchange pbp-alleles with S. pneumoniae. We studied whether a simple BLAST analysis could be used to predict phenotypic susceptibility in Danish S. pneumoniae isolates and in internationally collected MGS. Isolates with available WGS and phenotypic susceptibility data were included. For each isolate, the best matching PBP-profile was identified by BLAST analysis. The corresponding MICs for penicillin and ceftriaxone was retrieved. Category agreement (CA), minor-, major-, and very major discrepancy was calculated. Genotypic-phenotypic accuracy was examined with Deming regression. Among 88 S. pneumoniae isolates, 55 isolates had a recognized PBP-profile, and CA was 100% for penicillin and 98.2% for ceftriaxone. In 33 S. pneumoniae isolates with a new PBP-profile, CA was 90.9% (penicillin) and 93.8% (ceftriaxone) using the nearest recognized PBP-profile. Applying the S. pneumoniae database to non-S. pneumoniae MGS revealed that none had a recognized PBP-profile. For Streptococcus pseudopneumoniae, CA was 100% for penicillin and ceftriaxone in 19 susceptible isolates. In 33 Streptococcus mitis isolates, CA was 75.8% (penicillin) and 86.2% (ceftriaxone) and in 25 Streptococcus oralis isolates CA was 8% (penicillin) and 100% (ceftriaxone). Using a simple BLAST analysis, genotypic susceptibility prediction was accurate in Danish S. pneumoniae isolates, particularly in isolates with recognized PBP-profiles. Susceptibility was poorly predicted in other MGS using the current database.


Nucleation and growth study of nano-PbO2 on Ti in different additives for electrocatalytic oxidation process.
Electrocrystallization of PbO2 on Ti electrode was studied in different bath solutions using cyclic voltammetry (CV), chronoamperometry (CA), and scanning electron microscopy. The cyclic voltammetry studies revealed that the addition of methanol postponed the oxygen evolution region and made over potential nucleation of PbO2 on Ti. Oxidation of PbO2 is preferred in second cycle (a peak) in other studied bath solutions, except the Nafion and aniline containing solution. In the presence of the pyrrole, the PbO2 formed at under deposition potential with less in numbers. Nafion and aniline inclusion turn the process in to progressive nucleation and growth without inhibition. On the other hand, other solutions studied are revealed the instantaneous nucleation and growth or inhibition at high potentials. Surface morphology explained that approximately equal to 300 nm sizes PbO2 particles with vertical nucleation and growth phenomena evidenced the Nafion and aniline are the important dopants. The results indicated that large current density or high potential polarization can be obtained in presence of methanol, Nafion, and aniline, which is one of the most important and necessary factors for forming high surface area PbO2 with strong adherence towards mediated electro-oxidation process.


Probing crystal structures and transformation reactions of ammonium molybdates by 14N MAS NMR spectroscopy.
The unique high-resolution feature offered by 14N magic-angle spinning (MAS) NMR spectroscopy of ammonium ions has been used to characterize the crystal structures of various ammonium molybdates by their 14N quadrupole coupling parameters, i.e., CQ, the quadrupole coupling constant, and etaQ, the asymmetry parameter. Two polymorphs of diammonium monomolybdate, (NH4)2MoO4, recently structurally characterized by single-crystal X-ray diffraction (XRD) and named mS60 and mP60, show distinct but different 14N MAS NMR spectra from each of which two sets of characteristic 14N CQ and etaQ values have been obtained. Similarly, the well-characterized ammonium polymolybdates (NH4)2Mo2O7, (NH4)6Mo7O24.4H2O, and (NH4)6Mo8O27.4H2O also give rise to distinct and characteristic 14N MAS NMR spectra. In particular, it is noted that simulation of the experimental (NH4)6Mo7O24.4H2O spectrum requires an iterative fit with six independent NH4+ sites. For the slow spinning frequencies employed (nu(r) = 1500-3000 Hz), all 14N MAS NMR spectra of the ammonium molybdates in this study are fingerprints of their identity. These different 14N MAS NMR fingerprints are shown to be an efficient tool in qualitative and quantitative assessment of the decomposition of (NH4)2MoO4 in humid air. Finally, by a combination of the 14N and 95Mo MAS NMR experiments performed here, it has become clear that a recent report of the 95Mo MAS spectra and data for the mS60 and mP60 polymorphs of (NH4)2MoO4 are erroneous because the sample examined had decomposed to (NH4)2Mo2O7.


Antinociceptive and Discriminative Stimulus Effects of Six Novel Psychoactive Opioid Substances in Male Rats.
Compounds with novel or fentanyl-like structures continue to appear on the illicit drug market and have been responsible for fatalities, yet there are limited preclinical pharmacological data available to evaluate the risk of these compounds to public health. The purpose of the present study was to examine acetyl fentanyl, butyryl fentanyl, 3,4-dichloro-N-[[1-(dimethylamino)cyclohexyl]methyl]benzamide (AH-7921), 1-cyclohexyl-4-(1,2-diphenylethyl)piperazine (MT-45), 4-chloro-N-[1-(2-phenylethyl)-2-piperidinylidene]-benzenesulfonamide (W-15), and 4-chloro-N-[1-[2-(4-nitrophenyl)ethyl]-2-piperidinylidene]-benzenesulfonamide (W-18) for their relative potency to reference opioids and their susceptibility to naltrexone antagonism using the 55oC warm-water, tail-withdrawal assay of antinociception and a morphine drug discrimination assay in male, Sprague-Dawley rats. In the antinociception assay, groups of 8 rats per drug were placed into restraining tubes, their tails were immersed into 40o or 55oC water, and the latency for tail withdrawal was measured with a cutoff time of 15 seconds. In the drug discrimination assay, rats (n = 11) were trained to discriminate between 3.2 mg/kg morphine and saline, subcutaneously, in a two-choice, drug discrimination procedure under a fixed ratio-5 schedule of sucrose pellet delivery. Morphine, fentanyl, and four of the synthetic opioids dose dependently produced antinociception and fully substituted for morphine in the drug discrimination assay with the following rank order of potency: fentanyl > butyryl fentanyl > acetyl fentanyl > AH-7921 > MT45 > morphine. All drugs that produced antinociception or morphine-like discriminative stimulus effects were blocked by naltrexone. W-15 and W-18 did not show antinociceptive or morphine-like discriminative stimulus effects at the doses tested supporting a lack of opioid activity for these two compounds. These findings suggest that butyryl fentanyl, acetyl fentanyl, AH-7941, and MT-45 have abuse liability like other opioid agonists. SIGNIFICANCE STATEMENT: As novel psychoactive substances appear on the illicit drug market, preclinical pharmacological testing is required to assist law enforcement, medical professionals, and legal regulators with decisions about potential public health risks. In this study, four synthetic opioids, acetyl fentanyl, butyryl fentanyl, AH-7921, and MT-45 produced effects similar to fentanyl and morphine and were blocked by naltrexone. These data suggest the four synthetic opioids possess similar abuse liability risks as typical opioid agonists.


The effects of early weaning on Pavlovian fear conditioning in young rats.
Early life stress enhances memory for Pavlovian fear conditioning. Stress enhancements on fear conditioning following early weaning, however, have yet to be studied in periweaning rats. Early weaning is a relevant animal model for human early life trauma, and Pavlovian fear conditioning is useful for identifying links between stress-induced developmental changes and behavior. We hypothesized that early weaning-on postnatal day (P)15-would lead to higher levels of conditional freezing relative to rats weaned later in life. Periweaning rats were trained with a discrete conditional stimulus (CS) and a shock unconditional stimulus (US), and tested 1 or 15 days later. Enhanced retention was observed in early weaned rats receiving forward paired CS-US training in Experiment 1, though this did not replicate in the second experiment. Despite overall enhancements in early weaned rats in Experiment 1, infantile amnesia effects were not overcome in young rats tested 15 days after training. Enhanced freezing levels in early weaned rats were not observed in subjects receiving unpaired CS, US training, and sensitivity to the US was not different due to age at weaning. Potential mechanisms underlying weaning-related enhancements and considerations for future studies including the role of social transmission of fear information are discussed.


The finger domain of the human deubiquitinating enzyme HAUSP is a zinc ribbon.
Human deubiquitinating enzyme HAUSP is a cysteine protease that regulates the levels of the tumor suppressor protein p53. By comparative sequence and structural analysis, we show that the previously uncharacterized finger domain insert to the catalytic core of HAUSP is a zinc ribbon that has lost its zinc-binding ability.


