Syntheses and kinetic evaluation of racemic and optically active 2-benzyl-2-methyl-3,4-epoxybutanoic acids as irreversible inactivators for carboxypeptidase A.
Racemic and optically active 2-benzyl-2-methyl-3,4-epoxybutanoic acids were synthesized and evaluated as inactivators for carboxypeptidase A, a representative zinc-containing proteolytic enzyme. Only the threo-form of the inactivator is effective and its potency in terms of k(inact)/K(I) value is lower by 42-fold compared with 2-benzyl-3,4-epoxybutanoic acid, indicating that the alpha-methyl group affects adversely in the inactivation contrary to the expectation that it would enhance the inactivation activity of the inhibitor through additional interactions of the methyl group with a small cavity (alpha-methyl hole) present next to the S1' hydrophobic pocket. Of the enantiomeric pair, the inactivator having the (2S,3R)-configuration is more potent than its enantiomer by 44-fold. The observed kinetic results may be rationalized on the basis that the methyl group in the inactivator having the (2R,3S)-configuration experiences the van der Waals repulsive interactions with the bottom of the active site crevice in binding to CPA, casting a doubt on the presence of the so-called alpha-methyl hole at the active site of carboxypeptidase A.


Lifestyle and Environmental Factors Affecting Bone Mass in Japanese Female Adolescents.
A higher peak bone mass (PBM) in adolescence lowers the risk of osteoporosis later in life. This study examined the factors affecting bone mass in female adolescents in relation to lifestyle and environmental factors to promote bone mass development before reaching PBM. The subjects were female students aged 15-16 years and their mothers at a public high school in Osaka, Japan. Bone mass was measured using quantitative ultrasound parameters. The body composition was measured using a multi-frequency segmental body composition analyzer. Nutrient intake, exercise habits, and maternal factors as environmental factors were examined using a questionnaire. Logistic regression analyses revealed that the adolescents' lean mass was significantly related to the BUA (p < .05). The adjusted odds ratio was 1.29 (95% confidence interval [CI]: 1.07-1.54). In contrast, the adolescents' exercise habit was significantly related to the SOS (p < .05). The SOS was significantly higher in the adolescents who exercised >4 times a week than in those who exercised <2-3 times a week. The adjusted odds ratio was 2.83 (95% CI: 1.06-7.56). The adolescents' nutrient intake and maternal factors were not significant factors affecting the adolescents' bone mass. The present study suggests that increasing lean mass and exercising more than four times a week were important for increasing bone mass in female adolescents. Nurses should intervene to help female adolescents acquire healthy lifestyle skills and maintain proper body composition and exercise habits to promote bone mass development before reaching PBM.


Anomalous Subarcuate Canal and Artery: A Rare Anatomical Variation.
An aberrant or anomalous subarcuate artery and its canal is an extremely rare and clinically significant finding. If accidentally nicked or injured, it can cause inadvertent hemorrhage and obscure the surgical field. We present a case of 21 year old made with Chronic Otitis Media of the right ear who was incidentally diagnosed with a dilated subarcuate canal and an aberrant subarcuate artery atypically associated with lateral semicircular canal and facial nerve. Prior knowledge of this symptomatically dormant variation is important, particularly in retrofacial tympanomastoidectomy and cerebello-pontine angle tumor surgeries. Pre-operative temporal bone scans are advisable in such cases.


Therapeutic and diagnostic implication of inadequate circle of willis in a patient with acute spontaneous bilateral internal carotid artery dissection: case report and review of the literature.
Emphasizing the therapeutic and diagnostic implications of concomitant inadequate collaterals from the circle of Willis in a rare case of spontaneous acute bilateral internal carotid artery dissection (BICAD) following 5 days of isolated rigorous cough (pertussis like). A 45-year-old male has been referred to our department with rapid neurological deterioration consisting of dysarthria and severe left hemiparesis following 5 days of isolated rigorous cough. CTA demonstrated BICAD, a tiny anterior communicating artery and no bilateral posterior communicating artery. The patient had no personal or familial risk factors. Infectious, traumatic, vascular and connective tissue diseases were ruled out. Neurological deterioration persisted despite immediate provision of continuous 'full-heparinization' with concomitant rigorous control of blood pressure. Endovascular treatment consisting of bilateral stenting was undertaken. Ten days later, the patient was discharged with mild hemiparesis and resuming normal activity after 3 months. BICAD with concomitant inadequate collaterals from the circle of Willis may predispose to hypoperfusion which might not respond to the usual conservative treatment prompting for flow reestablishment. Moreover, isolated rigorous cough can cause acute spontaneous BICAD even among patients without any risk factors.


Effects of droperidol on the biosynthesis and release of endogenous opioid peptides in guinea-pig ileum.
Acute administration of droperidol 2 or 5 mg kg-1 induced an increase in the inhibitory response obtained by stimulation at 10 Hz of the myenteric plexus longitudinal muscle preparation of the guinea-pig ileum. The increase in the response induced by droperidol was markedly reduced by naloxone which suggests that it is mediated by endogenous opioid release. Cycloheximide treatment significantly reduced the increase of the inhibitory response induced by droperidol, indicating that the biosynthesis and the release of endogenous opioid are increased by droperidol.


MiR-26a Mediates Ultraviolet B-Induced Apoptosis by Targeting Histone Methyltransferase EZH2 Depending on Myc Expression.
Ultraviolet B (UVB) damage is the most essential etiological factor in skin carcinogenesis, and apoptosis leads to the efficient elimination of UVB-damaged cells. However, the mechanisms underlying resistance to UVB-induced apoptosis remain unclear. HaCaT and A431 cells were used in the present study. Quantitative real-time PCR, single cell PCR, and western blotting were used to examine cancer-related gene expression at the mRNA and protein levels. We report that miR-26a, which is upregulated upon UVB irradiation, promotes UVB-induced apoptosis in HaCaT cells by targeting the histone methyltransferase EZH2. Moreover, the UVB/miR-26a/EZH2 regulatory axis largely depends on the MYC expression level. Interestingly, treatment with EZH2 inhibitors significantly enhanced UVB-induced apoptosis. miR-26a/EZH2 might be potential targets for skin cancer prevention and therapy.


