Calorimetric study of extracellular tissue matrix degradation and instability after gamma irradiation.
Native extracellular tissue matrix (ECM) is increasingly used for tissue repair and regeneration. The kinetics of gamma irradiation damage on human dermis ECM was studied by differential scanning calorimetry (DSC). Dermis ECM was irradiated at a low-dose rate of 0.23 kGy h(-1) in order to study the progression of ECM damage as the gamma dose increased from 0 to 32 kGy. The study showed that the effect of gamma irradiation above 2 kGy was predominantly peptide chain scission. As the gamma dose increased, the stability of irradiated ECM decreased further, and multiple ECM domains of different stability were detected. Even a moderate gamma dose (7-12 kGy) could decrease the onset denaturation temperature of ECM to below body temperature. DSC analysis also showed partial and spontaneous protein denaturation in gamma-irradiated, rehydrated ECM at 37 degrees C. In vitro rehydration tests confirmed that a significant fraction of the irradiated ECM disintegrated into minute ECM fragments at 37 degrees C, although the irradiated ECM appeared to be normal at 4 degrees C and room temperature. DSC data were correlated well to effects of gamma irradiation on ECM microstructure, mechanical property and in vitro cell response reported earlier by us. A model was presented to describe the kinetics of gamma-irradiation-induced alterations of tissue ECM properties.


Scavenging of reactive species probed by EPR and ex-vivo nanomolar reduction of lipid peroxidation of manganese complexes.
Antioxidant activity toward H2O2, anion radical superoxide, hydroxyl and DPPH (2,2-diphenyl-1-picrylhydrazyl) of two manganese complexes [Mn(III)(bpa)2]Cl.H2O (1) and [(Cl)Mn(μ-hbpclnol)(μ-bpclnol)Mn](ClO4).3H2O (2) (hbpa = (2-hydroxybenzyl-2-pyridylmethyl)amine and h2bpclnol = (N-(2-hydroxybenzyl)-N-(2-pyridylmethyl)[(3-chloro)(2-hydroxy)]propylamine) are presented. X-ray diffraction studies were performed for complex (1). Both complexes presented similar or better activities than reference complex [Mn(salen)Cl], when the interaction between them and ROS (H2O2, O2•- and •OH), was monitored, by EPR (Electron Paramagnetic Resonance), in PBS, DMSO and water. The antioxidant activity rank of complexes toward •OH, generated by Fenton reaction and monitored by EPR, is (2) > (1) > [Mn(salen)Cl], in water (0.1% of DMSO for each complex), with the values of the IC50 of 7.2 (±1.6), 15.5 (±1.8) and 29.1 (±2.01) μM respectively. EPR data presented herein suggest that complex (2) presents the better scavenging activity toward hydroxyl, being in good agreement with TBARS assay results, in which complex (2) presented the best inhibitory activity toward lipid peroxidation, employing Swiss mice liver homogenate tissue model. IC50 values obtained from the interaction between these complexes and hydroxyl, using TBARS method, were: 0.88 (± 0.029); 0.73 (± 0.01) and 42.7 (± 3.5) nM, respectively for (1), (2) and [Mn(salen)Cl]. Complexes (1) and (2) are regulating the lipid homeostasis, protecting the tissue from the lipid peroxidation, in nanomolar scale, motivating in vivo studies. Redox properties and radical scavenging activity of complexes toward DPPH are non-linear and solvent dependent. Furthermore, the monitoring of antioxidant activity probed by EPR could be a fair and appropriate study to guide more advanced investigations.


Potentially toxic elements have adverse effects on moss communities in the manganese mines of Southern China.
This study investigated the distribution of moss species, physiological parameters (superoxide dismutase, peroxide, catalase, and total chlorophyll), and concentrations of potentially toxic elements (Mn, Cr, Zn, Cu, Pb, and Cd) in moss communities and topsoil at the Huayuan manganese mine, Xiangjiang manganese mine, and Nancha manganese mine (Southern China). Partial least squares path modeling (PLS-PM) was then performed to determine the relationship between the indicators. Cd, Mn, and Zn were the main topsoil pollutants, followed by Pb, Cr, and Cu. A total of 73 moss species, comprising 31 genera from 17 families, and 8 community functional groups were identified. The most dominant families were Pottiaceae (30.14%) and Bryaceae (21.92%). PLS-PM revealed that increasing topsoil Mn, Cr, Zn, Cu, Pb, and Cd significantly reduced species diversity and functional diversity. These potentially toxic elements in the topsoil impeded vegetation growth by deteriorating soil conditions and subsequently altering the microenvironment of the moss communities. The community-weighted means demonstrated that functional traits of turfs and warty leaves were the adaptation of the moss communities to an increasingly dry and exposed microenvironment. Moss species with curly and narrow leaves were used to reduce contact with particulate pollutants. PLS-PM also indicated that Mn, Cr, Pb, and Cd may have a detrimental effect on superoxide dismutase, peroxide, catalase, and total chlorophyll, although further validation studies are needed.


Organomercury (II) complexes with anti-carcinogenic agents. II. Anti-neoplastic activity.
Organomercury(II) complexes of the type, p-MeOC6H4HgL1 (I), p-NO2C6H4HgL2 (II), p-MeOC6H4HgL3 (III) and p-MeC6H4HgL4 (IV) (HL1-6-mercaptopurine, HL2-6-thioguanine, HL3-5-fluorouracil, L4-phenyldithiocarbazate) have been screened against the following cell panels: leukemia, non-small cell lung cancer, small cell lung cancer, brain cancer, melanoma, ovarian cancer and renal cancer. The variation in anti-neoplastic activity has been correlated with the structural parameters of the complexes.


Tropical obstetrics and gynaecology. 1. Anaemia in pregnancy in tropical Africa.
Major causes of anaemia in pregnancy in tropical Africa are malaria, iron deficiency, folate deficiency and haemoglobinopathies: now there is added also the acquired immune deficiency syndrome (AIDS). Anaemia is often multifactorial, with the different causes interacting in a vicious cycle of depressed immunity, infection and malnutrition. Anaemia progresses through 3 stages: compensation, with breathlessness on exertion only; decompensation, with breathlessness at rest and haemoglobin (Hb) below about 70 g/litre; cardiac failure, with Hb below about 40 g/litre. Without treatment, over half of the women with haematocrit less than 0.13 and heart failure die. Maternal anaemia, malaria and deficiencies of iron and folate cause intrauterine growth retardation, premature delivery and, when severe, perinatal mortality. Surviving infants have low birthweights, immune deficiency and poor reserves of iron and folate. They have entered already the vicious cycle of infection, malnutrition and impaired immunity. Treatment with blood transfusions is even more hazardous since the advent of AIDS, and should be limited to saving the life of the mother. Treatment of malaria is complex as chloroquine-resistant strains are now common. Prevention remains relatively easy with proguanil and supplements of iron and folic acid and is highly cost-effective in the improvement of maternal and infant health; it is more important than ever as it avoids the unnecessary exposure of women and infants to HIV transmitted through blood transfusion.


Rapid detection of cefotaxime-resistant Escherichia coli by LC-MS.
Antibiotic resistance is an unsolved healthcare problem with increasing impact on patient management in the last years. In particular, multidrug resistance among Gram-negative bacterial strains has become the most pressing challenge. In order to deliver the most efficacious antimicrobial therapy with minimum delay, rapid diagnostic tests are required in order to detect multidrug resistant pathogens early during infection. In line with these efforts, we have developed a mass spectrometry-based assay for the rapid determination of ampicillin and cefotaxime resistance. The assay quantifies beta-lactamase activities towards ampicillin and cefotaxime within a turnaround time of 150 min, which is substantially faster than classical susceptibility testing.


Creation and Validation of a Tool for Evaluating Caregiver Burnout Syndrome in Owners of Dogs (Canis lupus familiaris) Diagnosed with Behavior Disorders.
Currently, domestic dogs (Canis lupus familiaris) are the most common species among companion animals. The close bond that can grow between owners and their dogs could be worn out and finally broken due to various causes. One main cause is canine behavioral problems, leading to dogs being abandoned or euthanized due to the costs faced by the owner when caring for the animal. Tools have been developed to evaluate the mental and emotional cost of caring for humans, but there is currently no validated tool for evaluating this particular problem. The objective of this study was to develop a questionnaire to evaluate caregiver burnout syndrome for owners of dogs with behavioral disorders. The methodology used consisted of drafting the tool, peer validation using the Delphi methodology and internal validation via Cronbach's alpha. Non-linear snowball sampling was used (n = 156 participants). A questionnaire with 35 questions was obtained which referred to various aspects of caregivers' lives. Regarding the description of the sample used, 50% had Low Burnout, 41% had Medium-Low Burnout and 9% had Medium-High Burnout. Furthermore, regarding the internal validation of the questionnaire, the general Cronbach's alpha coefficient was α = 0.9468. We can thus conclude that the questionnaire is valid for measuring caregiver burnout syndrome in owners of dogs with behavioral disorders.


Effects of supplemental calcium and vitamin D on the APC/β-catenin pathway in the normal colorectal mucosa of colorectal adenoma patients.
APC/β-catenin pathway malfunction is a common and early event in colorectal carcinogenesis. To assess calcium and vitamin D effects on the APC/β-catenin pathway in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, nested within a larger randomized, double-blind, placebo-controlled, partial 2 × 2 factorial chemoprevention clinical trial of supplemental calcium (1200 mg daily) and vitamin D (1000 IU daily), alone and in combination versus placebo, we assessed APC, β-catenin, and E-cadherin expression in colon crypts in normal-appearing rectal mucosa biopsies from 104 participants at baseline and 1-yr follow up using standardized, automated immunohistochemistry and quantitative image analysis. For vitamin D versus no vitamin D, the ratio of APC expression to β-catenin expression in the upper 40% (differentiation zone) of crypts (APC/β-catenin score) increased by 28% (P = 0.02), for calcium versus no calcium it increased by 1% (P = 0.88), and for vitamin D + calcium versus calcium by 35% (P = 0.01). Total E-cadherin expression increased by 7% (P = 0.35) for vitamin D versus no vitamin D, 8% (P = 0.31) for calcium versus no calcium, and 12% (P = 0.21) for vitamin D + calcium versus calcium. These results support (i) that vitamin D, alone or in combination with calcium, may modify APC, β-catenin, and E-cadherin expression in humans in directions hypothesized to reduce risk for colorectal neoplasms; (ii) vitamin D as a potential chemopreventive agent against colorectal neoplasms; and (iii) the potential of APC, β-catenin, and E-cadherin expression as treatable, pre-neoplastic risk biomarkers for colorectal neoplasms. © 2016 Wiley Periodicals, Inc.