A case of oral geotrichosis caused by Geotrichum capitatum in an old patient.
Geotrichosis is an uncommon fungal infection. Geotrichum capitatum is commonly acknowledged as an opportunistic fungal pathogen that causes systemic geotrichosis in immunocompromised patients, especially patients with acute leukemia and severe neutropenia. Here, we report a case of oral geotrichosis caused by G. capitatum in an old patient with no hematological malignancies. Fungal cells were detected in clinical specimens obtained with oral swabs using the KOH technique. Yeast colonies with peripheral hairs were exclusively isolated as fungi from the oral mucosa and feces of the patient. The isolates were identified as G. capitatum by morphological findings, sugar-assimilation tests, and the nucleotide sequences of the ITS regions of the rDNA. Effective treatment of the patient was achieved with amphotericin B syrup in accord with the results of in vitro susceptibility tests. G. capitatum should be recognized as a fungal pathogen involved in superficial infections of older persons, as should Candida spp., even in the absence of hematological malignancies.


Effect of baclofen on sleep-related periodic leg movements.
Five patients with nocturnal myoclonus (periodic leg movements during sleep), mean age 59.6 years, were monitored polygraphically for fifteen successive nights. Using a double-blind drug study design with placebo at baseline, we investigated the effect of baclofen on these patients. All patients had the repetitive sleep-related abnormal movements during both the baseline nights and those on which baclofen had been administered. The number of movements varied during the four baseline nights, but the movements induced sleep fragmentation, i.e., very short electroencephalographic changes. Baclofen increased the number of movements but decreased their amplitude during non-rapid eye movement (REM) sleep and shortened the interval between movements. Its effect on sleep was dose related: as dosages increased, delta sleep progressively increased and REM sleep decreased. Sleep fragmentation resulting from muscle twitches decreased, as indicated by the diminution in alpha electroencephalographic arousals and K complexes. Baclofen dosages of 20 mg and 40 mg were the most efficacious.


Rupture of the acetabular cup in total arthroprosthesis of the hip (case report).
A case is reported of bilateral osteoarthritis of the hips treated in successive years by total prosthetic replacement of the Müller type. Six years after the second replacement, having been completely free from symptoms, she developed pain in the left hip due to rupture of the acetabular cup - a very rare complication.


Association of interleukin-6, C-reactive protein, interleukin-10 and adiponectin plasma concentrations with measures of obesity, insulin sensitivity and glucose metabolism.
Abnormal glucose tolerance is associated with subclinical chronic inflammation in patients with type 2 diabetes. The aim of this study was to investigate whether plasma concentrations of inflammatory markers are associated with measures of obesity, insulin sensitivity, and hyperglycemia. IL-6, adiponectin, CRP, and IL-10 plasma concentrations were evaluated in 142 patients with a wide range of obesity, insulin sensitivity and glucose tolerance. In parallel with the impairment of glucose tolerance, there was a significant increase in IL-6, and CRP, and a significant decrease in adiponectin and IL-10 plasma concentrations. There were significant correlations between the plasma concentrations of all inflammatory markers and % body fat, insulin sensitivity, and fasting plasma glucose. However, multivariate linear regression analysis identified insulin sensitivity as determined by glucose infusion rate during the steady state of an euglycemic-hyperinsulinemic clamp as the strongest predictor of adiponectin, CRP, IL-6, and IL-10 plasma concentrations. In addition, fasting plasma glucose was a significant determinant of adiponectin, CRP, and IL-6 plasma concentrations, whereas body fat content was only a significant predictor of CRP plasma concentration. In conclusion, our data suggest that abnormal inflammatory markers in patients with type 2 diabetes are primarily related to decreased insulin sensitivity.


Crystal structures and redox responses coupled with ion recognition of p-benzoquinone- and hydroquinone-fused [18]crown-6.
The crystal structures and redox properties of p-benzoquinone (BQ)-fused [18]crown-6 1 and bis-BQ-fused [18]crown-6 2 were examined. The anion radicals of these BQ molecules were stabilized by addition of metal ions, through effective electrostatic interactions between the negatively charged BQ moiety and positively charged ion-capturing [18]crown-6 unit. The electrostatic interactions and solvation energy played important roles in determining the magnitudes of anodic redox shifts in the reduction potentials. Regular π-stacking of BQ units and regular arrays of [18]crown-6 units were observed in crystal 2, in which one-dimensional π-electron columns were separated by ionic channels. The hydroquinone-fused [18]crown-6 molecule 3 and a new BQ- and phenol-fused [18]crown-6 derivative 4 were obtained as single crystals. The molecular conformations of [18]crown-6 in crystal 3 and hydrated crystal 3⋅H2 O were different from each other.


The effect of date versus sugar on sensory, physicochemical, and antioxidant properties of ice cream.
Despite the popularity of ice cream, its high content of sugar and fat is worrisome. Substituting sugar with natural and useful resources is one possible solution. Dates (Phoenix dactylifera) are rich in carbohydrates and are a good source of energy; they also have a large amount of phenolic compounds and anthocyanin. The aim of this study is to evaluate the effect of ice cream sugar replacement with date products. Accordingly, four ice cream samples with different sweeteners including 1) sucrose (as a control), 2) date pulp + sucrose, 3) date liquid sugar, and 4) sucrose + date liquid sugar, were produced. Total phenolics, anthocyanins, and antioxidant activities of dates and their effects on physicochemical and sensory properties of ice cream were investigated. A large amount of phenolic compounds and anthocyanin was found in the ice cream contained date pulp and liquid sugar, which enhanced the reducing power and antioxidant effect of it. The overrun and density of an ice cream did not change with sugar replacement. Total substitution of sucrose by date liquid sugar, increased the titratable acidity, viscosity, and antioxidant properties of ice cream, but it was found to have some negative effects on the organoleptically score of color. However, the partial replacement of granular sugar with date pulp/liquid sugar, improved the antioxidant value of this dairy dessert without any change in its color. It seems that the addition of date pulp to an ice cream, not only maintain the quality and sensory properties of an ice cream, but also provides an antioxidant property.


[Antibodies against hyaline cartilage. Antigen isolation and their characterization].
Extracts from human hyaline cartilage were analyzed quantitatively. The extracts were obtained by the action of salts, enzymatic processing and chromatography on Sephadex G-200 columns. The obtained fractions were characterized by thin layer chromatographic methods, electrophoretically, and immunochemically by means of polyclonal antibodies to individual components. Qualitative analysis of amino acids and electrophoretic separation showed that the 1st fraction contained mainly proteins and glycosaminoglycans after separation on Sephadex G-200, while the 2nd fraction exhibited mainly amino acids characteristic for collagen.


A new approach for bioethanol production from sugarcane bagasse using hydrodynamic cavitation assisted-pretreatment and column reactors.
Hydrodynamic cavitation (HC) was adopted to assist alkaline-hydrogen peroxide pretreatment of sugarcane bagasse (SCB). In the following condition: 0.29 M of NaOH, 0.78% (v/v) of H2O2, 9.95 min of process time and 3 bar of inlet pressure, 95.4% of digestibility of cellulosic fraction was achieved. To take the best use of the pretreated biomass, the overall process was intensified by way of employing a packed bed flow-through column reactor and thus enabling to handle a high solid loading of 20%, thereby leading to cellulose and hemicellulose conversions to 74.7% and 75%, respectively. In the fermentation step, a bubble column reactor was introduced to maximize ethanol production from the pretreated SCB by Scheffersomyces stipitis NRRL-Y7124, resulting in 31.50 g/L of ethanol, 0.49 g/g of ethanol yield and 0.68 g/L.h of productivity. All this showed that our HC-assisted NaOH-H2O2 pretreatment strategy along with the process intensification approach might offer an option for SCB-based biorefineries.


Absence of interferons-alpha and -gamma in renal lesions of systemic lupus erythematosus and membranous glomerulonephritis.
Frozen kidney biopsy sections from nine patients with systemic lupus erythematosus (SLE) as well as many other renal diseases, including IgA nephropathy, membranous nephritis, and minimal change nephrotic syndrome, were negative for interferons -alpha and -gamma by immunofluorescence. Lupus patients studied included several subjects with marked serum elevations of interferon activity as well as others with low or negative serum interferon levels. Isolated glomerular eluates prepared from normal and SLE kidneys showed no functional interferon activity by virus plaque inhibition assay. Components of normal as well as SLE serum showed no direct binding to interferon -alpha or -gamma by ELISA assays.