Magnetic resonance imaging of constant total heart volume and center of mass in patients with functional single ventricle before and after staged Fontan procedure.
It has been previously demonstrated that total heart volume (contents of pericardium) throughout the cardiac cycle varies by < 5% and location of center of mass by < 3 mm. The hypothesis has thus developed that for maximal efficiency, the heart should expend minimal energy in displacing extracardiac structures by maintaining a constant intracycle total heart volume and center of mass. This is achieved in the normal heart mainly by a piston-like movement of the atrioventricular valve plane toward the ventricular apex. As this has never been studied in the single ventricle heart or at various stages of Fontan reconstruction, it is conceivable that these patients may not exhibit the constancy of total heart volume and location of center of mass, which may lead to a poor outcome in some. The total heart volume and center of mass relationship was therefore evaluated in 25 children (0.4 to 237 months) with functional single ventricles at all stages of Fontan reconstruction using multiphase, multislice spin-echo or cine-magnetic resonance imaging. No significant difference was seen in variation between total heart volume and maximal volume between patients before bilateral cavopulmonary anastomosis (hemiFontan) (5.1 +/- 2.9%), after hemiFontan (3.6 +/- 1.6%) and after Fontan (8.2 +/- 7.7%); however, in 4 of 10, 1 of 8 and 5 of 7 patients, respectively, the total heart volume varied by < 5%. Across surgical subgroups, significant differences were found in the center of mass displacement (total, anteroposterior and superoinferior planes) but not in directionality of displacement.(ABSTRACT TRUNCATED AT 250 WORDS)


Data set showing the development of a hyperspectral imaging technique using LA-ICP-MS to determine the spatial distribution of nutrients in soil cores.
This data in brief article represents the data set associated with a research article published in Geoderma [1]. The data set represents figures showing the spatial distribution of selected macro and micronutrients, and their quantification in different crop or nutrient management systems practiced in the boreal ecosystem. Spatial distribution of nutrients was measured by laser ablation inductively coupled plasma mass spectrometry (LA‒ICP‒MS), using the new techniques we developed to visualize nutrient distribution in intact soil cores representative of the root rhizosphere. This data article supports the findings published in the main article [1]. This work also demonstrates that LA-ICP-MS is a valuable technique to image the spatial distribution of macro and micronutrients in intact soil cores as affected by different crop management practices.


Ventricular Tachycardia Precipitated by Short-long-short Sequence in a Patient with Implantable-cardioverter Defibrillator.
Abrupt changes in heart rate, particularly short-long-short sequences in the ventricular cycle length (CL), might precede initiation of ventricular tachycardia/fibrillation (VT/VF). These changes may be facilitated or caused by pacing activity in patients with pacemakers or implantable-cardioverter defibrillators (ICDs). We describe a patient with two episodes of acquired VT precipitated by short-long-short sequences and diagnosed from the ICD recordings. In such cases, the knowledge of the device parameters is extremely important for a correct diagnosis and management.


Enterovirus D68 Subclade B3 in Children with Acute Flaccid Paralysis in West Africa, 2016.
We tested for enterovirus D68 in fecal samples collected during June-September 2016 from 567 patients with acute flaccid paralysis in 7 West Africa nations. Children <5 years old comprised 64.3% of enterovirus D68 positive patients. Our findings emphasize the need for active surveillance for acute flaccid myelitis.


PolyMetformin combines carrier and anticancer activities for in vivo siRNA delivery.
Metformin, a widely implemented anti-diabetic drug, exhibits potent anticancer efficacies. Herein a polymeric construction of Metformin, PolyMetformin (PolyMet) is successfully synthesized through conjugation of linear polyethylenimine (PEI) with dicyandiamide. The delocalization of cationic charges in the biguanide groups of PolyMet reduces the toxicity of PEI both in vitro and in vivo. Furthermore, the polycationic properties of PolyMet permits capture of siRNA into a core-membrane structured lipid-polycation-hyaluronic acid (LPH) nanoparticle for systemic gene delivery. Advances herein permit LPH-PolyMet nanoparticles to facilitate VEGF siRNA delivery for VEGF knockdown in a human lung cancer xenograft, leading to enhanced tumour suppressive efficacy. Even in the absence of RNAi, LPH-PolyMet nanoparticles act similarly to Metformin and induce antitumour efficacy through activation of the AMPK and inhibition of the mTOR. In essence, PolyMet successfully combines the intrinsic anticancer efficacy of Metformin with the capacity to carry siRNA to enhance the therapeutic activity of an anticancer gene therapy.


Biological microanalysis by secondary ion mass spectrometry: status and prospects.
Secondary ion mass spectrometric (SIMS) analysis of biological problems is an evolving technique. Lateral resolution of currently available commercial instrumentation estimated from actual samples is 0.5 micron, and subcellular organelles can be distinguished. The interrelationship of lateral resolution, elemental concentration and ionizability are, however, important in controlling the actual lateral resolution achievable. Although depth resolutions of 5 nm have been measured in other systems, no test of depth resolution in biological systems has been done, and this parameter is also concentration and ionization dependent. The development of liquid metal ion sources in combination with scanning ion microprobes has a potential lateral resolution of as little as 20 nm, but initial studies with this instrumentation show that tissue preservation at the submicron level becomes an important issue. The current development of a cold-transfer stage for SIMS instruments may obviate the problem of submicron localization of diffusible elements, and initial studies indicate that much more needs to be understood about the ionization process in hydrated samples. Quantitation of diffusible elements using external standards has been achieved over a 30 micron diameter analyzed area. Strategies for analysis of areas limited to 1 micron or less has been suggested using image processing techniques, which take advantage of the lateral resolution inherent in the ion optical system. Matrix effects in biological tissues have been reported and constitute a serious problem for analysis of biologicals which must be addressed for each question. However, development of laser ionization of sputtered particles may both increase the sensitivity of analysis and decrease the importance of ionizability of elements. Chemical analysis of organic molecules is another use of SIMS, but, at present, at the cost of losing localized information. SIMS analysis of biological samples is being systematically evaluated and requires increased accessibility of this instrumentation to the end-user for full development of its role in physiological problems.


Mechanical Properties of Different Nanopatterned TiO2 Substrates and Their Effect on Hydrothermally Synthesized Bioactive Hydroxyapatite Coatings.
Nanotechnology is a very attractive tool for tailoring the surface of an orthopedic implant to optimize its interaction with the biological environment. Nanostructured interfaces are promising, especially for orthopedic applications. They can not only improve osseointegration between the implant and the living bone but also may be used as drug delivery platforms. The nanoporous structure can be used as a drug carrier to the surrounding tissue, with the intention to accelerate tissue-implant integration as well as to reduce and treat bacterial infections occurring after implantation. Titanium oxide nanotubes are promising for such applications; however, their brittle nature could be a significantly limiting factor. In this work, we modified the topography of commercially used titanium foil by the anodization process and hydrothermal treatment. As a result, we obtained a crystalline nanoporous u-shaped structure (US) of anodized titanium oxide with improved resistance to scratch compared to TiO2 nanotubes. The US titanium substrate was successfully modified with hydroxyapatite coating and investigated for bioactivity. Results showed high bioactivity in simulated body fluid (SBF) after two weeks of incubation.


How well do physical activity questions perform? A European cognitive testing study.
Only few studies have focused on the cognitive processes of the respondents that are involved when answering physical activity questionnaires (PAQs). This study aimed at examining whether two PAQs work as intended with different segments of the survey population in different cultural settings in Europe. The International Physical Activity Questionnaire - Short Form (IPAQ-SF) and the US National Health Interview Survey - Adult Core Physical Activity Questionnaire (NHIS-PAQ) were tested in Belgium, Estonia, Germany and the UK using a standardized cognitive interviewing procedure. IPAQ-SF measures total vigorous physical activity (PA), moderate PA, walking and sitting. NHIS-PAQ measures leisure-time vigorous PA, light and moderate PA and muscle-strengthening PA. In total 62 persons completed cognitive interviews, at least 15 interviews were conducted in each country. Both PAQs performed as intended with young and high-skilled persons and those having a regular exercise schedule. For the others, however, the testing revealed that problems occurred with both PAQs relating to understanding the concepts of '(light and) moderate' and 'vigorous' PA, classifying activities into the provided answer options of different PA intensities, recalling instances of 'normal' activities such as walking and sitting, and calculating the total duration of more than one activity or instance of an activity. The revealed problems with the questionnaires were quite similar in different countries; profound cultural differences were not observed. Both questionnaires were difficult to answer for many respondents and rather user-unfriendly. They are designed to measure an exactness of PA quantity (frequency and duration) and intensity which would be desirable to obtain from a scientific point of view; however, respondents can hardly provide this information for cognitive reasons. Studies investigating the respondents' perspective are useful for improving physical activity information based on self-reports.