Tachykinins and the potential causal factors for post-COVID-19 condition.
The most prevalent symptoms of post-COVID-19 condition are pulmonary dysfunction, fatigue and muscle weakness, anxiety, anosmia, dysgeusia, headaches, difficulty in concentrating, sexual dysfunction, and digestive disturbances. Hence, neurological dysfunction and autonomic impairments predominate in post-COVID-19 condition. Tachykinins including the most studied substance P are neuropeptides expressed throughout the nervous and immune systems, and contribute to many physiopathological processes in the nervous, immune, gastrointestinal, respiratory, urogenital, and dermal systems and participate in inflammation, nociception, and cell proliferation. Substance P is a key molecule in neuroimmune crosstalk; immune cells near the peripheral nerve endings can send signals to the brain with cytokines, which highlights the important role of tachykinins in neuroimmune communication. We reviewed the evidence that relates the symptoms of post-COVID-19 condition to the functions of tachykinins and propose a putative pathogenic mechanism. The antagonism of tachykinins receptors can be a potential treatment target.


Plasma ACTH and cortisol profiles in Addisonian patients receiving conventional substitution therapy.
Plasma ACTH and cortisol profiles were studied over 24 h in five Addisonian patients maintained in good health by conventional gluco- and mineralocorticoid treatment. Patients received their usual treatment (15--30 mg cortisol daily) in divided doses at 08.00 and 16.00 hours. Plasma cortisol concentrations differed from those of control subjects in being higher from 08.00 hours-noon and 17.00-18.00 hours and were unmeasurable (less than 20 nmol/l) during the period of active cortisol secretion (03.00-08.00 hours) observed in normal subjects. Peak plasma ACTH levels (618- greater than 1600 ng/l) occurred at 08.00-09.00 hours in the Addisonian patients and were much greater than those seen in control subjects (60-220 ng/l). Despite this, plasma ACTH fell promptly within 3 h of the morning dose to less than 100 ng/l and levels were indistinguishable from those seen in normal subjects over the period 12.00-02.00 hours. These results show that there are substantial differences between treated Addisonian and control subjects in respect of plasma cortisol and ACTH concentrations. The findings may lead to a better understanding of ACTH-cortisol relationships in disease states, including congenital adrenal hyperplasia where control of excessive ACTH secretion is clinically desirable.


Flap prefabrication using high-density porous polyethylene in an animal model – an experimental study.
The search for new surgical flap techniques and modifications of already existing ones is gaining increasing popularity. Progress in flap designing and harvesting have improved the functional and aesthetic results, especially in head and neck reconstruction. Ten pigs were used in this study. In the first operation, high-density porous polyethylene prefabrication was performed bilaterally in all pigs. After 8 weeks, each prefabricated complex was explored, resected, and macroscopically evaluated. All of 20 prefabricated flaps survived. No serious surgical complications were observed. In 2 cases there was chronic inflammation and in 4 cases there was instability of the implant. After this experimental study, we believe that the use of high-density porous polyethylene in flap prefabrication may be a good option for reconstruction of 3-dimensional defects, especially in patients with limited donor tissues.


The mechanical stability of internal fixation of fractured phalanges.
The rigidity of five techniques of internal fixation of fractured phalanges is tested experimentally and compared. The clinical relevance is discussed.


Evaluation of expanded bed adsorption chromatography for extraction of prothrombin complex from Cohn Supernatant I.
This study evaluated the feasibility of substituting expanded bed adsorption (EBA) chromatography for an existing chromatographic purification process for the isolation of prothrombin complex concentrate (PCC) from Cohn Supernatant I. The EBA chromatography (Streamline) resins were compared to the current DEAE-cellulose resin for the extraction of PCC from Cohn SNI. EBA chromatography resins efficiently bound PCC from Cohn SNI at a significantly higher flow rate of up to 300 cm/h compared to 30 cm/h for the current DEAE-cellulose process. Composition and yield of the recovered PCC reflected the elution conditions used. The results indicate that EBA chromatography could be used to efficiently produce PCC comparable to existing products.


Uterine growth in the follicular phase of spontaneous ovulatory cycles and during luteinizing hormone-releasing hormone-induced cycles in women with normal or polycystic ovaries.
The uterine response to follicular growth in luteinizing hormone-releasing hormone (LH-RH)-induced ovulatory cycles was assessed by serial ultrasound measurement of uterine cross-sectional area and endometrial thickness in 23 cycles in women with normal ovaries and 24 cycles in women with polycystic ovaries. Nine women with spontaneous ovulatory cycles also were studied. The authors correlated uterine cross-sectional area and endometrial thickness with follicle diameter (FD) and serum estradiol-17 (E2). In women with either normal or polycystic ovaries, there was an E2-related increase in uterine cross-sectional area and endometrial thickness, but both uterine area and endometrial thickness were greater in the late follicular phase of women with polycystic ovaries compared with those with normal ovaries.


A RANDOMIZED CONTROLLED TRIAL IN COMMUNITY MENTAL HEALTH CENTERS OF COMPUTER-ASSISTED COGNITIVE BEHAVIORAL THERAPY VERSUS TREATMENT AS USUAL FOR CHILDREN WITH ANXIETY.
This study aims to examine the real-world effectiveness of a computer-assisted cognitive behavioral therapy (CBT) protocol relative to treatment as usual (TAU) among anxious children presenting at community mental health centers. One hundred children (7-13 years) with clinically significant anxiety were randomized to receive either 12 weekly computer-assisted CBT sessions or TAU for an equivalent duration. Assessments were conducted by independent evaluators at screening/baseline, midtreatment, posttreatment, and 1-month followup (for computer-assisted CBT treatment responders). There were significant between-group effects favoring the computer-assisted CBT condition on primary anxiety outcomes. Thirty of 49 (61.2%) children randomized to computer-assisted CBT responded to treatment, which was superior to TAU (6/51, 11.8%). Relative to TAU, computer-assisted CBT was associated with greater reductions in parent-rated child impairment and internalizing symptoms, but not child-rated impairment and anxiety and depressive symptoms. Treatment satisfaction and therapeutic alliance in those receiving computer-assisted CBT was high. Treatment gains in computer-assisted CBT responders were maintained at 1-month followup. Within the limitations of this study, computer-assisted CBT is an effective and feasible treatment for anxious children when used in community mental health centers by CBT-naïve clinicians.


Neutral endopeptidase 188.8.131.52 inhibition potentiates the inhibitory effects of type-C natriuretic peptide on leukotriene D4-induced airway changes.
1. Microvascular leakage, a primary feature of inflammation, is well known for worsening the asthmatic condition. Gene expression of and a specific receptor for type-C natriuretic peptide (CNP), initially considered a neuropeptide, have been detected in the human vascular wall and secretion of CNP from vascular endothelial cells has recently been demonstrated. These facts suggest the presence of a vascular natriuretic peptide system and led us to expect that CNP may act beneficially on airway microvascular leakage in asthma. In the present study, we investigated the effects of CNP against leukotriene (LT) D4-induced airway microvascular leakage and bronchoconstriction and how these effects were potentiated by thiorphan, a potent neutral endopeptidase 220.127.116.11 (NEP) inhibitor. 2. Anaesthetized male guinea-pigs, ventilated via a tracheal cannula, were placed into a plethysmograph for 10 min, in order to measure pulmonary mechanics and mean blood pressure, after challenge with 2 micrograms/kg LTD4 and then the extravasation of 20 mg/kg Evans blue dye into airway tissue was investigated to indicate and evaluate microvascular leakage. 3. Intravenous administration of CNP (100, 300 and 1000 micrograms/kg) significantly inhibited the LTD4-induced microvascular leakage and bronchoconstriction in a dose-dependent manner. These inhibitory effects were enhanced by pretreatment with 20 mg/kg thiorphan, suggesting the important role of NEP in the pulmonary metabolism of CNP. 4. We believe that these results are encouraging for the further investigation of the therapeutic applications of exogenous CNP in asthma.


Venous Invasion and Perineural Invasion as Upstaging and Poor Prognostic Factors in N0 Gastric Cancers.
Lymph node metastasis is an important prognostic factor in gastric cancer patients. In node-negative (N0) gastric cancer patients, additional prognostic factors are needed to reinforce TNM staging. We semi-quantitatively recorded the presence of lymphatic, venous, and perineural invasion and evaluated the possibility that they could be used as upstaging factors in N0 gastric cancer by comparing N0 gastric cancer cases with N1 cases. Venous (p<0.001) and perineural (p<0.001) invasion were important factors in the relapse-free survival of N0 patients, but lymphatic invasion was not. N0 cases with venous or perineural invasion had survival curves similar to those of N1 patients. In addition, the number of invasive features (lymphatic, venous, or perineural) was an important factor in predicting poor patient survival. Venous and perineural invasion were significant prognostic factors in N0 gastric cancer cases. It is necessary to record lymphatic, venous, and perineural invasion separately in the pathology report, especially in cases of N0 gastric cancer.


A reproducible microanalytical method for the detection of specific RNA sequences by dot-blot hybridization.
A rapid, microanalytical procedure for the reproducible isolation of RNA from small cultured cell samples and application to dot-blot hybridization is described. The procedure employs guanidine hydrochloride solubilization of whole cells, disruption by syringing, and selective precipitation of RNA with ethanol. The method can be performed in a single tissue culture tube and obviates the need for removal of nuclei or for organic solvent extractions. Recovery of RNA from small cell samples (10(6) cells) is 51%, while 97% of the DNA and 99% of the protein are eliminated by the procedure. Detection of specific RNA by dot-blot hybridization using a labeled probe demonstrates high reproducibility of recovered RNA and lack of "masking" with up to a 10-fold excess of starting cell material. Applicability of the procedure to detection of virus-specific RNA in cells persistently infected with mouse hepatitis virus is described.