Optical force field mapping in microdevices.
We present a method for characterizing microscopic optical force fields. Two dimensional vector force maps are generated by measuring the optical force applied to a probe particle for a grid of particle positions. The method is used to map out the force field created by the beam from a lensed fiber inside a liquid filled microdevice. We find transverse gradient forces and axial scattering forces on the order of 2 pN per 10 mW laser power which are constant over a considerable axial range (>35 microm). These findings suggest future useful applications of lensed fibers for particle guiding/sorting. The propulsion of a small particle at a constant velocity of 200 microm s(-1) is shown.


Multiple Substrate Usage of Coxiella burnetii to Feed a Bipartite Metabolic Network.
The human pathogen Coxiella burnetii causes Q-fever and is classified as a category B bio-weapon. Exploiting the development of the axenic growth medium ACCM-2, we have now used 13C-labeling experiments and isotopolog profiling to investigate the highly diverse metabolic network of C. burnetii. To this aim, C. burnetii RSA 439 NMII was cultured in ACCM-2 containing 5 mM of either [U-13C3]serine, [U-13C6]glucose, or [U-13C3]glycerol until the late-logarithmic phase. GC/MS-based isotopolog profiling of protein-derived amino acids, methanol-soluble polar metabolites, fatty acids, and cell wall components (e.g., diaminopimelate and sugars) from the labeled bacteria revealed differential incorporation rates and isotopolog profiles. These data served to decipher the diverse usages of the labeled substrates and the relative carbon fluxes into the core metabolism of the pathogen. Whereas, de novo biosynthesis from any of these substrates could not be found for histidine, isoleucine, leucine, lysine, phenylalanine, proline and valine, the other amino acids and metabolites under study acquired 13C-label at specific rates depending on the nature of the tracer compound. Glucose was directly used for cell wall biosynthesis, but was also converted into pyruvate (and its downstream metabolites) through the glycolytic pathway or into erythrose 4-phosphate (e.g., for the biosynthesis of tyrosine) via the non-oxidative pentose phosphate pathway. Glycerol efficiently served as a gluconeogenetic substrate and could also be used via phosphoenolpyruvate and diaminopimelate as a major carbon source for cell wall biosynthesis. In contrast, exogenous serine was mainly utilized in downstream metabolic processes, e.g., via acetyl-CoA in a complete citrate cycle with fluxes in the oxidative direction and as a carbon feed for fatty acid biosynthesis. In summary, the data reflect multiple and differential substrate usages by C. burnetii in a bipartite-type metabolic network, resembling the overall topology of the related pathogen Legionella pneumophila. These strategies could benefit the metabolic capacities of the pathogens also as a trait to adapt for replication under intracellular conditions.


Low prevalence of long-term breastfeeding among women with type 2 diabetes.
To investigate the prevalence of long-term breastfeeding among women with type 2 diabetes compared to women with type 1 diabetes and to identify predictors of long-term breastfeeding for women with pre-gestational diabetes. In total, 149 women with diabetes were interviewed about long-term breastfeeding, defined as any breastfeeding 4 months postpartum. Ninety-eight percent of the women aimed to breastfeed. At time of discharge, any breastfeeding was frequent for both groups of women (86% versus 93%, p = 0.17). However, 4 months postpartum, the 44 women with type 2 diabetes showed significantly lower prevalence of breastfeeding than the 105 women with type 1 diabetes (34% versus 61%, p < 0.01). Number of feedings in the first 24 h was an independent positive predictor, whereas pre-pregnancy body mass index (BMI) and smoking were independent negative predictors of long-term breastfeeding. The prevalence of long-term breastfeeding among women with type 2 diabetes was considerably lower than in women with type 1 diabetes. Number of feedings in the first 24 h was positive and BMI and smoking were negative predictors of long-term breastfeeding in women with pre-gestational diabetes.


Release and permeation kinetics of caffeine from bioadhesive transdermal films.
The aim of this work was to investigate, in vitro, the kinetics of release and permeation of caffeine, chosen as model drug, from bioadhesive transdermal films. These films are not self-adhesive but become adhesive when applied to wet skin. Permeation experiments were performed from films with different drug loadings using rabbit ear skin as barrier. In order to characterize the release kinetics of caffeine from the film, a polyethylene membrane, impregnated with isopropyl myristate was employed. The data obtained in the present work suggest that caffeine release from transdermal bioadhesive films was controlled either by the permeability characteristics of the skin or by the film itself, depending on drug loading. When drug loading is low (ie, caffeine is dissolved in the polymers constituting the film), the control resides in the skin. When caffeine loading exceeds its solubility in the film, the permeation profile is not linear, but shows a sort of burst effect in the early times of permeation, probably owing to the presence of solid drug and/or to a certain degree of "conserved supersaturation" in the solid phase.


After total knee replacement younger patients demonstrate superior balance control compared to older patients when recovering from a forward fall.
National joint replacement registries have reported a substantial growth in younger knee osteoarthritic patients (<55years old) undergoing total knee replacement, however this younger population is generally understudied. Importantly, studies examining experimentally controlled perturbation have shown age-related differences between younger and older healthy adults, whether similar age-related differences exist among total knee replacement patients is unknown. A total of 59 participants, including 29 unilateral total knee replacement patients (six-months post-surgery) made up the four experimental groups: 1) younger patient (54.3 (SD 7.9) years), 2) younger control (55.2 (SD 4.0) years), 3) older patient (76.9 (SD 4.7) years), and 4) older control (77.7 (SD 4.1) years). Using a tether-release method to perturb balance and simulate a forward fall, center of mass and stepping characteristics were analyzed. Younger patients recovered following the perturbation with a significantly smaller center of mass displacement compared to the older patients (14.85 (SD 0.01) v. 18.13 (SD 0.02) %ht, p=0.02); utilizing a longer (0.43 (SD 0.02) v. 0.39 (SD 0.03) m, p<0.001) and higher velocity (2.01 (SD 0.2) v. 1.59 (SD 0.2) m/s, p=0.001) recovery step. Importantly, younger patients did not differ significantly from the younger controls in center of mass displacement or recovery step characteristics (p>0.05). The younger patients demonstrated superior center of mass control in response to a forward perturbation, suggesting that younger patients would be at a reduced risk of falling when recovering from a forward-directed postural perturbation compared to older patients.


Ontogeny of Sex-Related Differences in Foetal Developmental Features, Lipid Availability and Fatty Acid Composition.
Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs (brain, heart, liver and spleen). Cholesterol and triglyceride availability was similar in male and female offspring, but female foetuses showed evidence of higher placental transfer of essential fatty acids and synthesis of non-essential fatty acids in muscle and liver. These sex-related differences affected primarily the neutral lipid fraction (triglycerides), which may lead to sex-related postnatal differences in energy partitioning. These results illustrate the strong influence of the maternal lipid profile on foetal development and homeorhesis, and they confirm and extend previous reports that female offspring show better adaptive responses to maternal malnutrition than male offspring. These findings may help guide dietary interventions to ensure adequate fatty acid availability for postnatal development.


Exposure-Response Analysis of Necitumumab Efficacy in Squamous Non-Small Cell Lung Cancer Patients.
We sought to describe the exposure-response relationship of necitumumab efficacy in squamous non-small cell lung cancer patients and evaluate intrinsic and extrinsic patient descriptors that may guide dosing. SQUIRE was a phase III study comparing necitumumab in combination with gemcitabine and cisplatin vs. gemcitabine and cisplatin alone in 1,014 patients. An integrated model for tumor size dynamics and overall survival was developed, where reduction in tumor size results in a decrease in survival hazard. The change in tumor size was characterized using linear growth and first-order shrinkage. Overall survival was described using a combination of a Weibull function and Gompertz function for the hazard, with dynamic tumor size being a predictor for the hazard. Although body weight resulted in higher clearance and lower exposure, simulations showed that an 800 mg flat dose provided optimal response regardless of body weight.


Surgical treatments/interventions for pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines.
While considerable advances have been achieved in the medical treatment of pulmonary arterial hypertension (PAH) over the past decade, surgical and interventional approaches continue to have important roles in those patients for whom medical therapy is unavailable or has been unsuccessful. These techniques include pulmonary thromboendarterectomy for chronic thromboembolic pulmonary hypertension, thoracic transplantation, and atrial septostomy. This chapter will provide evidence-based recommendations for the selection and timing of surgical and interventional treatments of PAH for physicians involved in the care of these complex patients.