Actual situation of lipoprotein apheresis in Saxony in 2013.
Lipoprotein apheresis (LA) is an officially accepted therapeutic approach in Germany. Reliable population-based data on the patients are scarce. It is of special interest to learn what are the main indications for this extracorporeal treatment and how many new patients started over the last years. This paper is a summary of the situation of the treatment of high-risk patients via LA in the federal state of Saxony, Germany. The documentation of all patients who agreed to be included into this study have been evaluated. Patients were treated at the University Hospital Dresden (UHD) and in private practices of nephrologists. This evaluation aimed at the characterization of patients treated with LA in Saxony with respect to age, gender, lipid pattern, to the number of new patients per year and the development of the ratio of patients to the Saxon population between 2010 and 2013. The obtained data were compared with the official statistics published by the National Association of Statutory Health Insurance Physicians for whole Germany. In 2013, 181 patients, primarily males, were treated in 15 LA centers by 32 doctors. Still, the number of apheresis doctors per 1 million inhabitants is under the average in Germany (Saxony: 7.7/1 million inhabitants, average: 12/1 million inhabitants). The usage of LA is 45 per 1 million inhabitants in Saxony; in comparison to 2010, this is an increase of 16 per 1 million inhabitants. The number of new patients in 2013 with an isolated elevation of Lipoprotein(a) (Lp(a)) is twice as high than it was in 2011. The mean duration of all patients being treated with LA, most on a weekly basis, was 5.75 years (UHD: 6.2 years, range: 1 month to 23.1 years; other centers: 5.3 years, range: 1 month to 19.2 years). About 19.3% of all patients suffered from elevated triglyceride (TG) levels (>5 mmol/L). Non-high- density lipoprotein cholesterol (Non-HDL-C) was calculated, which is also acutely reduced by LA sessions. The following data were reported for those patients who are treated outside the UHD: risk factors such as hypertension and familial predisposition could be seen in almost every patient, and several others such as type 2 diabetes mellitus, genetic defects and obesity were also present. Almost all patients had suffered from cardiovascular events (CVE) occurring before the start of apheresis treatment. LA therapy led to a reduction in occurrence of CVE during LA therapy. In particular, patients with an isolated increased Lp(a) had the highest reduction when comparing CVE before and during apheresis therapy. In the official statistics published by the National Association of Statutory Health Insurance Physicians the number of LA patients with homozygous familial hypercholesterolemia (HoFH) is clearly too high. Moreover, these statistics do not include patients who are treated at hospitals like the UHD. All in all it can be shown that the extracorporeal therapy is performed effectively in Saxony, and that more centers than 2010 (additional 5) were conducting this therapy when lipid-lowering medication was not sufficiently effective. It is certain that the number of patients requiring LA will increase in the future.


Statin therapy and contrast-induced nephropathy after primary angioplasty.
A recent study suggested that statin therapy may prevent contrast-induced nephropathy (CIN) following primary angioplasty. Our aim was to assess the effect of statins in this setting in a larger population. We evaluated 589 consecutive patients with acute myocardial infarction who underwent primary angioplasty at our institution. Contrast-induced nephropathy was defined as an increase in serum creatinine by > or =0.5 mg/dL within 72 h following the procedure. Overall, 69 patients (11.9%) developed CIN. The incidence of CIN in the group on statins was 15.9%, as compared with 10.8% in the group not taking statins (p=0.2). Thus, we did not observe a protective effect of statin therapy on CIN development after primary angioplasty.


Mesenteric defect with internal herniation in the pediatric emergency department: an unusual presentation of acute abdomen.
Internal herniation is a rare cause of intestinal obstruction, especially in the emergency department. We report a child with acute abdomen resulting from transmesenteric internal herniation of the small bowel. Radiographic findings revealed gaseous distension of the bowel loops in the upper abdominal area with a paucity of gas in the lower abdomen. Operative finding showed gangrenous small bowel due to mesenteric defect with an internal herniation. The gangrenous bowel was resected and the patient was discharged with an uneventful outcome. We emphasize that early recognition of internal herniation warrants further evaluation and appropriate management.


Pain management for the pregnant, lactating, and neonatal to pediatric cat and dog.
Little information on the approach to analgesia in pregnant, nursing, or extremely young animals is available in the veterinary literature. Various analgesics and analgesic modalities are discussed, with emphasis placed on preference and caution for each group. Management of pain is extremely important in all animals but especially in the extremely young, in which a permanent hyperalgesic response to pain may exist with inadequate therapy. Inappropriate analgesic selection in pregnant and nursing mothers may result in congenital abnormalities of the fetus or neonate. Inadequate analgesia in nursing mothers may cause aggressive behavior toward the young. Review of the human and veterinary literature on the various analgesics available for use in this group of patients is discussed.


Protection against inflammatory neurodegeneration and glial cell death by 7beta-hydroxy epiandrosterone, a novel neurosteroid.
It has been demonstrated that neuroprotective effects of dehydroepiandrosterone (DHEA) may be mediated by its 7alpha- and 7beta-hydroxy derivatives. Epiandrosterone is also converted to 7beta-hydroxy epiandrosterone (7beta-OH EPIA) in numerous tissues. The aim of the present study was to establish whether treatment with 7beta-hydroxy epiandrosterone has a neuroprotective effect in animal models of Alzheimer's disease (AD) lesions. Intra-amygdaloid administration of amyloid beta [Abeta(25-35)] increased the number of tau-positive cells in the ipsilateral hippocampus. Intracerebroventricular administration of ethylcholine aziridinium (AF64A) caused cholinergic damage in the septum, and glial lesions in the lateral septal nucleus and in the lateral zones of the hippocampus. These effects were almost completely prevented when animals were treated subcutaneously (b.i.d.) for 10 days with 0.1 mg/kg 7beta-hydroxy epiandrosterone. These findings indicate that 7beta-hydroxy epiandrosterone has powerful cytoprotective effects suggesting that (a) this neurosteroid may have therapeutic potential in various neurodegenerative conditions such as Alzheimer's disease, and (b) 7beta-hydroxy steroids may constitute a novel class of endogenous neuroprotective agents.