Mutations in spike protein T cell epitopes of SARS-COV-2 variants: Plausible influence on vaccine efficacy.
With emerging SARS-CoV-2 variants, vaccines approved so far are under scrutiny for long term effectiveness against the circulating strains. There is a prevalent obsession with humoral immunity as in vitro studies have indicated diminished effects of vaccine-induced neutralizing antibodies. However, this need not clinically translate to vaccine resistance as immune response against all forms of present vaccine preparations is T dependent unlike that against native viral particles which can induce T independent immune responses. Thus, we focused on this major correlate of protection against infections, T cell response. Using bioinformatics tools, we analyzed SARS-CoV-2 Spike protein T cell epitopes and their diversity across Delta plus/B.1.617.2.1, Gamma/P.1 (variant of concern), B.1.1.429, Zeta/P.2 and Mink cluster 5/B.1.1.298 variants as well as Omicron/B.1.1.529 (variant of concern). We also compared HLA restriction profiles of the mutant epitopes with that of the native epitopes (from Wuhan_hu_1 strain, used in vaccine formulations). Our observations show ~90% conservation of CD4+ and CD8+ epitopes across Delta plus/B.1.617.2.1, Gamma/P.1 (variant of concern), B.1.1.429, Zeta/P.2 and Mink cluster 5/B.1.1.298. For the Omicron/B.1.1.529 variant, ~75% of CD4+ and ~ 87% CD8+ epitopes were conserved. Majority of the mutated CD4+ and CD8+ epitopes of this variant were predicted to retain the HLA restriction pattern as their native epitopes. The results of our bioinformatics analysis suggest largely conserved T cell responses across the studied variants, ability of T cells to tackle new SARS-CoV-2 variants and aid in protection from COVID-19 post vaccination. In conclusion, the results suggest that current vaccines may not be rendered completely ineffective against new variants.


Local perfusion of the thalamus with GABA increases sleep and induces long-lasting inhibition of somatosensory event-related potentials in cats.
The extracellular concentration of gamma-aminobutyric acid (GABA) was increased in the ventroposterolateral nucleus of the thalamus in cats using in vivo microdialysis probes. In freely moving cats, the permanent injection of 8 x 10(-9) M/mm2 x min GABA induced a significant increase in sleep proportion. The duration of paradoxical sleep was particularly increased resembling the effects of benzodiazepines. In chloralose anesthesia, a similar increase in GABA concentration in the thalamus induced a tonic decrease in the peak-to-peak amplitude of cortical event-related potentials evoked by stimulation of the radial nerve. Following 10-15 min of inhibition during which the responses were as small as 20% of the original ones, the potentials started to recover. Finally, the responses were stabilized at a reduced amplitude. The present data suggests the important role of the thalamic GABAergic neurons in the regulation of sleep.


A novel approach to assess temporal sensory perception of muscle foods: application of a time-intensity technique to diverse Iberian meat products.
Although dynamic sensory techniques such as time-intensity (TI) have been applied to certain meat products, existing knowledge regarding the temporal sensory perception of muscle foods is still limited. The objective of the present study was to apply TI to the flavour and texture perception of three different Iberian meat products: liver pâté, dry-cured sausages ("salchichon") and dry-cured loin. Moreover, the advantages of using dynamic versus static sensory techniques were explored by subjecting the same products to a quantitative descriptive analysis (QDA). TI was a suitable technique to assess the impact of composition and structure of the three meat products on flavour and texture perception from a dynamic perspective. TI parameters extracted from the TI-curves and related to temporal perception enabled the detection of clear differences in sensory temporal perception between the meat products and provided additional insight on sensory perception compared to the conventional static sensory technique (QDA).


Development of vestibular receptor surfaces in human fetuses.
The development of human vestibular receptors was studied between the 7th and 14th gestational weeks using scanning electron microscopy. The development phase appeared to last longer than previously described. At 7 weeks, no receptors were individualized, the vestibular epithelium was plicated, and scarce nascent hair bundles could be seen grouped in a small area. At 8 weeks, all receptors were well differentiated. Modifications in crista shapes were evaluated qualitatively and quantitatively along the length of their profile. Their growth occurred in two quick steps with a pause between the 9th and 12th weeks, during which growth slowed and a transformation occurred. In the utricle, the epithelium decreased in thickness, and this process underwent a pause between the 8th and 11th weeks. These results demonstrate pauses in the maturation process of the vestibular receptors and show that the utricles develop one week in advance of the cristae. At 14 weeks, all receptors had an adult profile, but the cristae had only reached 55 per cent of their adult size. The ciliary apparatus appeared to be nearly mature in the utricle but was still growing in the cristae. The differentiation of ciliary tufts in the cristae displayed an apex-base gradient. These developmental patterns were compared with those described in the mouse.


Formation of alpha-Pal/Max heterodimers synergistically activates the eIF2-alpha promoter.
The transcription factor alpha-Pal recognizes two tandem palindromic repeats within the promoter of eukaryotic translation initiation factor 2-alpha (eIF2-alpha). Whereas both binding sites have the same "core domain" sequence (CGCATGCG), they differ with respect to their flanking sequences. Of the two sites, the 5'-cap proximal site has a higher binding affinity for alpha-Pal than does the 5'-cap distal site (Jacob, W. F., Silverman, T. A., Cohen, R. B., and Safer, B. (1989) J. Biol. Chem. 264, 20372-20384). The well characterized transcription factor Max binds to sequences that are remarkably similar to the core domain that alpha-Pal recognizes. To date, all of the Max heterodimer partners lack DNA binding domains and are thus dependent on Max interacting with DNA. Here we report that the two alpha-Pal sites have very different binding activities with respect to the E-box-binding protein Max. The 5'-cap distal or low alpha-Pal affinity site binds both alpha-Pal and Max. Furthermore, both heterodimers and homodimers of each of these proteins bind to this site. In contrast to the low affinity site, the high affinity site does not bind Max as a homodimer. This is the first documented case where Max heterodimerizes with a transcription factor that has affinity for DNA independent of Max.


'Interfacial affinity chromatography' of lipases: separation of different fractions by selective adsorption on supports activated with hydrophobic groups.
Lipases contained in commercial samples of lipase extracts from Rhizopus niveus (RNL) and Candida rugosa (CRL) have been selectively adsorbed on hydrophobic supports at very low ionic strength. Under these conditions, adsorption of other proteins (including some esterases) is almost negligible. More interestingly, these lipases could be separated in several active fractions as a function of a different rate or a different intensity of adsorption on supports activated with different hydrophobic groups (butyl-, phenyl- and octyl-agarose). Thus, although RNL seemed to be a homogeneous sample by SDS-PAGE, it could be separated, via sequential adsorption on the different supports, into three different fractions with very different thermal stability and substrate specificity. For example, one fraction hydrolyzed more rapidly ethyl acetate than ethyl butyrate, while another hydrolyzed the acetate ester 7-fold slower than the butyrate. Similar results were obtained with samples of CRL. Again, we could obtain three different fractions showing very different properties. For example, enantioselectivity for the hydrolysis of (R,S) 2-hydroxy-4-phenylbutanoic acid ethyl ester ranged from 1.2 to 12 for different CRL fractions. It seems that very slight structural differences may promote a quite different interfacial adsorption of lipases on hydrophobic supports as well as a quite different catalytic behavior. In this way, this new 'interfacial affinity chromatography' seems to be very suitable for an easy separation of such slightly different lipase forms.


The matrix components of the epiphyseal growth plate and articular cartilages from dogs treated with ammonium tetrathiomolybdate, a copper antagonist.
As part of a project to study the effect of copper deficiency (CD) on bone development in young dogs, the composition and metabolism of proteoglycans (PGs) and extractability of collagens in the epiphyseal growth plate cartilage (EGPC) and articular cartilages (AC) were investigated. Copper deficiency was induced by feeding ammonium tetrathiomolybdate (TTM) a copper antagonist. The collagen of cartilages from TTM-treated animals was significantly more soluble in 0.5 saline than control tissues. While no distinction between TTM-treated and control cartilages was evident in terms of PG content or extractability under associative (0.5 M-GuHCl) or dissociative (4.0 M-GuHCl) conditions, the sedimentation behaviour of the PG aggregates following CsCl density gradient ultracentrifugation suggested less polydispersity of PGs in preparations from the TTM-treated animals. Moreover, analysis of the PG monomers from EGPC of TTM animals showed galactosamine/glucosamine ratios higher than control preparations, suggesting a reduced keratan sulphate content in these preparations. Organ culture of EGPC showed a significant reduction in the incorporation of 35S into PGs and of 3H-thymidine into DNA in the tissues of TTM-treated animals relative to controls. From these findings we deduce that the catabolism of PGs and the extent of collagen cross-linking in EGPC of TTM-treated animals may be reduced relative to age-matched control tissues.


The synergistic effects of temperature and food concentration of life history parameters of Daphnia.
Daphnia parvula experiences a wide range of thermal (4°-30°C) and food conditions during its annual population cycle. We used cohort life table experiments to determine the synergistic effects of temperature and food concentration on its life history parameters. A 3×3 factorial design experiments was conducted with animals raised at all combinations of three naturally experienced temperatures (10°, 15° and 25° C) and food levels (0.02, 0.20 and 2.0 mg C/l). D. parvula showed an increase in survivorship with decreasing temperature at all food levels. Fecundity parameters (number of broods/female, brood size and net reproductive rate) increased with increasing food at the two lower temperatures but showed a mid-range food optimum at the highest temperature. Development rates and realized rates of increase (r) showed an increase with both increasing temperature and food such that they were maximum at the highest temperature-food level treatment. The life history parameters, average lifespan, age at first reproduction, brood duration time, brood size and number of young per reproductive female all showed significant interaction between temperature and food as was suggested by trends in R o and r. Temperature had a reduced effect on fecundity, development rates and realized rates of increase at the low food level.Population birth rates of continuously reproducing zooplankton are typically calculated by the egg-ratio method (Edmondson 1960) and are based on thermally controlled development rates which neglect the effects of food limitation. Significant synergistic temperature-food effects on brood duration time and other life history parameters of Daphnia parvula suggest that food limitation and foodtemperature interaction should be considered when calculating field population birth rates. A comparison of realized rates of increase from this study with similar life table data for Daphnia parvula raised on natural food from Lake Oglethorpe indicate that synergistic effects are negligible in this eutrophic system due to abundant resources. However, synergistic effects are probably important in oligotrophic systems where resources are limited.


The "jam roll" flap for fingertip reconstruction.
A method of fingertip reconstruction using a deepithelialized cross-finger flap in "jam roll" fashion is described. The technique has found relatively frequent indications.