Expression of C-KIT and HER-2 tyrosine kinase receptors in poor-prognosis breast cancer.
This study investigated the expression of C-KIT and HER-2 receptors and their correlation with histopathological markers of cell proliferation, differentiation and apoptosis in poor-prognosis breast cancer. Formalin-embedded histopathological samples from forty patients with progressive metastatic breast cancer were reanalyzed to determine HER-2 expression by immunohistochemistry (ICH) and chromogenic in situ hybridization (CISH). C-KIT receptor expression, p53, Bcl-2 and Ki-67 were determined by immunohistochemistry. The mean p53 score was 18.03 (SD 30.69), that of Bcl-2 was 38.13 (39.25) and Ki-67 was 5.8 (SD 9.23), respectively. HER-2 expression was positive in 35% of patients by ICH and in 25% by CISH. C-KIT receptor staining was positive in 82% of the patients. A significant association was observed between HER-2-positive score in ICH and poorly-differentiated histology (p=0.03), negative Er/Pr status (p=0.04) and Bcl-2 expression (p=0.003). With CISH-determined HER-2, the corresponding p values were 0.07, 0.053, and 0.002, respectively. No correlation was found between HER-2 or C-KIT expression (p=0.456). CISH and ICH determination of HER-2 correlate similarly to hormone receptor status and Bcl-2 expression in breast cancer. C-KIT expression was commonly present and did not correlate to other prognosticators in poor-prognosis breast cancer.


Transcranial magnetic stimulation: applications for neuropsychopharmacology.
Transcranial magnetic stimulation (TMS) provides new possibilities for studying localized changes in the electrical properties of the human cortex. TMS combined with electromyography (EMG) has revealed that drugs blocking Na(+) or Ca(2+) channels such as phenytoin, lamotrigin or carbamazepine change the motor threshold without affecting intracortical inhibition or facilitation. Gabaergic agents vigabatrin, lorazepam, diazepam, baclofen and ethanol do not affect the motor threshold, but increase intracortical inhibition and decrease facilitation. N-methyl-D-aspartate receptor antagonists riluzole, dextromethorphan and memantine have similar effects. Dopamine receptor antagonists such as haloperidol, but not sulpiride, decrease intracortical inhibition and increase intracortical facilitation. Other monoamines, such as serotonin and noradrenaline, may have some modulating effect on the cortical excitability. However, TMS combined with EMG gives only indirect evidence about the excitability of the motor cortex because spinal mechanisms may contribute to the results. Cortical excitability can be studied directly by combining TMS with brain imaging methods such as electroencephalography (EEG). Motor and non-motor areas can be stimulated and subsequent brain activity can be measured. Ethanol has been shown to modulate EEG responses evoked by motor-cortex TMS, the effects being largest at the right prefrontal cortex, meaning that ethanol would have changed the functional connectivity. Furthermore, alcohol decreases amplitudes of EEG responses after the left prefrontal stimulation mainly in anterior parts of the cortex, which may be associated with the decrease of the prefrontal cortical excitability. Taken together, TMS provides a new insight to the actions of central nervous system drugs at the cortical level.


Characterization of calumenin in mouse heart.
Calumenin is a multiple EF-hand Ca2+-binding protein located in the endo/sarcoplasmic reticulum of mammalian hearts. Calumenin belongs to the CREC family of Ca2+-binding proteins having multiple EF-hands. Ca2+ homeostasis in the sarcoplasmic reticulum (SR) of mammalian hearts is maintained by RyR2, SERCA2 and other associated SR resident proteins. Evidence suggests that calumenin interacts with RyR2 and SERCA2, and therefore changes in the expression of calumenin could alter Ca2+ cycling in mouse heart. In this review, current knowledge of the biochemical and functional roles of calumenin in mouse heart is described.


The dynamics of medical care use in the British household panel survey.
We explore whether medical care use is persistent over a long panel using 18 waves of the British Household Panel Survey. Of particular interest is high medical care use because a few high users account for a disproportionate amount of use while many individuals use no medical care in a given year. If health is a primary driver of medical care demand, and we control for health, then past medical care use should be uninformative for future use. However, we find that conditional on health, other covariates and unobservable heterogeneity, medical care use remains significantly persistent. "No use" and "high use" are more strongly persistent, and persistence is generally stronger for women, those in poor health, and at older ages. We find that unobservable heterogeneity explains between 10% and 25% of the variation in medical care use. This heterogeneity is significantly correlated with both medical care use and health over our long panel. These findings have implications for the econometric modeling of medical care demand and suggest that policies aimed to reduce aggregate medical care spending by improving health, particularly the health of seniors, may be less effective than projected using static models.


Determination of Arbutin in Rat Plasma Using Liquid Chromatography-Tandem Mass Spectrometry: Application to a Pharmacokinetic Study After Oral Administration of the Extract of Vaccinium vitis-idaea.
A rapid and sensitive bioassay based on liquid chromatography-tandem mass spectrometry (LC-MS-MS) has been developed and validated to measure arbutin in rat plasma. Sample preparation of plasma after the addition of indapamide as internal standard (IS) involved solid-phase extraction (SPE) on C18 cartridges. Reversed-phase chromatography using acetonitrile and 0.5% formic acid solution (pH 2.56) was used for separation in a run time of 4.0 min. The analytes were detected in the negative ion mode using selective reaction monitoring (SRM) of the transitions at m/z 271.2 → 107.8 for arbutin and 364.3 → 189.0 for indapamide. The method has the following performance characteristics: a reliable response range of 7.5-5250.0 ng/mL with correlation coefficients (r) of >0.995. The lower limit of quantitation (LLOQ) was 7.5 ng/mL. The intra- and inter-day precision and accuracy of the quality control (QC) samples at low, medium and high concentration levels showed ≤8.79% relative standard deviation (RSD) and -1.15 to 1.49% relative error (RE). The method was successfully applied to a pharmacokinetic study to measure arbutin in rats after extracts of Vaccinium vitis-idaea was orally administered.


An Interprofessional Education Panel on Development, Implementation, and Assessment Strategies.
This report provides a primer for implementing interprofessional education (IPE) within pharmacy and health sciences curricula. In 2013, a panel of administrators and faculty members, whose institutions offered IPE, funded by the Josiah Macy Jr. Foundation, shared best collaborative practice models at the American Association of Colleges of Pharmacy (AACP) Annual Meeting. These presenters subsequently collaborated to write a primer as guidance for other institutions interested in successfully implementing and continuously enhancing the quality of IPE programs. In this article, these IPE faculty members provide a rationale for creating IPE reforms, discuss successful strategies for innovative IPE programs, and share lessons learned for implementing effective assessment tools. A structure and process for determining outcomes of IPE models are presented and strategies for exploring shared education opportunities across health professions and for integrating top-down and bottom-up methods for IPE programs are given.


Adjuvant immunotherapy with nivolumab versus observation in completely resected Merkel cell carcinoma (ADMEC-O): disease-free survival results from a randomised, open-label, phase 2 trial.
Merkel cell carcinoma (MCC) is an immunogenic but aggressive skin cancer. Even after complete resection and radiation, relapse rates are high. PD-1 and PD-L1 checkpoint inhibitors showed clinical benefit in advanced MCC. We aimed to assess efficacy and safety of adjuvant immune checkpoint inhibition in completely resected MCC (ie, a setting without an established systemic standard-of-care treatment). In this multicentre phase 2 trial, patients (any stage, Eastern Cooperative Oncology Group performance status 0-1) at 20 academic medical centres in Germany and the Netherlands with completely resected MCC lesions were randomly assigned 2:1 to receive nivolumab 480 mg every 4 weeks for 1 year, or observation, stratified by stage (American Joint Committee on Cancer stages 1-2 vs stages 3-4), age (<65 vs ≥65 years), and sex. Landmark disease-free survival (DFS) at 12 and 24 months was the primary endpoint, assessed in the intention-to-treat populations. Overall survival and safety were secondary endpoints. This planned interim analysis was triggered when the last-patient-in was followed up for more than 1 year. This study is registered with ClinicalTrials.gov (NCT02196961) and with the EU Clinical Trials Register (2013-000043-78). Between Oct 1, 2014, and Aug 31, 2020, 179 patients were enrolled (116 [65%] stage 3-4, 122 [68%] ≥65 years, 111 [62%] male). Stratification factors (stage, age, sex) were balanced across the nivolumab (n=118) and internal control group (observation, n=61); adjuvant radiotherapy was more common in the control group. At a median follow-up of 24·3 months (IQR 19·2-33·4), median DFS was not reached (between-groups hazard ratio 0·58, 95% CI 0·30-1·12); DFS rates in the nivolumab group were 85% at 12 months and 84% at 24 months, and in the observation group were 77% at 12 months and 73% at 24 months. Overall survival results were not yet mature. Grade 3-4 adverse events occurred in 48 [42%] of 115 patients who received at least one dose of nivolumab and seven [11%] of 61 patients in the observation group. No treatment-related deaths were reported. Adjuvant therapy with nivolumab resulted in an absolute risk reduction of 9% (1-year DFS) and 10% (2-year DFS). The present interim analysis of ADMEC-O might suggest clinical use of nivolumab in this area of unmet medical need. However, overall survival events rates, with ten events in the active treatment group and six events in the half-the-size observation group, are not mature enough to draw conclusions. The explorative data of our trial support the continuation of ongoing, randomised trials in this area. ADMEC-O suggests that adjuvant immunotherapy is clinically feasible in this area of unmet medical need. Bristol Myers Squibb.