Overexpression of acdS gene encoding 1-aminocyclopropane-1-carboxylic acid deaminase enzyme in petunia negatively affects seed germination.
Overexpression of acdS in petunia negatively affects seed germination by suppression of ethylene biosynthesis and signaling genes and induction of abscisic acid biosynthesis genes in the seeds. The acdS gene, which encodes 1-aminocyclopropane-1-carboxylic acid (ACC) deaminase, has been overexpressed in horticultural crops to improve their tolerance to abiotic stress. However, the role of acdS in the germination of crop seeds has not been investigated, despite its suppression of ethylene production. In this study, acdS overexpression significantly reduced seed weight and germination rate in transgenic petunia cv. Merage Rose (T5, T7, and T12) relative to wild type via the suppression of ethylene biosynthesis and signaling genes and induction of abscisic acid (ABA) biosynthesis genes. The germination rate of T7 was significantly lower than those of T5 and T12, which was linked to higher expression of acdS in the former than the latter. The addition of exogenous ACC and gibberellic acid (GA3) to the germination medium improved the germination rate of T5 seeds and GA3 promoted the germination rate of T12 seeds. However, neither ACC nor GA3 promoted the germination rate of T7 seeds. The improved germination rates in T5 and T12 were associated with the transcriptional regulation of ethylene biosynthesis genes, particularly that of the ACO1 gene, signaling genes, and ABA biosynthesis genes. In this study, we discovered a negative role of acdS in seed germination in petunia. Thus, we highlight the need to consider the negative effect of acdS on seed germination when overexpressing the gene in horticultural crops to improve tolerance to abiotic stress.


Sural nerve immunoreactivity for nerve growth factor receptor in a case of localized hypertrophic neuropathy.
Immunoreactivity for nerve growth factor receptor (NGFR) was examined using a monoclonal antibody against human NGFR in the sural nerve of a 24-year-old woman, affected by localized hypertrophic neuropathy (LHN). NGFR expression was correlated with electron microscopy and with immunoreactivity for S-100 protein, laminin, HLA-DR, HNK-1, P0 glycoprotein and neurofilament peptides. Our results indicate that in LHN most of whorl-forming cells are NGFR positive and S-100 protein or HLA-DR negative. These data along with the ultrastructural features suggest their origin from perineurium.


A phenylbutazone dose-finding study in rheumatoid arthritis.
Different doses of phenylbutazone have been compared in a double blind study on 32 patients with rheumatoid arthritis in order to determine the minimum effective dose. Of 8 different dose levels studied (90 mg, 150 mg, 180 mg, 240 mg, 270 mg, 300 mg, 360 mg and 450 mg/day) the most efficacious was found to be 300 mg/day. Doses below this did not produce full benefit; no further improvement occurs with higher doses. Although 7/32 patients developed adverse reactions there was no relationship between these and the plasma levels of either phenylbutazone or oxyphenbutazone. An attempt was made to distinguish 'responders' from 'non-responders'. We found no relationship between response and plasma levels of phenylbutazone or oxyphenbutazone.


The prognosis of prechemotherapy blastemal predominant histology subtype in Wilms tumor: A retrospective study in China.
This study aimed to retrospectively analyze survival outcomes for Chinese patients with prechemotherapy blastemal predominant histology type Wilms tumors (WTs). We collected and analyzed clinical data concerning patients aged <15 years with favorable histology (FH) WTs treated at the Sun Yat-Sen University Cancer Center from December 2005 to May 2016, based on the Children's Oncology Group protocol. Pathological specimens were collected through biopsy or surgical resection before initiation of chemotherapy. We analyzed survival outcomes involving different prechemotherapy histology subtypes. We enrolled 97 patients with FH WTs (median follow-up, 71.5 months; range, 22.2-170.7). The total recurrence rate was 17.5%, and the subtype recurrence rates were as follows: blastemal predominant (45.5%), mixed (7.5%), epithelial (14.3%), and mesenchymal (9.5%) (P = .010). Five-year event-free survival (EFS) and overall survival (OS) rates were 84.9% and 81.4%, respectively. Respective 5-year EFS and OS rates for subtypes were as follows: blastemal predominant (54.5% and 68.2%), mixed (90.0% and 88.9%), epithelial (85.7% and 85.1%), and mesenchymal (90.5% and 94.7%). Multivariate survival analyses showed that the blastemal predominant subtype was an independent prognostic factor of EFS (P = .001) and OS (P = .017). Our findings showed that prechemotherapy blastemal predominant WTs had higher recurrence and lower EFS and OS rates. Our findings suggested that, albeit with some deficiencies, blastemal predominant histology WT-diagnosed prechemotherapy may have prognostic relevance. Further research into other potential confounding variables are required to determine whether such patients warrant altered risk-stratified therapy.


Racial and ethnic differences in the relationship between financial worry and white matter hyperintensities in Latinx, non-Latinx Black, and non-Latinx White older adults.
Socioeconomic status (SES) is associated with white matter hyperintensities (WMHs) and contributes to racial and ethnic health disparities. However, traditional measures of SES may not accurately represent individual financial circumstances among non-Latinx Black and Latinx older adults due to longstanding structural inequities. This study examined associations between multiple SES indicators (education, income, subjective financial worry) and WMHs across non-Latinx Black, Latinx, and non-Latinx White older adults in the Washington Heights-Inwood Columbia Aging Project (N = 662). Latinx participants reported the lowest SES and greatest financial worry, while Black participants evidenced the most WMHs. Greater financial worry was associated with higher WMHs volume above and beyond education and income, which were not associated with WMHs. However, this association was only evident among Latinx older adults. These results provide evidence for the minority poverty hypothesis and highlight the need for systemic socioeconomic interventions to alleviate brain health disparities in older adulthood.


NFkappaB and AP-1 differentially contribute to the induction of Mn-SOD and eNOS during the development of oxidant tolerance.
Exposure of cardiac myocytes to anoxia/reoxygenation (A/R) increases myocyte oxidant stress and converts the myocytes to a proinflammatory phenotype. These oxidant-induced effects are prevented by pretreatment of the myocytes with an oxidant stress (A/R or H2O2) 24 h earlier (oxidant tolerance). Although NF-kappaB and AP-1 (nuclear signaling) and Mn-SOD and eNOS (effector enzymes) have been implicated in the development oxidant tolerance, the precise relationship between the nuclear transcription factors and the effector enzymes in the development of oxidant tolerance has not been defined. Herein, we show that an initial A/R challenge results in nuclear accumulation of both NF-kappaB and AP-1 (EMSA). In addition, blockade of nuclear translocation of NF-kappaB (SN50) or AP-1 (decoy oligonucleotide) prevents the development of oxidant tolerance, i.e., the second A/R challenge produces the same quantitative effects as the initial A/R challenge. In this model, nuclear translocation of both NF-kappaB and AP-1 is required for induction of Mn-SOD, while nuclear translocation of AP-1, but not NF-kappaB, is a prerequisite for induction of eNOS. Collectively, our findings indicate that NF-kappaB and AP-1 work in concert to ensure the induction eNOS and Mn-SOD, which in turn are important for the development of oxidant tolerance.