Incidence and Risk of Hypertension in Cancer Patients Treated With Atezolizumab and Bevacizumab: A Systematic Review and Meta-Analysis.
This study aims to inform previous clinical assessments to better understand the total risk of hypertension with atezolizumab and bevacizumab (hereafter referred to as "A-B") in cancer patients, and reduce future incidence of hypertension-related cardiovascular complications. Databases, including PubMed, Embase, Cochrane, and Web of Science were searched to identify relevant studies, which were retrieved from inception to March 6, 2021. Studies focused on cancer patients treated with A-B that provided data on hypertension were included. Statistical analyses were conducted to calculate hypertension incidence and relative risk (RR) with a random-effects or fixed-effects model, hinging on heterogeneity status. Ten studies including 2106 patients with renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), ovarian cancer, anal cancer, neuroendocrine tumors (NETs), and cervical cancer were selected for this meta-analysis. For patients treated with A-B, the all-grade and high-grade (grade 3) hypertension incidence were 31.1% (95% CI: 25.5-37.3) and 14.1% (95% CI: 10.9-18.1), respectively. No significant difference was observed in all-grade hypertension incidence between RCC and a non-RCC patients (32.9% [95% CI: 25.3-42.6] v.s. 29.2% [95% CI: 19.7-39.6)]). However, the number of high-grade hypertension incidence in RCC patients (9.4% [95% CI: 4.1-21.3]) was lower than that of non-RCC patients (15.6% [95% CI: 12.8-19.1]). RCC or HCC patients who received the A-B treatment were associated with significantly increased risk of all-grade hypertension with a RR of 7.22 (95% CI: 3.3-15.7; p = 0.6) compared with patients treated with atezolizumab. Cancer Patients treated with atezolizumab and bevacizumab have a significantly increased risk of hypertension. Sufficient monitoring is highly recommended to prevent the consequences of treatment-induced hypertension and other cardiovascular complications.


Investigation of the utility of published in vitro intrinsic clearance data for prediction of in vivo clearance.
This study was conducted to compare and contrast published in vitro intrinsic clearance values reported for compounds from different laboratories and the predictivity of these data to project in vivo clearance. A total of 103 compounds were selected for investigation and an exhaustive literature search was conducted to identify in vitro intrinsic clearance (CL,i) values for comparative purposes. The simple well-stirred model was used to predict in vivo clearance using these in vitro intrinsic clearance values. Data were available in the literature for <10% of the compounds of interest in rat, dog, monkey, or human S9, as well as <10% for dog or monkey microsomes or hepatocytes. Therefore, this comparative exercise was limited to rat and human microsomes and hepatocytes. Examination of the available CL,i values indicated a substantial (up to 100 s-fold) variation in values reported in the literature; this variability translated into substantial variation in predicted in vivo clearance. The literature paucity and variability described here demonstrate the importance of generating experimentally consistent de novo CL,i data for the purpose of method validation or in vitro-in vivo scaling.


BMP2 response pattern in human lung fibroblasts predicts outcome in lung adenocarcinomas.
Bone morphogenetic proteins play important roles in development, morphogenesis and cancer. With this study we aimed to characterize the response of lung stromal fibroblasts to BMPs and their antagonists on a genome wide level and investigate its potential role in human lung adenocarcinomas. We used an ex vivo culture model and measured gene expression changes in human lung fibroblasts after stimulation with BMPs and their antagonists using HEEBO microarrays. The in vitro data were correlated with in vivo observations in published expression datasets of human lung adenocarcinomas. We have systematically analyzed the response to BMP2, BMP4, BMP7 and their antagonists, Gremlin and Noggin, to define common and specific gene expression patterns. A BMP2 induced gene expression signature was defined, which is specific for stromal fibroblasts. Gene expression profiles from lung adenocarcinoma biopsies were analyzed to determine the prognostic significance of the "Fibroblast specific BMP2 induced gene list". This gene list successfully segregated patients with different prognostic outcome in 3 datasets. In a small dataset (Garber et al.) there was a strong trend for a worse prognosis of patients with adenocarcinomas of all stages over-expressing the "Fibroblast specific BMP2 induced gene list". In two larger datasets with stage I adenocarcinomas we observed a significantly worse disease-free (p = 0.002, Lee et al. and p = 0.002, Bhattacharjee et al.) and overall survival (p = 0.0002). The effects of BMPs and their antagonists are heterogeneous in different cell types. The gene expression pattern induced by BMP2 in primary lung fibroblasts may predict outcomes of patients with lung adenocarcinomas.


Preparation of fat substitute based on maize starch hydrolysates and application in reduced-fat acidified milk gel.
Reduced-fat food has become a popular choice among contemporary consumers. This study aims to develop a starch-based fat substitute and incorporate it into reduced-fat milk gel acidified with glucono-δ-lactone (GDL) to achieve similar rheological properties as a full-fat gel. The gel properties of the fat substitute were assessed. The study examined the rheological properties, syneresis, textural properties and microstructure of acidified milk gels while also monitoring acidification process. Starch hydrolysates with low dextrose equivalent (DE) (<5.1 %) can serve as an effective fat substitute due to their excellent gelling properties The rheological and textural properties of the reduced-fat acidified milk gel with DE at 3.1 % of starch hydrolysate and 30 % fat substitution are similar to those of the full-fat milk gel. The syneresis and confocal laser scanning microscopy (CLSM) results indicated that the microstructure of the reduced-fat acidified milk gel was similar to the full-fat version. Moreover, the sensory properties of the reduced-fat acidified milk gel were acceptable when the DE was 3.1 %, and 30 % fat was replaced. In our study, we utilized hydrolyzed starch to produce reduced-fat acidified milk gels, which could potentially be used in the development of reduced-fat yogurt formulations.


Xiaoyin Jiedu Granules may alleviate psoriasis-like skin diseases in mice by regulating sphingosine 1-phosphate receptor expression and reducing Th17 cells.
Sphingosine-1-phosphate (S1P) is associated with the onset and severity of psoriasis, a chronic inflammatory skin disease linked to innate and adaptive immune responses. This study explores the therapeutic effect of Xiaoyin Jiedu Granules, a combination of traditional Chinese medicines, on psoriasis-like skin lesions in mice and the underlying mechanism. We used imiquimod (IMQ) to induce psoriasis-like dermatitis in mice; the effects of Xiaoyin Jiedu Granules on S1P receptors (S1PRs) were investigated using histology and immunohistochemistry. The effects of Xiaoyin Jiedu Granules on the proliferation, differentiation, and activation of the NF-κB pathway in keratinocytes were verified using quantitative polymerase chain reaction (qPCR) and western blotting analyses. CD4+Th17 cells were screened using flow cytometry; the effects of Xiaoyin Jiedu Granules on the differentiation of Th17 cells and the content of related inflammatory factors were also verified. S1PR1-5 was highly expressed in psoriatic lesions. Xiaoyin Jiedu Granules significantly inhibited the secretion of proliferation-related proteins (K6, K16, K17, and IL-36γ) and proinflammatory cytokines (IL-17 and IL-22), transformation of Th17 cells, and activation of the NF-κB pathway and effectively alleviated IMQ-induced psoriasis-like dermatitis. Overall, our findings indicate that Xiaoyin Jiedu Granules have anti-inflammatory activity against S1PR expression, keratinocytes, and immune cells and can therefore mitigate psoriasis. Inhibiting the expression of S1PRs may be an effective treatment strategy against psoriasis.


Organization of the oxygen-evolution enzyme complex studied by butanol/water phase partitioning of spinach photosystem II particles.
The oxygen-evolving photosystem II particles prepared from spinach chloroplasts with brief sonication and Triton X-100 treatment were subjected to butanol/water phase partitioning. Three peripheral proteins of photosystem II having relative molecular masses of 33,000, 24,000, and 18,000 daltons and a part of the manganese atoms associated with photosystem II were partitioned into the aqueous phase, depending on the concentration of salt which was included in the suspension of the photosystem II particles. Quantitative analysis of the phase partitioning of the photosystem II particles under the various ionic conditions at pH 6.5 suggested the following: (a) two of the four atoms of manganese associated with photosystem II are located at a relatively hydrophilic environment and easily extracted from the membrane; (b) one of these "hydrophilic manganese atoms" is structurally in close proximity to the protein of the relative molecular mass of 33,000 daltons and stabilized by the protein specifically; (c) the protein of the relative molecular mass of 24,000 daltons as well as that of 33,000 daltons is involved in the stabilization of the other "hydrophilic manganese" in the membrane; (d) each of the three proteins has an independent binding site on the membrane and organizes a specific catalytic domain where oxidation of water is carried out efficiently in collaboration with the reaction center of photosystem II.


Autocategorization: a new technique for statistical comparisons of medical diagnoses.
Autocategorization is a new technique appropriate for studies involving relative frequencies of illness diagnoses using the International Classification of Diseases. It is ideally suited for emergency department illness patterns. The technique uses the standard chi-square statistical test, but is novel in objectively determining the aggregation of diseases into categories for analysis. The numbers of observed occurrences of the various diseases are used. without applying any a priori judgements, to decide whether a disease should be analyzed alone, or aggregated with others. This technique, because it is based on the ICDA code, will permit comparisons between various studies while retaining the statistical validity of the individual studies.


Thoracic epidural versus patient-controlled analgesia in elective bowel resections.
This study was undertaken to determine if thoracic epidural analgesia is of practical benefit after bowel resection. Patients were prospectively randomized to receive either a thoracic epidural or patient-controlled analgesia for pain control after bowel resection. A standardized postoperative protocol was instituted after surgery. Pain scores were significantly lower in the epidural group. Return of bowel function, and interval to discharge was not different between groups. Cost and complication rates were significantly higher in the epidural group. Although pain scores were significantly lower in the epidural group, this did not translate into a quicker return of bowel function or earlier discharge of the patient. Furthermore, the epidural group had a significantly higher complication rate and cost. Therefore, while thoracic epidural analgesia provides superior pain control, it does not offer a significant advantage over patient-controlled analgesia in return of bowel function after bowel resection.