Shiga toxin-producing Escherichia coli infection and antibodies against Stx2 and Stx1 in household contacts of children with enteropathic hemolytic-uremic syndrome.
Ninety-five household contacts (aged 2 months to 73 years) of patients with enteropathic hemolytic-uremic syndrome (HUS) were investigated for the presence of immunoglobulin (Ig) G antibodies to Shiga toxins Stx2 and Stx1 by Western blot assay. Thirty-one percent of the household contacts and 19% of 327 controls had anti-Stx2 IgG (heavy and light chain [H + L]), 5 and 8%, respectively, had anti-Stx1 IgG (H + L), and 3 and 2%, respectively, had both anti-Stx2 and anti-Stx1 IgG (H + L). The incidence of infections with Stx-producing Escherichia coli (STEC) was determined based on the following diagnostic criteria: STEC isolation, detection of stx gene sequences, free fecal Stx in stool filtrates, and serum IgM antibodies against E. coli O157 lipopolysaccharide. Evidence of STEC infection was observed in 25 household contacts, of whom 18 (72%) were asymptomatic and represented a potential source of infection. Six of 13 (46%) household contacts with Stx2-producing E. coli O157:H7 in stool culture developed anti-Stx2 IgG (H + L), compared to 71% of Stx2-associated HUS cases. In individuals showing anti-Stx2 IgG (H + L), the antibody response was directed against the B subunit in 69% of household contacts and 71% of controls, in contrast to 28% of HUS patients. In this investigation controls had a significant increase of the median of IgM antibodies to O157 lipopolysaccharide (LPS) with age, up to the fifth decade. The lack of disease in household contacts with B subunit-specific antibodies, as well as the significantly higher median of anti-O157 LPS IgM antibodies in controls beyond 4.9 years of age, suggests a protective role for anti-Stx and anti-O157 LPS antibodies.


Invalidity of Tokyo guidelines in acute biliary pancreatitis: A multicenter cohort analysis of 944 pancreatitis cases.
There is a noteworthy overlap between the clinical picture of biliary acute pancreatitis (AP) and the 2018 Tokyo guidelines currently used for the diagnosis of cholangitis (AC) and cholecystitis (CC). This can lead to significant antibiotic and endoscopic retrograde cholangiopancreatography (ERCP) overuse. We aimed to assess the on-admission prevalence of AC/CC according to the 2018 Tokyo guidelines (TG18) in a cohort of biliary AP patients, and its association with antibiotic use, ERCP and clinically relevant endpoints. We conducted a secondary analysis of the Hungarian Pancreatic Study Group's prospective multicenter registry of 2195 AP cases. We grouped and compared biliary cases (n = 944) based on the on-admission fulfillment of definite AC/CC according to TG18. Aside from antibiotic use, we evaluated mortality, AC/CC/AP severity, ERCP performance and length of hospitalization. We also conducted a literature review discussing each criteria of the TG18 in the context of AP. 27.8% of biliary AP cases fulfilled TG18 for both AC and CC, 22.5% for CC only and 20.8% for AC only. Antibiotic use was high (77.4%). About 2/3 of the AC/CC cases were mild, around 10% severe. Mortality was below 1% in mild and moderate AC/CC patients, but considerably higher in severe cases (12.8% and 21.2% in AC and CC). ERCP was performed in 89.3% of AC cases, common bile duct stones were found in 41.1%. Around 70% of biliary AP patients fulfilled the TG18 for AC/CC, associated with a high rate of antibiotic use. Mortality in presumed mild or moderate AC/CC is low. Each of the laboratory and clinical criteria are commonly fulfilled in biliary AP, single imaging findings are also unspecific-AP specific diagnostic criteria are needed, as the prevalence of AC/CC are likely greatly overestimated. Randomized trials testing antibiotic use are also warranted.


Right abdominal mass in a 2 year-old child.
The authors report a case of a wandering spleen presenting as a right lower quadrant abdominal mass, 2 years post a transabdominal left diaphragmatic hernia repair in a 2-year-old child with a congenital diaphragmatic hernia. The wandering spleen was fixed laparoscopically in an extraperitoneal pouch.


Plasmid-controlled colonization factor associated with virulence in Esherichia coli enterotoxigenic for humans.
An enterotoxin-producing strain of Escherichia coli isolated from a case of cholera-like diarrhea (E. coli strain H-10407) was found to possess a surface-associated colonization factor. Colonization was manifested as the ability of small inocula (10(5) bacteria) to attain large (10(9)) populations in the infant rabbit intestine with a concomitant diarrheal response. A laboratory-passed derivative of E. coli H-10407, designated H-10407-P, failed to exhibit an increase in population in the infant rabbit and also failed to induce diarrhea. Cell-free culture supernatant fluids of E. coli H-10407 and H-10407-P produced equivalent enterotoxic responses in infant and in adult rabbits. Specific anti-colonization factor antiserum was produced by adsorbing hyperimmune anti-H-10407 serum with both heat-killed and living cells E. coli H-10407-P. This specific adsorbed serum protected infant rabbits from challenge with living E. coli H-10407 although the serum did not possess bactericidal activity. The anti-colonization factor serum did not agglutinate a strain of E. coli K-12 possessing the K88 colonization factor peculiar to E. coli enterotoxigenic for swine. By electron microscopy it was demonstrated that E. coli H-10407, but not H10407-, possessed pilus-like surface structures which agglutinated with the specific adsorbed (anti-colonization factor) antiserum. E. coli H-10407 possessed three species of plasmid deoxyribonucleic acid, measuring 60 X 10(6), 42 X 10(6), and 3.7 X 10(6) daltons, respectively. E. coli H-10407-P possessed only the 42 X 10(6)- and the 3.7 X 10(6)-dalton plasmid species. Spontaneous loss of the specific H-10407 surface-associated antigen was accompanied by loss of the 60 X 10(6)-dalton species of plasmid deoxyribonucleic acid and loss of colonizing ability. Thus, it is concluded that the E. coli colonization factor described here is a virulence factor which may play an important and possibly essential role in naturally occurring E. coli enterotoxic diarrhea in man.


CO tolerance of Pt and PtSn intermetallic electrocatalysts on synthetically modified reduced graphene oxide supports.
Pt and PtSn intermetallic nanoparticle (NP) catalysts were grown directly on various reduced graphene oxide (rGO) supports and were characterized by a combination of X-ray photoelectron spectroscopic (XPS), Raman microscopy, transmission electron microscopy (TEM), and powder X-ray diffraction (XRD) studies. Electrochemical CO stripping and rotating disk electrochemical (RDE) experiments showed the four rGO-PtSn catalysts to be superior to the four rGO-Pt catalysts for CO and CO-H2 electrooxidation in acidic solutions regardless of the rGO support, in agreement with earlier reports on PtSn NP electrocatalysts. For the four rGO-Pt catalysts, the rGO support causes a 70 mV spread in CO oxidation peak potential (ΔEpeak) and a 200 mV spread in CO-H2 electrooxidation onset. The more oxygenated graphenes show the lowest CO oxidation potentials and the best CO tolerance. For the four rGO-PtSn intermetallic catalysts, a ∼160 mV spread in CO-H2 electrooxidation onset is observed. With the exception of the nitrogen-doped graphene (NGO), a similar trend in enhanced CO electrooxidation properties with increasing oxygen content in the rGO support is observed. The NGO-PtSn electrocatalyst was superior to the other rGO-PtSn catalysts and showed the largest improvement in CO tolerance relative to the pure Pt system. The origin of this enhancement appears to stem from the unique rGO-PtSn support interaction in this system. These results are discussed in the context of recent theoretical and experimental studies in the literature.