Circ_HECW2 functions as a miR-30e-5p sponge to regulate LPS-induced endothelial-mesenchymal transition by mediating NEGR1 expression.
Endothelial-mesenchymal transition (EndoMT) plays a critical role in the dysfunction of the blood-brain barrier (BBB). Circular RNAs (circRNAs) function as crucial regulatory factors in EndoMT. Nevertheless, the underlying mechanisms of circRNA HECW2 (circ_HECW2, hsa_circ_0057583) in lipopolysaccharide (LPS)-induced EndoMT remain largely unclear. The levels of circ_HECW2, miR-30e-5p and neuronal growth regulator 1 (NEGR1) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) or western blot. Ribonuclease (RNase) R and Actinomycin D assays were performed to validate the stability of circ_HECW2. Cell colony formation, proliferation and apoptosis were tested by a standard colony formation assay, the 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and flow cytometry, respectively. Targeted relationships among circ_HECW2, miR-30e-5p and NEGR1 were verified by a dual-luciferase reporter assay. Our data indicated that LPS increased circ_HECW2 expression and reduced miR-30e-5p expression in human brain microvascular endothelial cells (HBMECs). Circ_HECW2 silencing promoted cell proliferation and suppressed cell apoptosis and EndoMT in LPS-treated HBMECs. Mechanistically, circ_HECW2 directly interacted with miR-30e-5p by binding to miR-30e-5p. MiR-30e-5p was a functional mediator of circ_HECW2 in regulating LPS-induced cell EndoMT. Furthermore, Circ_HECW2 regulated NEGR1 expression through functioning as a miR-30e-5p sponge. Moreover, miR-30e-5p overexpression repressed the EndoMT of LPS-treated HBMECs by targeting NEGR1. Collectively, our current study demonstrated that circ_HECW2 silencing suppressed LPS-triggered HBMEC EndoMT at least in part through the regulation of the miR-30e-5p/NEGR1 axis, illuminating a promising strategy for EndoMT inhibition.


Palladium-catalyzed total synthesis of euchrestifoline using a one-pot Wacker oxidation and double aromatic C-H bond activation.
We describe the total synthesis of euchrestifoline featuring an unprecedented one-pot Wacker oxidation and double aromatic C-H bond activation.


[Kabuki syndrome: Update and review].
Kabuki syndrome (OMIM: 147920) is a rare condition, mainly associating intellectual deficiency, a polymalformative syndrome, and specific morphological changes in the face. It nevertheless has a strong clinical and biological heterogeneity with rarer but very different symptoms (endocrinological anomalies, autoimmune disorders, obesity, etc.). Clinical diagnosis is difficult because it is based on a spectrum of clinical, radiological, and biological factors. Complications are numerous, sometimes interpenetrating, and early diagnosis of the disease is essential for optimal management. The development of genetic testing is therefore essential for the diagnosis of this disease. Recently, exome sequencing has helped identify two genes responsible for the disease: KMT2D (lysine (K)-specific methyltransferase 2D, better known as MLL2 - mixed lineage leukemia), and KDM6A (lysine-specific demethylase 6A). Functional studies of these genes should help clarify their role in the pathogenesis of the disease, in particular to test the hypothesis of epigenetic changes during embryogenesis and development. Finally, understanding the interactions between KMT2D and its target genes could unravel other candidate genes for hitherto unexplained Kabuki syndrome cases.


Who is eligible for randomized trials? A comparison between the exclusion criteria defined by the ISCHEMIA trial and 3102 real-world patients with stable coronary artery disease undergoing stent implantation in a single cardiology center.
Randomized controlled trials are the gold standard for evaluating therapy; however, controversy exists regarding the applicability of such results to daily practice, as patients are often pre-selected and may not reflect real-world clinical settings. We studied the eligibility criteria for 3102 "real-life" patients with stable coronary artery disease (SCAD) according to the ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trial exclusion criteria. The aim of our analysis was to estimate the percentage of real-life patients who would have met the exclusion criteria for the ISCHEMIA trial. We analyzed 3102 patients with SCAD referred to the Silesian Center for Heart Disease who underwent both coronary angiography and stent implantation between January 2006 and December 2011. The patients were divided into two groups. Group A was composed of patients with SCAD who would have been excluded from the ongoing ISCHEMIA trial, whereas group B represented the remaining patients. A total of 1900 (61.3%) patients met at least one of the exclusion criteria. The most frequent exclusion criterion noted was revascularization within the previous 12 months (938 patients; 49.4%), followed by unacceptable level of angina symptoms (532 patients; 28 %), low ejection fraction (467 patients; 24.6%), and acute coronary syndrome within the previous 2 months (456 patients; 24%). Patients from our cohort who would have been excluded from the ISCHEMIA trial were older, had more comorbidities, and experienced worse long-term outcomes. The ISCHEMIA trial exclusion criteria ruled out the majority of the patients with SCAD undergoing percutaneous coronary intervention in "real life". Our cohort of patients who would have been excluded from the ISCHEMIA trial had more comorbidities and experienced significantly worse long-term outcomes than patients who did not meet the ISCHEMIA trial exclusion criteria. ClinicalTrials.gov NCT01471522.


[Composite resins and enamel-dentin adhesives. A new fixation technic].
The Authors discuss basic concepts for bonding agents and composite resins as luting cement in fixed prosthodontics. Five years of clinical experience show the operative advantages and the reliability of such a new procedure.


The role of nesfatin and selected molecular factors in various types of endometrial cancer.
Endometrial cancers (ECs) are the most common gynaecological cancers in well developed countries. Diabetes and metabolic syndrome are among the biggest risk factors. Nesfatin-1, the adipokine derivative of NUCB2 (nucleobindin derivative 2) is linked to the clinical course of EC. Molecular factors, including mutations in MLH1 and MHS2 genes, c-MET and ARID1A are also related to prognosis in endometrial cancer. Using sections of paraffin-embedded preparations and immunohistochemistry, the expression of NESF1, MLH1, MSH2,c-MET and ARID1A were examined. In this study on protein expression, EC tissues manifested (although insignificantly) an elevated expression of NESF-1 in type II EC. In type I EC, NESF-1 expression was significantly higher in G1 in comparison to G2 and G3 together. A significantly lower expression of MLH1 was demonstrated in type I EC. The most pronounced expression involved c-MET in all EC I and EC II tissues (in over 80% of cases). A tendency was detected for a high expression of NESF-1 in patients with type II EC, who also exhibited a high expression of MSH2.


Treatment of Lung Cancer Patients With Actionable Mutations in the Intensive Care Unit.
Patients with advanced-stage non-small-cell lung cancer (NSCLC) have high mortality rates in the intensive care unit (ICU). Although the benefit of chemotherapy for hematologic malignancies in the ICU has previously been explored, few data exist regarding the use of targeted therapy for NSCLC in such settings. The primary objective of the present study was to report our experience with the use of targeted therapy in patients with NSCLC in the ICU. We performed a single-institution, retrospective medical record review. The eligibility criteria included patients with NSCLC with targetable mutations who had received tyrosine kinase inhibitors (TKIs) in the ICU. Cases were identified by queries of our institution's information warehouse database and pharmacy dispensary records from 2010 to 2015. All 9 patients who had received TKIs in the ICU had acute respiratory failure. Three patients were successfully extubated after initiating TKI therapy, although 1 required later tracheostomy. TKI therapy stabilized another patient's refractory disseminated intravascular coagulation. The remaining 5 patients showed no measurable clinical improvement and were transitioned to comfort care. The overall ICU mortality rate was 56%. Patients with metastatic NSCLC requiring mechanical ventilation have high mortality rates. Cytotoxic chemotherapy is generally contraindicated for poor performance status patients. However, targeted TKI therapy should be considered, given its proven efficacy and few systemic side effects. We recommend the empiric use of targeted therapy for NSCLC patients with suspected and/or known actionable mutations presenting with multifactorial respiratory failure to the ICU, with aggressive determination of the mutation status if not known.