Photoprotective effects of 2S,3R-6-methoxycarbonylgallocatechin isolated from Anhua dark tea on UVB-induced inflammatory responses in human keratinocytes.
Ultraviolet B (UVB) induces inflammation and causes skin aging. The signs of skin aging, such as wrinkles, discolored spots, loss of skin moisture, and disruption of the skin barrier, are mostly caused by inflammatory signaling among various skin layers. The cells on the outermost surface of the skin are keratinocytes; these cells protect the skin against environmental stress and play an important role in immunomodulation by secreting cytokines in response to environmental stress. In the present study, we found that UVB activates STAT1 to mediate inflammatory signaling, yet STAT1 (S272) and STAT (Y702) shows different responses against UVB exposure. Anhua drak tea is a post-fermented dark tea produced in Anhua and Xinhua country in Hunan province of China. Treatment with 2S,3R-6-methoxycarbonylgallocatechin (MCGE), an epigallocatechin gallate derivative isolated from black tea (Anhua dark tea), effectively suppresses STAT1 activation and inflammatory cytokines, and activates Nrf2 pathway to protect cells from reactive oxygen species production in UVB exposed keratinocyte cells (HaCaT). Interestingly, the effects of MCGE were independent on MAPK signaling pathway. Moreover, MCGE regulates inflammatory cytokines in monocyte-keratinocyte (THP-1, HaCaT) co-culture and macrophage differentiation models. These results suggest that MCGE potentially can be used as a photoprotective agent against UVB-induced inflammatory responses.


[Bilateral anterior shoulder luxation--an overlooked case].
A case of missed first time bilateral anterior dislocation of the shoulders caused by a grand mal seizure is presented. The lack of asymmetry of the shoulders is stressed as a potential pitfall in the clinical evaluation of patients with this condition.


Evaluation of different hybridization procedures for the detection of mycoplasma contamination in cell cultures.
Cell culture samples were analysed for mycoplasma contaminations with two different DNA probes which have been described earlier. One probe (the H900 probe), derived from the 23S rRNA gene of Mycoplasma hyorhinis, cross-hybridized with virtually all mycoplasmas (including the acholeplasmas). The other probe (the T2 probe), derived from a protein gene of Acholeplasma laidlawii, cross-hybridized with most acholeplasmas. The two probes were compared in three different direct filter hybridization procedures without previous isolation of DNA or RNA. One of the procedures, developed in the present study, gave the highest sensitivity in DNA-RNA hybridization but also worked satisfactorily in DNA-DNA hybridization. The sensitivity of the H900 probe in filter hybridization experiments was compared with the sensitivity of a commercial probe for detection of mycoplasma contaminations in cell cultures. The H900 probe was found to be at least 25 times more sensitive for all cell culture mycoplasmas except for A. laidlawii, for which they were equally sensitive.


Swine Farming Is a Risk Factor for Infection With and High Prevalence of Carriage of Multidrug-Resistant Staphylococcus aureus.
Livestock-associated Staphylococcus aureus (LA-SA) has been documented worldwide. However, much remains unknown about LA-SA colonization and infection, especially in rural environments. We conducted a large-scale prospective study of 1342 Iowans, including individuals with livestock contact and a community-based comparison group. Nasal and throat swabs were collected to determine colonization at enrollment, and skin infection swabs over 17 months were assessed for S. aureus. Outcomes included carriage of S. aureus, methicillin-resistant S. aureus (MRSA), tetracycline-resistant S. aureus (TRSA), multidrug-resistant S. aureus (MDRSA), and LA-SA. Of 1342 participants, 351 (26.2%; 95% confidence interval [CI], 23.8%-28.6%) carried S. aureus. MRSA was isolated from 34 (2.5%; 95% CI, 1.8%-3.5%) and LA-SA from 131 (9.8%; 95% CI, 8.3%-11.5%) of the 1342 participants. Individuals with current swine exposure were significantly more likely to carry S. aureus (prevalence ratio [PR], 1.8; 95% CI, 1.4-2.2), TRSA (PR, 8.4; 95% CI, 5.6-12.6), MDRSA (PR, 6.1; 95% CI, 3.8-10.0), and LA-SA (PR, 5.8; 95% CI, 3.9-8.4) than those lacking exposure. Skin infections (n = 103) were reported from 67 individuals, yielding an incidence rate of 6.6 (95% CI, 4.9-8.9) per 1000 person-months. Current swine workers are 6 times more likely to carry MDRSA than those without current swine exposure. We observed active infections caused by LA-SA. This finding suggests that individuals with livestock contact may have a high prevalence of exposure to, and potentially infection with, antibiotic-resistant S. aureus strains, including LA-SA strains.


Cardiac involvement in polymyositis: a clinicopathologic study of 20 autopsied patients.
Cardiac involvement in polymyositis was investigated in 20 autopsied cases. Clinically, 13 of 18 patients had abnormal electrocardiograms, and 9 of the 20 patients had previous evidence of congestive heart failure. Histologically documented myocarditis was detected in 6 patients (4 with congestive heart failure and 2 without), 4 of whom also had small vessel disease of the myocardium. Patients with polymyositis may have a cardiopathy in the absence of overt myocardial inflammatory disease.


Interaction effects of the 5-HTT and MAOA-uVNTR gene variants on pre-attentive EEG activity in response to threatening voices.
Both the serotonin transporter polymorphism (5-HTTLPR) and the monoamine oxidase A gene (MAOA-uVNTR) are considered genetic contributors for anxiety-related symptomatology and aggressive behavior. Nevertheless, an interaction between these genes and the pre-attentive processing of threatening voices -a biological marker for anxiety-related conditions- has not been assessed yet. Among the entire sample of participants in the study with valid genotyping and electroencephalographic (EEG) data (N = 140), here we show that men with low-activity MAOA-uVNTR, and who were not homozygous for the 5-HTTLPR short allele (s) (n = 11), had significantly larger fearful MMN amplitudes -as driven by significant larger ERPs to fearful stimuli- than men with high-activity MAOA-uVNTR variants (n = 20). This is in contrast with previous studies, where significantly reduced fearful MMN amplitudes, driven by increased ERPs to neutral stimuli, were observed in those homozygous for the 5-HTT s-allele. In conclusion, using genetic, neurophysiological, and behavioral measurements, this study illustrates how the intricate interaction between the 5-HTT and the MAOA-uVNTR variants have an impact on threat processing, and social cognition, in male individuals (n = 62).


CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment.
Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named PFH@LSLP) for sorafenib-resistant HCC treatment. The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O2-saturated PFH core could alleviate the tumor hypoxia by O2 supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8+ T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.


Variability of plasma anti-Xa activities with different lots of enoxaparin.
Previous studies have indicated the variability of anti-Xa activity in different sources of heparin and the variability of different methods used for measuring anti-Xa activity. Manufacturers of low-molecular-weight heparins (LMWHs) determine each lot's anti-Xa activity against the World Health Organization standard, but little information is known about anti-Xa activity variation between lots of LMWH and the impact on reported anti-Xa activity in patient samples. To determine the variation of plasma anti-Xa activity in patients receiving enoxaparin when different lots of enoxaparin are used for test calibration. We obtained 7 lots of enoxaparin containing approximately 10,000 IU/mL and one lot containing approximately 15,000 IU/mL of anti-Xa activity. For each lot, a 2.0 anti-Xa IU/mL dilution was prepared and a calibration curve performed using a chromogenic method. To test the variation in reported results between the different calibration lots, 20 patient samples were tested. Nineteen patients receiving enoxaparin and one patient not receiving enoxaparin (negative control) were tested in a blinded fashion, and the changes in light absorbance recorded. Anti-Xa activity results from tested plasmas were then extrapolated from each enoxaparin lot calibration curve. Using Student's paired t-test, there were statistically significant differences between the plasma anti-Xa activities generated from the various enoxaparin lots. In the range of 0.5-1.0 IU/mL of anti-Xa activity, 3 (4.2%) samples had a >0.2 IU/mL difference (maximum difference 0.33 IU/mL) in anti-Xa activity between 2 lots of enoxaparin. For samples that had supratherapeutic anti-Xa activities (1.0-1.5 IU/mL anti-Xa activity), there was a wider variation (>0.2 IU/mL) in anti-Xa activity, which may have resulted in a dosing change. The statistical differences in plasma anti-Xa activities noted between enoxaparin lots are not clinically significant. However, anti-Xa activities in the upper therapeutic and supratherapeutic ranges (>1.0 IU/mL of anti-Xa activity) resulted in a deviation of >0.3 IU/mL in reported anti-Xa activity, which may result in dosing changes.


Indoor radon levels in the northeastern U.S.: effects of energy-efficiency in homes.
The expectation of elevated 222Rn levels in modern homes that have low air interchange rates with the out-of-doors caused us to survey both solar and conventional homes in northeastern New York State. The solar homes as a group have three times the 222Rn levels of the conventional homes, and specific problems exist that are introduced or exaggerated by modern construction. For example the highest two levels of radon in the solar homes give radiation doses over 30 yr that are known to produce lung cancer in 1% of uranium miners. Summer readings in more than half of the cases are different from winter ones by a factor of two or more, so that year-round measurements are necessary for precise dosimetry. The track etching technique is ideally suited for such measurements.


Can ecological history influence immunomarker responses and antioxidant enzyme activities in bivalves that have been experimentally exposed to contaminants? A new subject for discussion in "eco-immunology" studies.
Numerous studies have demonstrated that environmental parameters affect bivalve immunomarkers. In the present study, we tested the hypothesis that clams (Venerupis philippinarum) collected in sites with different environmental conditions respond differently to experimental contaminant exposure. Clams were collected at two sites within the Lagoon of Venice that are influenced differently by both anthropogenic impact and natural conditions: Marghera, which is characterised by relatively high contamination levels and restricted clam fishing, and Chioggia, which is inside a licensed clam culture area that is characterised by lower contamination levels. Total haemocyte count, haemocyte diameter and volume, lysozyme activity in both haemocyte lysate and cell-free haemolymph, superoxide dismutase and catalase activities in gills and digestive glands were measured at time 0 (clam sampling time), after 7 days of acclimation in the laboratory and after 1, 3 and 7 days of copper exposure. Interestingly, statistical analyses (three-way ANOVA and Canonical Correlation Analysis) revealed persistent differences in the biological responses of clams from the two sampling sites before and after copper exposure. Conversely, the influence of copper on cellular and biochemical parameters was negligible. Overall, the results obtained indicated that animals with a different ecological history respond differently to experimental contaminant exposure. In addition, this study suggested that immunomarkers and other biomarkers might be used to determine the origin of fishing products.


[The wordless story from institution obsession to hysteria passion].
Silence and immobility: mutism and catatonia, this patient gives nothing to to hear, he gives to see. Could the catatonia concept, usually used for schizophrenic psychosis and primitively described by Kahlbaum in 1874, be used for neurosis?