Butyrate Protects Myenteric Neurons Loss in Mice Following Experimental Ulcerative Colitis.
The enteric nervous system is affected by inflammatory bowel diseases (IBD). Gut microbiota ferments dietary fibers and produces short-chain fatty acids, such as Butyrate, which bind to G protein-coupled receptors, such as GPR41, and contribute to maintaining intestinal health. This work aimed to study the GPR41 in myenteric neurons and analyze the effect of Butyrate in mice submitted to experimental ulcerative colitis. The 2, 4, 6 trinitrobenzene sulfonic acid (TNBS) was injected intrarectally in C57BL/6 mice (Colitis). Sham group received ethanol (vehicle). One group was treated with 100 mg/kg of Sodium Butyrate (Butyrate), and the other groups received saline. Animals were euthanized 7 days after colitis induction. Analyzes demonstrated colocalization of GPR41 with neurons immunoreactive (-ir) to nNOS and ChAT-ir and absence of colocalization of the GPR41 with GFAP-ir glia. Quantitative results demonstrated losses of nNOS-ir, ChAT-ir, and GPR41-ir neurons in the Colitis group and Butyrate treatment attenuated neuronal loss. The number of GFAP-ir glia increased in the Colitis group, whereas Butyrate reduced the number of these cells. In addition, morphological alterations observed in the Colitis group were attenuated in the Butyrate group. The presence of GPR41 in myenteric neurons was identified, and the treatment with Butyrate attenuated the damage caused by experimental ulcerative colitis.


The hidden ethical element of nursing care rationing.
To explore nurses' experiences and perceptions about prioritizations, omissions, and rationing of bedside nursing care. A total of 23 nurses participated in four focus groups. The interviews were based on a semi-structured interview guide; data were analyzed using a thematic analysis approach. Four themes were developed based on the data: (a) priorities in the delivery of care; (b) professional roles, responsibilities, and role conflicts; (c) environmental factors influencing care omissions; and (d) perceived outcomes of rationing. The delivery of nursing care is framed by the biomedical ethos and inter-professional role conflict while the standards of basic care are jeopardized. Organizational and environmental factors appear to exert significant influence on prioritization. Failure to carry out necessary nursing tasks may lead to adverse patient outcomes, role conflict, and an ethical burden on nurses. There is a need for further exploration and possible redesign of the nursing role, scope, and responsibilities, as well as addressing the arising ethical issues of rationing in nursing care.


Complement proteins and macrophages. II. The secretion of factor B by lipopolysaccharide-stimulated macrophages.
The secretion of factor B by mouse peritoneal macrophages was found to be enhanced following in vivo or in vitro stimulation with lipopolysaccharide (LPS). The intravenous administration of LPS to mice of various strains caused an increased release of factor B but not the release of acid phosphatase by the peritoneal macrophages obtained from the stimulated mice. In vitro stimulation of cultured macrophages with LPS resulted in an enhanced secretion of both factor B and acid phosphatase. The dose-dependent augmentation of factor B secretion by LPS was found in the macrophages from LPS-responsive C3H/HeN mice, whereas the macrophages from LPS-unresponsive C3H/HeJ mice did not respond to either phenol-extracted LPS or butanol-extracted LPS. The ability of LPS to cause the enhancement of factor B secretion by macrophages was abolished by alkali or acid treatment of LPS, indicating that its lipid A part was responsible for the observed effect.


Constituents of Two Dioscorea Species That Potentiate Antibiotic Activity against MRSA.
The isolation of two diarylnonanoids from Dioscorea cotinifolia possessing antibiotic-potentiating activity against resistant strains of S. aureus are reported. The diarylnonanoids are a class of natural products similar in structure to the diarylheptanoids, which have a wide spectrum of reported biological activities. One of the diarylnonanoids (1) isolated possesses a chiral center, and to deduce its configuration, the modified Mosher ester method was used. Using both 1D and 2D NMR data, as many protons as possible were assigned to both the R- and S-MTPA esters, and the configuration of the chiral center in 1 was determined to be R. Both the chiral and achiral diarylnonanoid (2) exhibited potent antibiotic-potentiating activity with the chiral natural product showing a greater tetracycline-potentiating activity than 2. Interestingly, 2 gave a higher norfloxacin-potentiating activity with a resultant higher efflux pump inhibitory activity. Manipulation of the structure of the diarylnonanoids through synthesis could lead to improved biological activity.


Synthesis of a new intercalating nucleic acid 6H-INDOLO[2,3-b] quinoxaline oligonucleotides to improve thermal stability of Hoogsteen-type triplexes.
A new intercalating nucleic acid monomer X was obtained in high yield starting from alkylation of 4-iodophenol with (S)-(+)-2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethanol under Mitsunobu conditions followed by hydrolysis with 80% aqueous acetic acid to give a diol which was coupled under Sonogashira conditions with trimethylsilylacetylene (TMSA) to achieve the TMS protected (S)-4-(4-((trimethylsilyl)ethynyl)phenoxy)butane-1,2-diol. Tetrabutylammonium flouride was used to remove the silyl protecting group to obtain (S)-4-(4-ethynylphenoxy)butane-1,2-diol which was coupled under Sonogashira conditions with 2-(9-bromo-6H-indolo[2,3-b]quinoxalin-6-yl)-N,N-dimethylethanamine to achieve (S)-4-(4-((6-(2-(dimethylamino)ethyl)-6H-indolo[2,3-b]quinoxalin-9-yl)ethynyl)phenoxy)butane-1,2-diol. This compound was tritylated with 4,4'-dimethoxytrityl chloride followed by treatment with 2-cyanoethyltetraisopropylphosphordiamidite in the presence of N,N'-diisopropyl ammonium tetrazolide to afford the corresponding phosphoramidite. This phosphoramidite was used to insert the monomer X into an oligonucleotide which was used for thermal denaturation studies of a corresponding parallel triplex.


Microdialysis as a potential tool for comparative assessment of tissue pharmacokinetics of two different patches containing lidocaine: A crossover pilot study.
Lidocaine 5% patches are approved for the treatment of post-herpetic neuralgia in adults. Little information is available on the penetration of lidocaine into skin and skin-related soft tissue, which are thought to be closer to the site where lidocaine exerts its pharmacological action on neuronal structures. This pilot study investigated subcutaneous and systemic pharmacokinetics of lidocaine during topical application of two different lidocaine 5% patches. This randomized two-way, two-period crossover study assessed lidocaine concentrations in subcutaneous tissue (by microdialysis) and plasma of n = 5 healthy subjects during 12-hour-long applications of a recently developed lidocaine 5% patch (Laboratorios Gebro Pharma, SA, Barcelona, Spain) and a marketed reference patch (Versatis 5% lidocaine patch, Grünenthal, Brunn am Gebirge, Austria), respectively. Lidocaine was detectable in subcutaneous tissue within 60 minutes from start of patch application, and in plasma only after a marked delay. The test formulation led to increased exposure to lidocaine in both subcutaneous tissue and plasma. This study has underscored the potential of microdialysis to comparatively assess the pharmacokinetics of two different drug formulations and encourages its further use in this area.


Effects of COVID-19 on Blood Culture Contamination at a Tertiary Care Academic Medical Center.
The COVID-19 pandemic has changed health care, from increased needs of personal protective equipment (PPE) to overloaded staff and influxes of patients. Blood cultures are frequently used to detect bloodstream infections in critically ill patients, but it is unknown whether the COVID-19 pandemic has had an impact on blood culture contamination rates. A total of 88,332 blood cultures taken over a 33-month period were analyzed to compare blood culture contamination rates before the COVID-19 pandemic to rates during the pandemic. A significant increase in the average number of monthly nurse-drawn and peripherally collected cultures occurred after the start of the pandemic, but there was a decrease in the average number of phlebotomy cultures. A significant increase in contamination rates (P < 0.001) was found in all nonemergency hospital departments during the COVID-19 pandemic, increasing from 2.1% to 2.5%. Increased rates during the COVID-19 pandemic were also found for nursing staff (2.0% to 2.4%) and both peripheral (2.1% to 2.5%) and indwelling line draws (1.1% to 1.7). The number of cultures drawn monthly increased in acute adult departments and both adult and pediatric emergency departments. Blood culture contamination rates in adult acute, adult emergency, and pediatric intensive care units increased after the start of the pandemic by 23%, 75%, and 59%, respectively. A positive correlation was found between blood culture contamination rates and COVID-19 incidence rates. Additional periodic staff training on proper blood collection technique and awareness of the workload of health care workers are recommended to decrease contamination rates during the COVID-19 pandemic. IMPORTANCE Understanding factors that contribute to blood culture contamination is important in order to take steps to limit contamination events. Here, we examine the effect the COVID-19 pandemic has had on blood culture contamination rates and specifically detail the effects based on the staff, draw types, and unit types. The conclusions provided here can be used as hospitals and laboratories navigate the COVID-19 pandemic or other times of high patient volume.