HIV-1 Rev-RRE functional activity in primary isolates is highly dependent on minimal context-dependent changes in Rev.
During HIV infection, intron-containing viral mRNAs are exported from the cell nucleus to the cytoplasm to complete the replication cycle. Cellular restrictions on the export of incompletely spliced transcripts are overcome by a viral protein, Rev, and an RNA structure found in all unspliced and incompletely spliced viral mRNAs, the Rev Response Element (RRE). Primary HIV isolates display substantial variation in the sequence and functional activity of Rev proteins. We analyzed Rev from two primary isolates with disparate activity that resulted in differences in in vitro fitness of replication-competent viral constructs. The results showed that amino acid differences within the oligomerization domain, but not the arginine-rich motif or the nuclear export signal, determined the level of Rev activity. Two specific amino acid substitutions were sufficient to alter the low-activity Rev to a high-activity phenotype. Other mutations in Rev sequences had unpredictable effects on activity that differed between the two Rev backbones. The sensitivity of Rev function level to small sequence changes likely permits modulation of Rev-RRE activity during HIV infection, which may play a role in pathogenesis. The functional consequences of Rev mutations differed between primary isolates, highlighting the challenge of generalizing studies of Rev conducted using laboratory HIV strains.


Clinical Comparison of Super Pulse Thulium Fiber Laser and High-Power Holmium Laser for Ureteral Stone Management.
Purpose: To evaluate the efficacy of new super pulse thulium fiber laser (SP TFL) and compare it with holmium laser for ureterolithotripsy. Patients and Methods: A total of 174 patients with solitary ureteral calculi were enrolled in 2016 to 2018. Stone sizes ranged between 0.6 and 2.4 cm. The SP TFL FiberLase U2 and 120H Ho:YAG laser with fibers diameters of 400 and 365 μm, respectively, were used. The laser settings were 1 J × 10 Hz = 10 W for both devices. All patients were randomized into two groups. The age, stone size, location, and density were comparable in both groups. The evaluated parameters were operation time, endoscopic view quality, retropulsion grade, stone-free rate, and complication rate. Results: The total operation time and lasering time were longer in the Ho:YAG group (24.7 ± 0.7 minutes vs 32.4 ± 0.7 minutes, p = 0.05), and postoperative stenting was necessary in one vs four cases, respectively. At 30 days of follow-up, no residual stones were observed in the SP TFL group (vs five cases of Ho:YAG). Conclusion: SP TFL technology was associated with excellent efficacy/safety ratio. The SP TFL may be considered as a viable alternative to Ho:YAG laser stone management.


Weekly work hours and health-related behaviours in full-time students.
This article examines associations between the number of hours of paid work and smoking, alcohol use, episodic heavy drinking and leisure-time physical activity among full-time students aged 15 to 17. Analyses are based on data from the 2003 Canadian Community Health Survey and the 1994/95 to 2002/03 National Population Health Survey. Selected characteristics and health-related behaviours of working and non-working students were compared. Logistic regression was used to examine relationships between average weekly hours at the main job and health-related behaviours, as well as maintenance of and changes in these behaviours, while controlling for possible confounders. Students who worked even a modest number of hours per week had higher odds of drinking alcohol regularly, and occasionally heavily, compared with those who had not worked. Students working any number of hours had higher odds of becoming regular drinkers within two years of their baseline interview. Longer working hours were associated with higher odds of smoking. Employed students had higher odds of being physically active in their leisure time. The influences of age, household income and urban/rural residence were taken into account.


Successful technical note-Identification of the Adamkievicz artery with 1.5 Tesla MR angiography in a 14-month-old child.
Posterior mediastinal tumors surgery may be complicated by their proximity to the artery of Adamkiewicz (AKA) and its segmental supplier, increasing the risk of ischemia of the spinal cord. We describe a case of preoperative identification of the AKA with magnetic resonance angiography (MRA) in a 14-month-old boy diagnosed with a thoracic neuroblastoma, thus allowing an accurate surgical planning in order to avoid injury to those vessels. Given the relatively high incidence of posterior mediastinal tumors in the pediatric age, MRA may establish itself as a viable alternative for this purpose, even in young children.


Pressure necrosis of the outlet septum caused by two adjacent implants.
A patient had a history of a Ross-Konno procedure, stenting of the pulmonary homograft, and an aortic valve replacement. Pressure necrosis developed in the tissues in between the stent and the prosthetic valve. This resulted in a defect between the right and left ventricular outflow tracts that required a complex operation for its correction.


Plant induced defenses that promote cannibalism reduce herbivory as effectively as highly pathogenic herbivore pathogens.
Plant induced defenses may benefit plants by increasing cannibalism among insect herbivores. However, the general efficacy of plant defenses that promote cannibalism remains unclear. Using a generalist Lepidopteran herbivore (Helicoverpa zea), we examined whether plant induced defenses in Solanum lycopersicum increased cannibalism among H. zea and whether defense-mediated cannibalism benefits both the plant and the cannibal. In a separate experiment, we also examined whether defense-mediated cannibalism has effects on H. zea herbivory that are comparable to the effects of pathogenic virus of H. zea (HzSNPV) and whether defense-mediated cannibalism modified pathogen efficacy. We found that both plant defenses and cannibalism decreased herbivory: H. zea consumed less plant material if plants were induced, if dead conspecifics were provided, or both. Cannibalism increased cannibal growth rate: cannibals effectively overcome the costs of plant defenses by eating conspecifics. Inoculating half of H. zea with virus strongly reduced caterpillar survival. Cannibalism occurred sooner among virus-inoculated groups of H. zea, and all caterpillars in virus-inoculated treatments died before the end of the 7-day experiment. Although the rise in mortality caused by HzSNPV occurred more rapidly than the rise in mortality due to defense-mediated cannibalism, overall H. zea mortality at the end of the experiment was equal among virus-inoculated and induced-defense groups. Defense-mediated cannibalism and viral inoculation equally reduced herbivory on S. lycopersicum. Our results provide evidence that defense-mediated increases in cannibalism can be as effective as other forms of classic herbivore population regulation, and that both viral pathogens and defense-induced cannibalism can have significant benefits for plants.


Integrated targeted and non-targeted analysis of water sample extracts with micro-scale UHPLC-MS.
A sensitive method is introduced to detect selected pharmaceutical residues and polar pesticides with UHPLC-MS in water samples of different origin. Active or passive water sampling was combined with a laboratory solid-phase extraction cleanup and stable isotope dilution analysis. Recovery experiments demonstrated that the internal standard correction performed well for the compensation of matrix effects. Besides, the original targeted analysis approach was expanded by non-target analysis of the samples with only one more consecutive injection run needed. The key benefits of this multi-residue analysis are:•Targeted analysis and quantification combined with non-target analysis on a micro-scale UHPLC-MS system usually employed for qualitative analysis only.•The internal standards for targeted analysis were used in non-target runs to calculate the partition coefficient log P of unknown substances employing the retention time index (RTI).•The filtering of database hits for two criteria (exact mass and partition coefficient) significantly reduced the list of suspects and at the same time rendered it possible to perform non-target analysis with lower mass accuracy (no lock-spray) in the range of 20-500 ppm.