In response to pathogens, glial cells dynamically and differentially regulate Toll-like receptor gene expression.
The mechanisms that mediate innate immune recognition of CNS infections are unknown. This study provides a comparison of Toll-like receptor (TLR) gene expression in resting and virus infected CNS cells. N2a neuroblastoma cells expressed TLR 3 but demonstrated no change in TLR gene expression in response to either LPS or virus infection. N9 microglia and differentiated primary astrocytes expressed most TLR genes. TLR 2 expression was highest in N9 microglia and TLR 7 in astrocytes. In both glial cell types, LPS stimulation upregulated pro-inflammatory cytokines, TLR 2 and TLR 3 gene expression but down-regulated other TLR genes. RNA virus infection substantially increased levels of type-I interferon (IFN) and TLR 3 transcripts and to a lesser extent TLR 9 transcripts. Microglia and astrocytes thus have the ability to discriminate between pathogens and elicit an appropriate response.


Comparative proteomic analysis of the contractile-protein-depleted fraction from normal versus dystrophic skeletal muscle.
In basic and applied myology, gel-based proteomics is routinely used for studying global changes in the protein constellation of contractile fibers during myogenesis, physiological adaptations, neuromuscular degeneration, and the natural aging process. Since the main proteins of the actomyosin apparatus and its auxiliary sarcomeric components often negate weak signals from minor muscle proteins during proteomic investigations, we have here evaluated whether a simple prefractionation step can be employed to eliminate certain aspects of this analytical obstacle. To remove a large portion of highly abundant contractile proteins from skeletal muscle homogenates without the usage of major manipulative steps, differential centrifugation was used to decisively reduce the sample complexity of crude muscle tissue extracts. The resulting protein fraction was separated by two-dimensional gel electrophoresis, and 2D-landmark proteins were identified by mass spectrometry. To evaluate the suitability of the contractile-protein-depleted fraction for comparative proteomics, normal versus dystrophic muscle preparations were examined. The mass spectrometric analysis of differentially expressed proteins, as determined by fluorescence difference in-gel electrophoresis, identified 10 protein species in dystrophic mdx hindlimb muscles. Interesting new biomarker candidates included Hsp70, transferrin, and ferritin, whereby their altered concentration levels in dystrophin-deficient muscle were confirmed by immunoblotting.


The Enticing Path of miR Therapeutics: Difficult but Not without Prospects.
MicroRNAs (miRs) are short non-coding RNAs that regulate the translation and stability of mRNAs to fine-tune gene expression [...].


WITHDRAWN: A lasp family protein of Ciona intestinalis.
The Publisher regrets that this article is an accidental duplication of an article that has already been published in Biochim. Biophys. Acta, doi:10.1016/j.bbagrm.2007.08.001. The duplicate article has therefore been withdrawn.


Oncologic outcomes after nipple-sparing mastectomy: A single-institution experience.
Long-term oncologic outcomes in nipple-sparing mastectomy (NSM) continue to be defined. Rates of locoregional recurrence for skin-sparing mastectomy (SSM) and NSM in the literature range from 0% to 14.3%. We investigated the outcomes of NSM at our institution. Patients undergoing NSM at our institution from 2006 to 2014 were identified and outcomes were analyzed. From 2006 to 2014, 319 patients (555 breasts) underwent NSM. One-hundered and fourty-one patients (237 breasts) had long-term follow-up available. Average patient age and BMI were 47.78 and 24.63. Eighty-four percent of patients underwent mastectomy primarily for a therapeutic indication. Average tumor size was 1.50 cm with the most common histologic type being invasive ductal carcinoma (62.7%) followed by DCIS (23.7%). Average patient follow-up was 30.73 months. There was one (0.8%) incidence of ipsilateral chest-wall recurrence. There were 0.37 complications per patient. We examined our institutional outcomes with NSM and found a locoregional recurrence rate of 0.8% with no nipple-areolar complex recurrence. This rate is lower than published rates for both NSM and SSM.


Interaction of human serum apolipoprotein B with sodium deoxycholate.
Preparation of apolipoprotein B (Apo B)-deoxycholate (DOC) complexes by gel filtration chromatography in the presence of 20 mM DOC, pH 8.5, gave two populations of particles with 5% (peak I) and 13% (peak II) lipid remaining bound. These complexes were initially shown to be very large and elongated, with partition radii of approx. 131 +/- 0.5 A, weight average molecular weights of approx. 164 000 +/- 1 000, and an intrinsic viscosity of 80.19 +/- 2.21 ml/g. Additionally, they appeared very similar to native low-density lipoprotein on sodium dodecyl sulfate-polyacrylamide gels, giving one major band. Incubation of these samples for 10 days under nitrogen at 4 degrees C in the presence of antibiotics and protease inhibitor resulted in dissociation to many smaller subunits. Results of scanning molecular sieve chromatography and analytical ultracentrifugation showed that dissociation of these complexes was relatively slow and indicated the presence of at least two classes of components in fresh samples: one a very elongated complex with a radius directly correlated to the DOC/Apo B ratio and inversely correlated to sample aging; and another of much smaller radius which was independent of DOC/Apo B ratio but directly correlated to sample aging; indicating that these dissociated subunits interact with each other to an appreciable extent. Furthermore, these complexes were found to undergo a preferential hydration upon interaction with DOC, which may contribute to large changes in their effective specific volumes, as well as to dissociation of subunits.


Motor imagery training of goal-directed reaching in relation to imagery of reaching and grasping in healthy people.
The study aimed to determine whether four weeks of motor imagery training (MIT) of goal-directed reaching (reaching to grasp task) would affect the cortical activity during motor imagery of reaching (MIR) and grasping (MIG) in the same way. We examined cortical activity regarding event-related potentials (ERPs) in healthy young participants. Our study also evaluated the subjective vividness of the imagery. Furthermore, we aimed to determine the relationship between the subjective assessment of motor imagery (MI) ability to reach and grasp and the cortical activity during those tasks before and after training to understand the underlying neuroplasticity mechanisms. Twenty-seven volunteers participated in MIT of goal-directed reaching and two measurement sessions before and after MIT. During the sessions 128-channel electroencephalography (EEG) was recorded during MIR and MIG. Also, participants assessed the vividness of the MI tasks using a visual analog scale (VAS). The vividness of imagination improved significantly (P < .05) after MIT. A repeated measures ANOVA showed that the task (MIR/MIG) and the location of electrodes had a significant effect on the ERP's amplitude (P < .05). The interaction between the task, location, and session (before/after MIT) also had a significant effect on the ERP's amplitude (P < .05). Finally, the location of electrodes and the interaction between location and session had a significant effect on the ERP's latency (P < .05). We found that MIT influenced the EEG signal associated with reaching differently than grasping. The effect was more pronounced for MIR than for MIG. Correlation analysis showed that changes in the assessed parameters due to MIT reduced the relationship between the subjective evaluation of imagining and the EEG signal. This finding means that the subjective evaluation of imagining cannot be a simple, functional insight into the bioelectrical activity of the cerebral cortex expressed by the ERPs in mental training. The changes we noted in ERPs after MIT may benefit the use of non-invasive EEG in the brain-computer interface (BCI) context.Trial registration: NCT04048083.


Anti-AIDS agents. Part 57: Actein, an anti-HIV principle from the rhizome of Cimicifuga racemosa (black cohosh), and the anti-HIV activity of related saponins.
Actein (1), a tetracyclic triterpenoid from the rhizome of Cimicifuga racemosa (black cohosh), and 82 related triterpenoid and steroidal saponins isolated from higher plants were evaluated for anti-HIV activity as a continuing study to discover potential anti-AIDS agents from natural products. Actein showed potent activity and another twelve saponins showed moderate activity. The active compounds included two steroidal, seven tetracyclic triterpenoid, and four pentacyclic triterpenoid compounds.


The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.
Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Downregulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs' speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.


Moving out but not for the better: Health consequences of interprovincial rural-urban migration in China.
Using panel data from a survey conducted by the Research Center for Rural Economy, this study overcomes the selection bias associated with most health status measures by incorporating dialect proximity as an instrumental variable to evaluate the causal effects of interprovincial migration on individuals' health status in China. The results indicate that, compared to an absorbed category, which includes intraprovincial migration and non-migration, interprovincial migration worsens health (measured by the self-reported health status score) by 3%. It is also found that, compared to intraprovincial migrants, interprovincial migrants are more likely to report a lower SHS score, whereas the health effect differences between interprovincial migrants and non-migrants are insignificant. The study identifies two potential mechanisms that explain this result: (i) The increase in income following migration may improve interprovincial migrants' health, and (ii) the exposure to hazardous working environments worsens health to a significant extent. This finding is also linked to the following gender-related finding: Compared to women, men are more likely to be employed in heavy industries with hazardous working environments; the negative effects of interprovincial migration on the health status are stronger for men than for women migrants, suggesting that the industry effect dominates.


Cerebrospinal fluid acidosis complicating therapy of experimental cardiopulmonary arrest.
Cardiopulmonary resuscitation (CPR) may be followed by slow recovery of brain function. The possible role of bicarbonate therapy was assessed by analysis of arterial blood and cerebrospinal fluid (CSF) in 20 dogs during cardiac arrest and CPR. Samples were taken in the control period and every 5 minutes post-arrest of 20 minutes. Group I received no post-arrest CPR. Arterial pH fell from 7.37 to 7.31 (P less than 0.01) and CSF pH from 7.34 to 6.94 (P less than 0.001). Arterial pCO2 rose from 39 to 65 mm Hg (P less than 0.005) and CSF pCO2 increased from 47 to 123 (P less than 0.02). With CPR alone (group II) arterial pH decreased from 7.39 to 7.19 (P less than 0.005), while arterial pCO2 and CSF pH and pCO2 were undhanged. CPR with bicarbonate therapy (mEq = weight in kg times 0.43 times 1.1 mEq/min of arrest) given every 5 minutes (group III), resulted in a rise in arterial pH from 7.41 to 7.81 (P less than 0.02). Excess bicarbonate administration during CPR may result in a marked dissociation between arterial and CSF pH as a consequence of rapid CO2 diffusion across the blood-brain barrier. Large ampounts of NaHCO3 given during CPR may contribute to post-CPR cerebral depresssion.