Generation of perfect vortex and vector beams based on Pancharatnam-Berry phase elements.
Perfect vortex beams are the orbital angular momentum (OAM)-carrying beams with fixed annular intensities, which provide a better source of OAM than traditional Laguerre-Gaussian beams. However, ordinary schemes to obtain the perfect vortex beams are usually bulky and unstable. We demonstrate here a novel generation scheme by designing planar Pancharatnam-Berry (PB) phase elements to replace all the elements required. Different from the conventional approaches based on reflective or refractive elements, PB phase elements can dramatically reduce the occupying volume of system. Moreover, the PB phase element scheme is easily developed to produce the perfect vector beams. Therefore, our scheme may provide prominent vortex and vector sources for integrated optical communication and micromanipulation systems.


An unusual haemorrhagic complication of an anastomotic leak and a novel method of controlling the haemorrhage.
Introduction Restorative proctocolectomy (RP) is undertaken for patients with familial adenomatous polyposis (FAP) and ulcerative colitis, but is associated with a risk of anastomotic leak. Case history A 20-year-old male with a family history of FAP had a RP with a double-stapled J-pouch and covering loop ileostomy. At ileostomy reversal 21 months later, he presented with significant anal bleeding. He proceeded to theatre for endoscopy. Pouchoscopy showed a pouch full of blood and a foreign object trapped in a diverticulum. The foreign object (an undigested tablet) was removed with grasping forceps and the bleeding spot identified. Hemospray® (Cook Medical, Winston-Salem, NC, USA) was deployed in the bleeding cavity to enable immediate control of haemorrhage. Recovery was uneventful and he was discharged home 72 hours later. Conclusions This case: (i) demonstrates a successful and novel method of controlling haemorrhage not amenable to use of conventional haemostatic mechanisms; (ii) highlights the potential problems of using prolonged-release medications in patients with gastrointestinal strictures/diverticulae.


[Effect of a beta-adrenergic blocking agent on erythropoietin production in the mouse (author's transl)].
The effects of the beta-adrenergic blocking agent (propranolol) on erythropoietin production in carbon monoxide intoxicated mice were studied. The raise in plasma erythropoietin after a 4 hour intoxication with carbon monoxide was 47% less in the propranolol treated group. A decrease of 65% in the endogenous erythropoietic response after 75 minutes of carbon monoxide intoxication was found in policithemic treated mice, as against the untreated ones. The tissue oxygen tension was reduced in the propranolol treated group. No changes was found in the hemoglobin oxygen affinity.


Development of a luminescence-based biosensor for detection of methylmercury.
A recombinant whole-cell bacterial sensor for highly selective and sensitive detection of the bioavailable methylmercury in the environment was constructed. The biosensor carries luciferase gene, luxAB, from Vibrio harveyi as a reporter under the control of the mercury inducible regulatory part of mer-operon from Pseudomonas K-62 plasmid pMR26. In addition, a merB gene encoding organomercurial lyase which cleaves the C-Hg bond of methylmercury to give Hg(2+ )was coexpressed in the sensor. The resulting bacterial sensor responded specifically to methylmercury, and the lowest detectable concentration of methylmercury was 10 pM with 1 ml sample in the optimized assay conditions. This detection limit is enough to detect this compound in many contaminated and some pristine environmental samples.


Evaluation of genotoxic and oxidative effects in workers exposed to jet propulsion fuel.
Jet fuel is a common occupational exposure risk among military and civilian populations. The purpose of this study was to evaluate genotoxic and oxidative effects in workers occupational exposure to jet propulsion fuel (JP-8). In this study, sister-chromatid exchange (SCE), high frequency of SCE cells (HFCs), and micronuclei (MN) were determined for 43 workers exposed to JP-8 and 38 control subjects. We measured the antioxidant enzyme activities including that of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). The levels of thiobarbituric acid-reactive substances (TBARS) were also studied. Urinary 1- and 2-naphthol excretion was used as a biomarker of occupational exposure to JP-8. The results obtained from cytogenetic analysis show a statistically significant increase in frequency of SCE in the exposed workers when compared to controls (P < 0.05). Interestingly, the mean value of the frequency (%o) of MN and HFCs for workers and controls did not show any statistical differences (P > 0.05). Oxidative stress parameters were not statistically different between exposed and control groups except for TBARS levels. Urinary 1-and 2-naphthol levels of exposed workers were found to be significantly higher than those of control subjects. Occupational exposure to JP-8 resulted in no significant genotoxic and oxidative effects, while smoking is the principal confounding factor for the some parameters. To understand the genotoxic and oxidative effects of JP-8 exposure, further studies should be planned to find out whether human populations may be at increased risk for cancer because of the exposures related to occupation and lifestyle.


Calcified wall portal venous aneurysm: a case report.
Portal vein aneurysms are extremely rare, less than 200 cases have been reported until late 2015. They are defined as a portal vein diameter exceeding 19 mm for cirrhotic patients and 15 mm in normal livers. Most patients are asymptomatic, but complications may occur. We report a case of a 68-year-old female admitted for etiological assessment of a portal hypertension revealed by an upper gastro intestinal bleeding, who was incidentally diagnosed with a portal vein aneurysm.


cDNA and deduced amino acid sequence of mouse matrix gla protein: one of five glutamic acid residues potentially modified to gla is not conserved in the mouse sequence.
A cDNA library was constructed using the mouse osteoblastic cell line MC3T3-E1 treated with 1 alpha,25-dihydroxyvitamin D3, based on the finding that the treatment increased ninefold the expression of 0.7 kb matrix gla protein (MGP) mRNA. cDNA clones encoding mouse MGP were isolated from the library. The nucleotide sequence showed an open reading frame of 312 nucleotides encoding 104 amino acids. Murine MGP shared 84-89% amino acid sequence homology with bovine, rat, and human MGP. However, there are five glutamic acid residues potentially modified to gamma-carboxyglutamic acid (gla) in those species; in murine MGP, lysine replaced glutamic acid 37. Also, an extra tyrosine was added at the carboxyl terminus. The significance of the substitution is discussed in relation to the gamma-carboxylation sites in MGP protein.


[Effect of a number of biologically active substances on the activity of membrane-bound Na+,K+-ATPase from the bovine brain].
Cellular Na+, K+-transport ATPase appears to be more resistant to the influence of DNA intercalators and other agents than ATP-synthetase complex of inner mitochondrial membrane. Neither synthetic intercalators, nor antibiotics olivomycin and actinomycin D, some uncouplers of oxidative phosphorylation, alkaloids and inorganic bivalent cations selectively (up to 10(-4) M) inhibit Na+, K+-ATPase activity. Besides ouabain, alkaloid sanguinarine and cation Ag+ (the latter in the absence of anion Cl-) cause a significant decrease of Na+, K+-ATPase activity. Ag+ is most potent as inhibitor, while sanguinarine is weaker than ouabain. Inhibition of Na+, K+-ATPase by sanguinarine may result presumably from modification of SH-groups of the enzyme.


Recommended precautions for patients with Legionnaires' Disease.
As diagnostic techniques for the identification of Legionella species have become readily available, recognition of the pneumonic form of Legionellosis has increased. In particular, cases of hospital-acquired Legionella pneumophila are being identified and this has led to concern over possible person-to-person transmission. In most epidemiologic investigations where a source has been identified, water has been implicated. Person-to-person transmission has not been convincingly documented. Therefore, we discourage expensive or inconvenient special precautions for patients hospitalized with Legionnaires' Disease. Rather, we recommend that such patients be placed in secretion precautions until effective antimicrobial therapy has eradicated the organism.