PEANUT experiment in NQR spectroscopy for I=3/2.
The experiment with phase inversion and phase-inverted echo-amplitude detected nutation (PEANUT) was introduced in the nuclear quadrupole resonance (NQR). Formulas were obtained describing the NQR (I=3/2) experiment. Exemplary experiments are provided confirming the predicted particularities of the PEANUT spectra in NQR Cl-35. It is proposed to apply the method for the purpose of determination the asymmetry parameter of the electric field gradient (EFG) tensor in powders with the help of the analysis of PEANUT interferograms. Application of two-dimensional PEANUT experiments, in which the nutation frequencies correlate with the resonance NQR frequencies, can substantially simplify the interpretation of complex spectra.


The Parasomnias.
Parasomnias usually present in childhood and resolve spontaneously. The diagnosis of non-rapid eye movement-related parasomnias is mainly based on clinical descriptors and can be challenging. Rapid eye movement-related parasomnias may index an underlying psychiatric disorder. Even if benign, parasomnias can affect quality of life. Pediatricians and child psychiatrists should be familiarized with these sleep disorders and suggest adequate sleep hygiene, avoidance of sleep deprivation, and regular bedtimes even on weekends as the first step in management of these disorders. Clinicians should pursue the opportunity for tailoring treatments and consider referral to a sleep expert when indicated.


Associative organization of nursing: struggles for the social recognition of the profession (1943-1946).
To describe the circumstances that determine the creation of the Brazilian Association of Graduate Nurses of the Federal District Section and analyze its implications for the reorganization of the field of nursing. Qualitative, socio-historical, documentary study. The analysis generated the following category: Creation of a new group to guarantee unity: Brazilian Association of Graduate Nurses in the Federal District Section. The economic crisis resulting from the Second World War, the creation of the Paulista Association of Graduate Nurses and the increase in the number of Schools of Nursing in the country were decisive for the Brazilian Association of Graduate Nurses to reformulate its statute as to guarantee its unit. The creation of the Federal District Section consisted of one of the strategies of the Association to reorganize the field of nursing, in order to ensure the recognition of the profession by the society. Descrever as circunstâncias que determinam a criação da Associação Brasileira de Enfermeiras Diplomadas Seção do Distrito Federal e analisar as implicações dessa criação para a reorganização do campo da enfermagem. Estudo qualitativo, sócio-histórico, documental. A análise gerou a seguinte categoria: Criação de um novo grupo para garantir a unidade: Associação Brasileira de Enfermeiras Diplomadas Seção do Distrito Federal. A crise econômica, decorrente da Segunda Guerra Mundial, a criação da Associação Paulista de Enfermeiras Diplomadas e o aumento do número de escolas de enfermagem no país foram determinantes para que a Associação Brasileira de Enfermeiras Diplomadas reformulasse seu estatuto, de modo a garantir sua unidade. A criação da Seção do Distrito Federal consistiu em uma das estratégias da associação para reorganizar o campo da enfermagem, de modo a assegurar o reconhecimento da profissão pela sociedade.


Forensic nanopore sequencing of microhaplotype markers using QitanTech's QNome.
In recent years, extraordinary progress has been made in genome sequencing technologies, which has led to a decrease in cost and an increase in the diversity of sequenced genomes. Nanopore sequencing is one of the latest genome sequencing technologies. It aims to sequence longer contiguous pieces of DNA, which are essential for resolving structurally complex regions, and provides a new approach for forensic genetics to detect longer markers in real time. To date, multiple studies have been conducted to sequence forensic markers using MinION from Oxford Nanopore Technologies (ONT), and the results indicate that nanopore sequencing holds promise for forensic applications. Qitan Technology (QitanTech) recently launched its first commercial nanopore genome sequencer, QNome. It could achieve a read length of more than 150 kbp, and could generate approximately 500 Mb of data in 8 h. In this pilot study, we explored and validated this alternative nanopore sequencing device for microhaplotype (MH) profiling using a custom set of 15 MH loci. Seventy single-contributor samples were divided into 7 batches, each of which included 10 samples and control DNA 9947A and was sequenced by QNome. MH genotypes generated from QNome were compared to those from Ion Torrent sequencing (Ion S5XL system) to evaluate the accuracy and stability. Twelve samples randomly selected from the last three batches and Control DNA 9947A were also subjected to ONT MinION sequencing (with R9.4 flow cell) for parallel comparison. Based on MHtyper, a bioinformatics workflow developed for automated MH designation, all MH loci can be genotyped and reliably phased using the QNome data, with an overall accuracy of 99.83% (4 errors among 2310 genotypes). Three occurred near or in the region of homopolymer sequences, and one existed within 50 bp of the start of the sequencing reaction. In the last 15 samples (12 individual samples and 3 replicates of control DNA 9947A), two SNPs located at 4-mer homopolymers failed to obtain reliable genotypes on the MinION data. This study shows the potential of state-of-the-art nanopore sequencing methods to analyze forensic MH markers. Given the rapid pace of change, sporadic and nonrepetitive errors presented in this study are expected to be resolved by further developments of nanopore technologies and analysis tools.


Bioactive amines and phenolic compounds in cocoa beans are affected by fermentation.
Cocoa is the target of increased scientific research as it is one of the richest source of bioactive compounds. The formation of bioactive amines and their changes in cocoa beans during seven days of traditional fermentation was investigated for the first time. In addition, total phenolic compounds, anthocyanins contents and the scavenging capacity against ABTS radical were determined to monitor the fermentation process. Only two biogenic amines (tryptamine and tyramine) and two polyamines (spermidine and spermine) were detected in cocoa beans during fermentation. Fermentation was characterized by three stages: i) high levels of tryptamine, phenolics, and scavenging capacity; ii) high contents of spermine, total biogenic amines and total polyamines; and iii) the highest spermidine levels and total acidity, but the lowest total phenolic compounds and anthocyanins contents. The scavenging capacity of cocoa beans during fermentation correlated with total phenolic compounds and anthocyanins contents.


Assessing the phytotoxicity of different particle-size aged refuse using Zea mays L. bioassay.
With increasing attention paid to the recycling use of aged refuse as vegetated soil, it is important to check its possible polluting risk and probe the tolerance of plant system to its stress. For this reason, several physiological responses in Zea mays L. (maize) to the leaching samples of aged refuse in different particle-size (900-300, 300-150, 150-105, 105-90, and 90-0 microm) were investigated in the present study, including growth, lipid peroxidation, protein oxidation and activities of antioxidant enzymes. The results indicate that the aged refuse affected the growth of maize seedlings, and elevated the levels of lipid peroxidation and protein oxidation in leaf tissues in a time-dependent manner, accompanying by the changes of antioxidant status. Also, above physiological responses varied as a function of particle-size distribution of the aged refuse, and statistical growth inhibition and oxidative stress occurred after the exposure of smaller particle-size samples, which contained higher level trace metals, the characteristic pollutants in the aged refuse. The results implicate that aged refuse might cause environmental stress on plant system, but the polluting risk mainly resulted from smaller particle-size samples. Therefore, the critical point of utilizing aged refuse as vegetated soil focused on analyzing its particle-size distribution, and screening out appropriate particle-size samples.