Composite tumor of metanephric adenoma and Wilms' tumor of the kidney: A case report and review of the literature.
Metanephric adenoma (MA) and Wilms' tumor (WT) are two distinct types of renal tumors. Composite MA and WT of the kidney are extremely rare. Here, a rare case of composite MA and WT of the kidney in a 36-year-old male is described. MA and WT each have their own histopathological features, respectively, and they focally share morphological similarities, which can be a diagnostic challenge. Immunohistochemistry is useful in the differential diagnosis of MA and WT. The histopathological features and differential diagnosis of the composite tumor are emphasized here to promote a better and broader understanding of this less understood subject.


A modelling approach to explore the optimum bubble size for micro-nanobubble aeration.
Bubble aeration has been widely applied in water/wastewater treatment, however its low gas utilization rate results in high energy consumption. Application of micro-nanobubbles (MNB) has emerged as a process with the potential to significantly increase gas utilisation due to their high relative surface area and high gas-liquid mass transfer efficiency. In this study, we demonstrate through calibrated models that MNB of an optimum bubble size can shrink and burst at or below the water surface enabling (1) all encapsulated gas to thoroughly dissolve in water, and (2) the bursting of nanobubbles to potentially generate free radicals. Through the understanding of MNB dimensional characteristics and bubble behaviour in water, a dynamic model that integrated force balance (i.e. buoyancy force, gravity, drag force, Basset force and virtual mass force), and mass transfer was developed to describe the rising velocity and radius variation of MNB along its upward trajectory. Unlike for conventional millimetre-sized bubbles, intensive gas dissolution of MNBs led to radius reduction for small bubbles, while a large initial radius triggers bubble swelling. The initial water depth was also crucial, where greater depth could drive the potential for bubble shrinkage so that they were more liable to contract. For example, the optimum bubble size of air (42-194 μm) and oxygen (127-470 μm) MNB that could achieve complete gas transfer (100% gas utilisation) for a range of specific water depths (0.5-10 m) were calculated. The modelling results for microbubbles (10-530 μm) were well validated by the experimental data (R2>0.85). However, the validation of the modelling results for nanobubble (<1 μm) aeration requires further study due to a lack of available empirical data. In this study, the proposed model and analysis provided new insights into understanding bubble dynamics in water and offered fundamental guidance for practitioners looking to upgrade bubble aeration system.


Transcatheter closure of the patent ductus arteriosus at a public sector hospital in Soweto, South Africa: a review of patient outcomes over 15 years.
Methods of closing patent ductus arteriosus (PDA) have evolved over time. We review this development in our setting. This was a retrospective analysis of children who had transcatheter PDA closure at Chris Hani Baragwanath Hospital between 1993 and 2008. Over 15 years, 1 254 PDAs were diagnosed, of which 293 required intervention; 139 patients had transcatheter closure, the median age was 1.8 years (interquartile range = 1-4.5 years) and 66% were female (92/139). Mean PDA diameter was 3.2 mm (standard deviation = 1.6 mm), with an average 2:1 shunt. Transcatheter closure was performed using COOK® Flipper coils (n = 93) or Amplatzer™ devices (n = 46). Early occlusion rates for coils were 52% (39/75) and late occlusion occurred in 91% (68/75) of patients. For Amplatzer devices, early occlusion rates were 94% (33/35) and late occlusion was 100%. Amplatzer™ devices, available since 2003, were overwhelmingly used in the later years. Transcatheter PDA closure was safe and effective in this setting, with outcomes similar to reports elsewhere.


Effect of 17beta-estradiol on gamete quality and maturation in two salmonid species.
In the present study the effect of environmentally relevant concentrations of 17beta-estradiol on gamete quality and gamete maturation in rainbow trout (Oncorhynchus mykiss) and grayling (Thymallus thymallus) was investigated. Male rainbow trout were exposed to 0.5-2.5ngl(-1) 17beta-estradiol for 35days during the spawning season. At concentrations of > or =1ngl(-1) the semen volume obtained per male was significantly reduced, and after 50days also the sperm density and the sperm fertility. When male grayling were exposed to 1.0ngl(-1) 17beta-estradiol for 50days during the prespawning season a similar number of males gave semen as in the control. However, the volume of semen produced per male was decreased. The percentage of motile spermatozoa and their sperm swimming velocity were decreased while the percentage of locally motile spermatozoa was increased. In rainbow trout and grayling also the sperm motility pattern was affected by 17beta-estradiol exposure. When female rainbow trout were exposed to 0.5-2.5ngl(-1) 17beta-estradiol and egg portions were stripped in 1 week intervals the egg viability changed in a similar way as in the control indicating that egg overripening processes were not influenced by 17beta-estradiol. When female grayling were exposed to 1.0ngl(-1) 17beta-estradiol during the prespawning time ovulation occurred earlier than in the control group (group exposed to 17beta-estradiol: 35days after the onset of the experiment, control group 35-50days after the onset of the experiment).


Pore-scale analysis of formation damage; A review of existing digital and analytical approaches.
Formation damage is one of the most challenging problems that occurs during the lifetime of a well. Despite numerous previous studies, an organized review of the literature that introduces and describes the digital and analytical approaches developed for formation damage analysis is lacking. This study aims to fill this gap through briefly describing the main mechanisms behind formation damage in porous media as well as investigating the main related experimental methods with an emphasis on novel imaging techniques. Specifically, there will be a focus on a number of modern and nondestructive analytical methods, such as dry/cryogenic Scanning Electron Microscopy (SEM), X-Ray Diffraction (XRD), CT-scanning (both using adapted medical scanners and the use of high-resolution micro-CT instruments) and Nuclear Magnetic Resonance (NMR), which obtain outstanding results for the identification of formation damage mechanisms. These approaches when used in combination provide a robust identification of damage processes, while they reduce the risk of operational mistakes for decision makers through visualization of the distribution, severity, and nature of the damage mechanisms.


Considerations for Voice and Communication Training Software for Transgender and Nonbinary People.
Transgender and gender diverse people often experience voice-gender incongruence, which is inversely correlated with health and quality of life. Such incongruence could be reduced with voice and communication training, but expert-administered training is often inaccessible while self-guided training is difficult and potentially risky. Training could alternatively be provided through software (eg, smartphone apps), but such software is at an early stage. This qualitatively driven mixed-methods study thus includes surveys and interviews with 21 transfeminine, transmasculine and nonbinary people to identify general views of voice and communication training software as well as most desirable features of such software. Participants were positive about the general idea and described ways to effectively implement four critical features: feedback, accountability, automated goal setting, and training characteristics other than pitch. They also discussed optional or undesirable features. These findings may inform development of voice and communication training software, thus improving health and quality of life for gender minorities.


Clinical and pathological analysis of hepatic artery aneurysm in a patient with systemic lupus erythematosus: report of a case.
A hepatic artery aneurysm is an unusual but life-threatening hepatobiliary complication occurring in patients with systemic lupus erythematosus (SLE), and early diagnosis and treatment of this complication are essential. A 31-year-old man with SLE presented with recurring epigastric pain and jaundice for 2 months; he was diagnosed with choledocholithiasis and underwent surgery. Hemobilia was found intraoperatively, and two hepatic artery aneurysms were identified in the left lateral lobe during postoperative arteriography. Major hemobilia occurred 6 days after the operation, and the patient was immediately treated with selective embolization of the hepatic artery. However, the major hemobilia recurred 2 days later, and he was treated with a left lateral lobectomy and ligation of the proximal hepatic artery. The patient recovered uneventfully and is in good condition. A histological analysis revealed small- and medium-sized arteritis as well as hepatic artery aneurysm. Systemic lupus erythematosus complicated by a hepatic artery aneurysm should be considered in the differential diagnosis of patients showing symptoms of abdominal pain, jaundice, or gastrointestinal bleeding.


Plasminogen activators, activation inhibitors and alpha 2-macroglobulin produced by cultured normal and malignant human cells.
In the present paper we have characterized the plasminogen activators (PA) synthesized by 25 different human cell lines. Technically easy methods were adopted for concentration and immunological characterization of the activators even in the presence of PA inhibitors. Most cell lines produced u-PA (mol. wt 55,000), melanoma and HeLa cells t-PA (mol. wt 66,000) and two carcinoma cell lines and normal skin fibroblasts produced no detectable PA. The classical 125I-fibrin method was compared to a caseinolytic assay and some of the discrepancies between results obtained with the two methods were shown to be due to cell-derived NaDodSO4-sensitive proteinase inhibitors in culture media. Additionally, synthesis and uptake by the cells of the wide-spectrum proteinase inhibitor alpha-2-macroglobulin ( alpha 2M ) were studied by radioimmunoassay and immunofluorescence. No production of alpha 2M could be measured in any of the malignant cell lines. In normal cells no correlation existed between the production of alpha 2M and the observed inhibition of PA activity, which indicates that other proteinase inhibitors are produced by the cells.


Automatic recognition of epileptic seizures in the EEG.
During prolonged EEG monitoring of epileptic patients, the continuous EEG tracing may be replaced by a selective recording of ictal and interictal epileptic activity. We have described previously methods for the EEG recording of seizures with overt clinical manifestations and for the automatic detection of spikes. This paper describes a method for the automatic detection of seizures in the EEG, independently of the presence of clinical signs; it is based on the decomposition of the EEG into elementary waves and the detection of paroxysmal bursts of rhythmic activity having a frequency between 3 and 20 c/sec. Simple procedures are used to measure the amplitude of waves relative to the background, their duration and rhythmicity. The evaluation of the method on 24 surface recordings (average duration 12.4 h) and 44 recordings from intracerebral electrodes (average duration 18.7 h) indicated that it was capable of recognizing numerous types of seizures. False detections due to non-epileptiform rhythmic EEG bursts and to artefacts were quite frequent but were not a serious problem because they did not unduly lengthen the EEG tracing and they could be easily identified by the electroencephalographer. The program can perform on-line and simultaneously the automatic recognition of spikes and of seizures in 16 channels.


Ear transplantations reveal conservation of inner ear afferent pathfinding cues.
Vertebrate inner ear neurons project into the correct brainstem nuclei region before target neurons become postmitotic, or even in their absence. Moreover, afferents from transplanted ears in frogs have been shown to navigate to vestibular nuclei, suggesting that ear afferents use molecular cues to find their target. We performed heterochronic, xenoplastic, and heterotopic transplantations in chickens to investigate whether inner ear afferents are guided by conserved guidance molecules. We show that inner ear afferents can navigate to the vestibular nuclei following a delay in afferent entry and when the ear was from a different species, the mouse. These data suggest that guidance molecules are expressed for some time and are conserved across amniotes. In addition, we show that chicken ears transplanted adjacent to the spinal cord project dorsally like in the hindbrain. These results suggest that inner ear afferents navigate to the correct dorsoventral brainstem column using conserved cues.