Molecular Detection of Avian Infectious Bronchitis Viruses in Live Bird Markets, Gilan Province.
Coronaviruses (AvCoV) which include infectious bronchitis virus (IBV) and other bird coronaviruses belong to the genus gammacoronavirus, subfamily Coronavirinae. One of the most prominent representatives of gammacoronavirus genus is infectious bronchitis virus (IBV) which is a highly contagious viral pathogen of chickens causing considerable economic losses to the poultry industry. IBVs mostly affect the respiratory, urinary, and reproductive tracts leading to a substantial drop in production. Backyard poultry in the villages usually share their food and water with free flight birds which puts them at serious risk of disease transmission. Furthermore, the poor hygienic measurements which are often used in backyard flocks make them a potential reservoir for diseases that can be transferred to commercial poultry flocks. Live bird markets (LBMs) which receive live poultry to be resold or slaughtered and sold onsite play a significant role in spreading infectious diseases among the different bird species. In the present study, a number of 354 cloacal swab samples were collected from different bird species from LBMs of Gilan province. Subsequently, after RNA extraction, reverse transcription-polymerase chain reaction (RT-PCR) technique was carried out using specific primers of S1 gene to detect coronavirus infectious bronchitis virus. Two samples from backyard chickens were reported to be positive to coronavirus which were named Iran/Backyardchicken 96/2017 and Iran/Backyardchicken 94/2017. The results of the phylogenetic analysis demonstrated that these two isolates are placed in QX and IS-1494 strains, respectively. On a final note, the obtained results highlighted the role of live birds offered in LBMs in the epidemiology of IBV and the transmission of the virus to the industrial flock.


Nephropathy caused by methicillin therapy for staphylococcal septicemia.
Nephropathy, eosinophilia and fever were observed in an 18-year-old man being treated for staphylococcal septicemia. Parenteral challenge with suspected sensitizing agents confirmed methicillin as the likely offender. Review of the literature relating to methicillin-induced nephropathy suggests a hypersensitivity origin for this disorder, but immunologic and ultrastructural investigation to date has failed to elucidate pathogenesis.


[Demonstration of reticulocytes and three-dimensional presentation of blood cells by means of reflexion contrast (author's transl)].
Reticulocytes and erythrocytes are distinguishable in Giemsa-stained blood smears by means of reflexion contrast, and adjunct to a reflected-light microscope. The surface topography of red cells can be quantitatively analyzed; it is directly visible in oblique illumination after decentralization of the central diaphragm. Reticulocytes are about 15% larger and show less deviations from the circular form and a less deep deviations from the circular form and a less deep central depression than mature erythrocytes. After supravital staining with brilliant cresyl blue, 72% more red cells can be diagnosed as being reticulocytes in reflexion contrast than in bright field.


Survival of Anaerobic Fe2+ Stress Requires the ClpXP Protease.
Shewanella oneidensis strain MR-1 is a versatile bacterium capable of respiring extracellular, insoluble ferric oxide minerals under anaerobic conditions. The respiration of iron minerals results in the production of soluble ferrous ions, which at high concentrations are toxic to living organisms. It is not fully understood how Fe2+ is toxic to cells anaerobically, nor is it fully understood how S. oneidensis is able to resist high levels of Fe2+ Here we describe the results of a transposon mutant screen and subsequent deletion of the genes clpX and clpP in S. oneidensis, which demonstrate that the protease ClpXP is required for anaerobic Fe2+ resistance. Many cellular processes are known to be regulated by ClpXP, including entry into stationary phase, envelope stress response, and turnover of stalled ribosomes. However, none of these processes appears to be responsible for mediating anaerobic Fe2+ resistance in S. oneidensis Protein trapping studies were performed to identify ClpXP targets in S. oneidensis under Fe2+ stress, implicating a wide variety of protein targets. Escherichia coli strains lacking clpX or clpP also display increased sensitivity to Fe2+ anaerobically, indicating Fe2+ resistance may be a conserved role for the ClpXP protease system. Hypotheses regarding the potential role(s) of ClpXP during periods of high Fe2+ are discussed. We speculate that metal-containing proteins are misfolded under conditions of high Fe2+ and that the ClpXP protease system is necessary for their turnover.IMPORTANCE Prior to the evolution of cyanobacteria and oxygenic photosynthesis, life arose and flourished in iron-rich oceans. Today, aqueous iron-rich environments are less common, constrained to low-pH conditions and anaerobic systems such as stratified lakes and seas, digestive tracts, subsurface environments, and sediments. The latter two ecosystems often favor dissimilatory metal reduction, a process that produces soluble Fe2+ from iron oxide minerals. Dissimilatory metal-reducing bacteria must therefore have mechanisms to tolerate anaerobic Fe2+ stress, and studying resistance in these organisms may help elucidate the basis of toxicity. Shewanella oneidensis is a model dissimilatory metal-reducing bacterium isolated from metal-rich sediments. Here we demonstrate a role for ClpXP, a protease system widely conserved in bacteria, in anaerobic Fe2+ resistance in both S. oneidensis and Escherichia coli.


A nutrient-wide association study for the risk of cardiovascular disease in the China Health and Nutrition Survey (CHNS) and the National Health and Nutrition Examination Survey (NHANES).
Evidence on the association between dietary nutrient-wide intake and cardiovascular disease (CVD) is inconclusive. Therefore, we systematically assessed the association between dietary intake of 29 nutrients and CVD risk using a nutrient-wide association study. Data were obtained from 7878 Chinese adults participating in the China Health and Nutrition Survey (CHNS) wave 2004-2015. We estimated the association of 29 nutrients with CVD risk. Significant findings were replicated in the National Health and Nutrition Examination Survey (NHANES). Four nutrients (selenium, vitamin A, carotenoids, and total protein) were significantly associated with CVD risk in the CHNS. The hazard ratio (HR) and 95% confidence interval (CI) for nutrient intake in the third tertile compared to the first tertile were 0.68 (0.51-0.90), 0.70 (0.54-0.91), 0.64 (0.50-0.83), and 0.54 (0.38-0.77), respectively. In the NHANES replication, selenium maintained a similar direction and strength of association, while the other nutrients were not replicated successfully. Our results provide support for a negative association between selenium intake and CVD risk, while the association of vitamin A, carotenoids and protein with CVD warrants further studies to confirm.


Toward Low-Symmetry Systems: An Adaptive Differential Evolution Algorithm for Global Structure Searching.
The reduction in the symmetry of nanomaterials can produce unexpected properties, while the determination of atomic structures is a sizable challenge in related fields, including low-dimensional materials, surface science, defects, etc. Herein, we develop an adaptive algorithm based on the differential evolution algorithm, which provides benefits for structure searching on low-symmetry systems. The dynamic strategy pool and the island concept are proposed to accelerate the efficiency in the full search space. With several test examples, the designed program not only locates reported structures but also affords new stable configurations that were not located by previous structure search algorithms. Moreover, we provide frameworks and interfaces for stable structure searching on complex systems like grain boundaries, supported clusters, surfaces, and edges. The success in repeatable structure searching with high efficiency demonstrates the reliability and practicability of our algorithm and ensures its potential applications as an advanced technology in many newly arising fields.


Geniposide improves insulin production and reduces apoptosis in high glucose-induced glucotoxic insulinoma cells.
Our previous work revealed that in the pancreatic β cell line, geniposide modulated ATP production and glucose-stimulated insulin secretion (GSIS) induced by the acute stimulation of high glucose concentration. However, the effects of geniposide on functional impairment and the mass of β-cells exposed to elevated levels of glucose remains unknown. In the present study, impaired GSIS and restrained proliferation were observed in the prolonged culture of insulinoma INS-1 cells with 33mM of glucose (high glucose). Our results indicate that the glucose-induced impairment of insulin release was significantly reverted by the inclusion of 1 or 10μM of geniposide. Moreover, induction of the phosphorylation of AMP-activated protein kinase (AMPK) was observed, which promoted the utilization of nutrient stores for energy production. AMPK phosphorylation was enhanced by an increased number of INS-1 cells, and the increased expression of AMPK downstream target heme oxygenase 1 (HO-1), under high glucose concentration. Furthermore, geniposide protected rat insulinoma cells from apoptosis in high-glucose concentrations. We have shown that these effects were associated with an increased apoptosis-related Bcl-2/BAX protein ratio. In conclusion, geniposide dose dependently improves β-cell function and increases the proliferation of β-cells exposed to prolonged hyperglycemia.