JNK signaling during IL-3-mediated differentiation contributes to the c-kit-potentiated allergic inflammatory capacity of mast cells.
Mast cells are leukocytes that mediate various aspects of immunity and drive allergic hypersensitivity pathologies. Mast cells differentiate from hematopoietic progenitor cells in a manner that is largely IL-3 dependent. However, molecular mechanisms, including the signaling pathways that control this process, have yet to be thoroughly investigated. Here, we examine the role of the ubiquitous and critical mitogen-activated protein kinase signaling pathway due to its position downstream of the IL-3 receptor. Hematopoietic progenitor cells were harvested from the bone marrow of C57BL/6 mice and differentiated to bone marrow-derived mast cells in the presence of IL-3 and mitogen-activated protein kinase inhibitors. Inhibition of the JNK node of the mitogen-activated protein kinase pathway induced the most comprehensive changes to the mature mast cell phenotype. Bone marrow-derived mast cells differentiated during impaired JNK signaling expressed impaired c-kit levels on the mast cell surface, first detected at week 3 of differentiation. Following 1 wk of inhibitor withdrawal and subsequent stimulation of IgE-sensitized FcεRI receptors with allergen (TNP-BSA) and c-kit receptors with stem cell factor, JNK-inhibited bone marrow-derived mast cells exhibited impediments in early-phase mediator release through degranulation (80% of control), as well as late-phase secretion of CCL1, CCL2, CCL3, TNF, and IL-6. Experiments with dual stimulation conditions (TNP-BSA + stem cell factor or TNP-BSA alone) showed that impediments in mediator secretion were found to be mechanistically linked to reduced c-kit surface levels. This study is the first to implicate JNK activity in IL-3-mediated mast cell differentiation and also identifies development as a critical and functionally determinative period.


Synthesis and reactivities of 3-indocyanine-green-acyl-1,3-thiazolidine-2-thione (ICG-ATT) as a new near-infrared fluorescent-labeling reagent.
A new near-infrared fluorescent-labeling reagent (ICG-ATT) bearing the 3-acyl-1,3-thiazolidine-2-thione (ATT) moiety with the chemoselective acylation feature and the dye moiety of indocyanine green (ICG) has been developed. Synthesis and reactivities of the ICG-ATT are described.


Uncommon EEG pattern in an 8-year-old boy with recurrent migraine aura without headache.
A case of an 8-year-old boy with recurrent migraine auras without headache, precipitated by minor head trauma, is reported. Aura was characterized, besides other brain-stem signs, by confusional state. An uncommon electroencephalographic pattern recorded during the episodes, characterized by diffuse continuous beta activity, is described. Recognition of this finding may prevent an inappropriate diagnosis of drugs ingestion.


Comparison of the preventive activity of isorhamnetin glycosides from atsumi-kabu (red turnip, Brassica, campestris L.) leaves on carbon tetrachloride-induced liver injury in mice.
Isorhamnetin 3-O-glucoside, which was contained together with isorhamnetin 3,7-di-O-glucoside in atsumi-kabu leaves, suppressed increases in the plasma ALT and AST activities of mice with liver injury induced by the injection of carbon tetrachloride, but no suppression by isorhamnetin 3,7-di-O-glucoside was apparent. This result indicates that the release of glucose at the 7-position in isorhamnetin 3,7-di-O-glucoside was very important to mitigating liver injury.


Effects of the acute administration of ethanol on the sleep of the rat: a dose-response study.
Seven-hr sleep recordings were performed on rats following intraperitoneal injection of saline or one of four doses of ethanol (1.1, 1.5, 2.0 or 2.5 g/kg). Total minutes of REM sleep and percentage REM sleep were decreased in a dose-dependent manner. Percentage nonREM sleep increased with progressively higher doses. The decrease in REM sleep appeared to be related to a decrease in the number of REM sleep episodes and an increase in the length of the REM-nonREM cycle. Other variables such as mean length of REM sleep episodes and REM sleep efficiency were unchanged. An analysis of the first and second 3.5 hr of the recording showed that ethanol continued to have marked effects on REM and nonREM sleep during the second 3.5 hr, when blood levels were declining. Ethanol produced decreases in sleep latency, but total sleep time was unchanged.


The trend of ammonia levels in patients with glufosinate ammonium poisoning with respect to neurotoxicity.
Since glufosinate irreversibly inhibits glutamine synthetase, leading to intracellular accumulation of ammonia, hyperammonemia is considered one of the main mechanisms of glufosinate ammonium toxicity in humans. However, whether hyperammonemia causes neurotoxicity has not yet been studied. Therefore, the purpose of this study was to determine whether the serum ammonia level is elevated before the development of neurotoxicity. In this retrospective observational study, we analyzed data from consecutive patients diagnosed with acute glufosinate ammonium poisoning. The primary outcome was the development of neurotoxicity following the poisoning. Patients who developed neurotoxicity were characterized by higher initial ammonia levels compared to patients without neurotoxicity (121.0 µg/dL [87.0; 141.0] vs 83.0 µg/dL [65.0; 119.0], p < 0.01). However, there was no increase in ammonia levels over time in both the asymptomatic and neurotoxicity groups when serial serum ammonia levels were examined from emergency department admission to hospital discharge. In addition, there was no statistically significant difference between the peak ammonia levels in the asymptomatic group and the peak ammonia levels before symptom onset in the neurotoxicity group (135.0 µg/dL [109.0; 158.0] vs 144.0 µg/dL [120.0; 189.0], p = 0.15). Following the onset of neurotoxicity, the serum ammonia level increased significantly (125.0 [111.0; 151.0] µg/dL to 148.0 [118.0; 183.0] µg/dL, p < 0.01). In conclusion, hyperammonemia cannot be assumed as the cause of neurotoxicity in glufosinate ammonium poisoning and further research is needed to examine the exact mechanism of GA poisoning.


COVID-19 free oncologic surgical hub: The experience of reallocation of a gynecologic oncology unit during pandemic outbreak.
During the SARS-CoV-2 pandemic, the majority of healthcare resources of the affected Italian regions were allocated to COVID-19 patients. Due to lack of resources and high risk of death, most cancer patients have been shifted to non-surgical treatments. The following reports our experience of a Gynaecologic Oncology Unit's reallocation of resources in a COVID-19 free surgical oncologic hub in order to guarantee standard quality of surgical activities. This is a prospective observational study performed in the Gynaecologic Oncology Unit, on the outcomes of the reallocation of surgical activities outside the University Hospital of Bologna, Italy, during the Italian lockdown period. Here, we described our COVID-19 free surgical oncologic pathway, in terms of lifestyle restrictions, COVID-19 screening measures, and patient clinical, surgical and follow up outcomes. During the lockdown period (March 9th - May 4th, 2020), 83 patients were scheduled for oncological surgery, 51 patients underwent surgery. Compared to pre-COVID period, we performed the same activities: number of cases scheduled for surgery, type of surgery and surgical and oncological results. No cases of COVID-19 infection were recorded in operated patients and in medical staff. Patients were compliant and well accepted the lifestyle restrictions and reorganization of the care. Our experience showed that the prioritization of oncological surgical care and the allocation of resources during a pandemic in COVID-19 free surgical hubs is an appropriate choice to guarantee oncological protocols.


The effect of information on preferences stated in a choice-based conjoint analysis.
The objective of the study was to investigate the effect of a priori information on preferences for treatment elicited in a discrete choice experiment. A convenience sample of 100 subjects was randomly split into two groups. The groups received minimal or extensive information on the treatment of ankle and foot impairment in stroke. Then, they participated in a discrete choice experiment. Possible treatment was described using eight decision criteria with two to four levels each. Part-worth utility coefficients for the criteria levels, criteria importance and overall treatment preference were estimated. It was tested whether the amount of information that was received influenced the outcome of the discrete choice experiment. In the extensively informed group fewer reversals in the expected order of part-worth utilities were found. Criteria importance for four of the eight criteria and criteria importance ranking between the minimally and extensively informed subject groups were significantly different. The difference in part-worth utility of the levels had a minor effect on the predicted utility of the available treatments. The lower number of level rank reversals in the extensively informed subjects indicates a better understanding of outcome desirability and thus a better understanding of the decision task. The effect of more extensive information on predicted treatment preference was minimal. While interpreting the results of a discrete choice experiment, the effect of prior knowledge on the decision problem has to be taken into account. Although information seems to increase the understanding of the decision task, outcomes valuation can also be directed by information and more extensive information increases the cognitive burden which is placed on the subjects. Future research should focus on the exact nature and size of the effects and the results of this study should be clinically validated.


Prognostic effect of incongruous lymph node status in early-stage non-small cell lung cancer.
Tumor recurrence is an important issue for patients with stage I non-small cell lung cancer (NSCLC) and adjuvant therapy is considered of no benefit to a tumor less than 4 cm. The purpose of this study was to evaluate the impact of positron emission tomography/computed tomography (PET/CT) on tumor recurrence in patients with a completely resected pN0 NSCLC less than 4 cm. Between January 2011 and December 2016, 211 consecutive patients with diagnoses of stage I NSCLC less than 4 cm after complete resection were included. The maximum of standard uptake value (SUVmax) of primary tumor and the presence of positive lymph nodes on PET/CT scans were documented. Disease-free survival was evaluated by the Kaplan-Meier method and recurrence risk factors were identified by univariable and multivariable analyses. Patients with positive lymph nodes on PET/CT had a lower 5-year disease-free survival (37.6% vs 72.7%, p < 0.001). Multivariable analysis demonstrated that the tumor SUVmax >2.93, the presence of positive lymph nodes on PET/CT, and poor differentiation were significant factors for tumor recurrence. Patients with the tumor SUVmax >2.93 and positive lymph nodes on PET/CT simultaneously had 5.33-fold increase in the risk of recurrence (p < 0.001). The presence of positive lymph nodes on PET/CT scans can be a good indicator in predicting patients with high risk of developing recurrence in pN0 NSCLC less than 4 cm. This result helps identify patients likely to benefit from adjuvant therapy.