Vaniprevir plus peginterferon alfa-2b and ribavirin in treatment-experienced Japanese patients with hepatitis C virus genotype 1 (GT1b) infection: Phase 3 studies.
Vaniprevir is a macrocyclic hepatitis C virus (HCV) non-structural (NS)3/4A protease inhibitor. The objective of these phase 3 multicenter, open-label trials was to evaluate the safety and efficacy of vaniprevir + peginterferon alfa-2b + ribavirin (PR) in Japanese patients with HCV genotype (GT)1 infection who had previously failed treatment with interferon-based regimens. Japanese patients with chronic HCV GT1 were enrolled. In PN044, patients with previous relapse or virologic breakthrough were randomized to vaniprevir (300 mg twice daily) + PR for 12 weeks followed by PR for another 12 weeks (12-week arm) or vaniprevir + PR for 24 weeks (24-week arm). In PN045, patients with previous partial/null response received vaniprevir + PR for 24 weeks. The primary endpoint was sustained virologic response at 24 weeks after completing treatment (SVR24 ). In PN044 (n = 51), SVR24 was 92.0% and 96.2% in the 12- and 24-week arms, respectively. In PN045 (n = 42), SVR24 was 61.9% in all patients and 55.2% in previous null responders. In both studies, vaniprevir + PR was generally safe and well tolerated; the majority of adverse events were mild/moderate and included pyrexia, decreased hemoglobin, headache, nausea, pruritus, and decreased platelet count. Polymorphisms in the HCV NS3 gene at baseline (Y56, Q80, and V170) did not impact treatment outcome. Virologic failure was principally associated with the on-treatment emergence of R155 or D168 mutations. Vaniprevir + PR is an effective, well-tolerated treatment for Japanese patients with HCV GT1 infection who failed previous interferon-based treatment. ClinicalTrials.gov Identifier NCT01405937 and NCT01405560 (Protocols PN044 and PN045).


The management of EGFR inhibitor adverse events: a case series and treatment paradigm.
Epidermal growth factor receptor (EGFR) inhibitors are widely used medications in the treatment of cancers. To review the cutaneous adverse events related to EGFR inhibitors. A retrospective chart review of all cases referred for the management of cutaneous adverse events after the initiation of EGFR inhibitor therapy between the years of 2006 and 2009 was performed. The study was approved by the institutional review board. Four men and 11 women had cutaneous adverse events while receiving erlotinib (mean dose: 112.5 mg) for lung and pancreatic cancer. The most common cutaneous adverse reaction observed was a papulopustular rash in 12 cases (80%). Eczema and xerosis were the only findings in three patients, alopecia in one case, and nail changes in three cases. The treatment modalities prescribed were doxycycline and topical antibiotics for the papulopustular rash; topical high potency steroids, tacrolimus, pimecrolimus, and moisturizers for xerosis and eczema; and cetirizine for the pruritus. The paronychia was treated with warm soaks, topical steroids, and podiatry referral. The majority of patients improved with symptomatic therapy, with the exception of one patient who experienced herpes zoster super infection and Stevens-Johnson syndrome. The patient was hospitalized and required discontinuation of the erlotinib therapy. The most common cutaneous adverse event in our cohort was papulopustular rash, followed by eczema and xerosis. Patients were managed with symptom target therapy, and suspension of the EGFR inhibitor was rarely required. As the use of EGFR inhibitors increases, it is important to promptly identify and treat adverse events. Further studies are necessary to develop targeted therapeutic and preventative measures.


The dexamethasone suppression test in genetically different rats exposed to inescapable and escapable electric shocks.
The Dexamethasone Suppression Test (DST) was applied to male rats of Koltushi high- (KHA) and low-avoidance (KLA) strains, genetically selected on the basis of divergent acquisition of a conditioned avoidance response in a two-way shuttlebox. Rats were exposed to either inescapable (IS) or escapable (ES) electroshock. IS produced escape deficit in a shuttle box only in KHA rats. ES enhanced escape failures only in KLA rats. There were no differences in plasma corticosterone levels between naive KLA and KHA rats. IS led to increase of the post-dexamethasone corticosterone levels in KHA rats, while both basal and stress-induced corticosterone levels in the KHA strain remained unchanged following IS. In KLA rats exposed to IS, both pre- and post-dexamethasone basal corticosterone levels were increased and stress-induced corticosterone levels were decreased. Thus, resistance to the DST after IS occurred only in KHA rats. ES led to enhanced basal and reduced stress-induced corticosterone levels in KLA rats compared to KHA rats before and after dexamethasone treatment. These findings suggest that the HPA axis reactivity following aversive stimuli depends on the interaction between genotype and stressor controllability.


Assessment of breast cancer response to neoadjuvant chemotherapy based on ultrasound backscattering envelope statistics.
Neo-adjuvant chemotherapy (NAC) is used in breast cancer before tumor surgery to reduce the size of the tumor and the risk of spreading. Monitoring the effects of NAC is important because in a number of cases the response to therapy is poor and requires a change in treatment. A new method that uses quantitative ultrasound to assess tumor response to NAC has been presented. The aim was to detect NAC unresponsive tumors at an early stage of treatment. The method assumes that ultrasound scattering is different for responsive and nonresponsive tumors. The assessment of the NAC effects was based on the differences between the histograms of the ultrasound echo amplitude recorded from the tumor after each NAC dose and from the tissue phantom, estimated using the Kolmogorov-Smirnov statistics (KSS) and the symmetrical Kullback-Leibler divergence (KLD). After therapy, tumors were resected and histopathologically evaluated. The percentage of residual malignant cells was determined and was the basis for assessing the tumor response. The data set included ultrasound data obtained from 37 tumors. The performance of the methods was assessed by means of the area under the receiver operating characteristic curve (AUC). For responding tumors, a decrease in the mean KLD and KSS values was observed after subsequent doses of NAC. In nonresponding tumors, the KLD was higher and did not change in subsequent NAC courses. Classification based on the KSS or KLD parameters allowed to detect tumors not responding to NAC after the first dose of the drug, with AUC equal 0.83 ± $\pm$ 0.06 and 0.84 ± $\pm$ 0.07, respectively. After the third dose, the AUC increased to 0.90 ± $\pm$ 0.05 and 0.91 ± $\pm$ 0.04, respectively. The results indicate the potential usefulness of the proposed parameters in assessing the effectiveness of the NAC and early detection of nonresponding cases.


Oxygen free radical producing activity of polymorphonuclear leukocytes in patients with Parkinson's disease.
Oxygen free radicals (OFRs) have been suggested in the pathogenesis of Parkinson's disease (PD). These free radicals exert their cytotoxic effect by peroxidation of lipid membrane resulting in the formation of malondialdehyde (MDA). Polymorphonuclear (PMN) leukocyte is one of the major sources of OFR. However, the oxygen free radical producing activity of PMN leukocytes in patients with PD is not known. We therefore studied the oxygen free radical producing activity of polymorphonuclear leukocytes and MDA levels in the serum of healthy subjects and in patients with Parkinson's disease. The oxygen free radical producing activity of PMN leukocytes in blood and the MDA content in serum were significantly higher in patients with Parkinson's disease than in healthy subjects. These results indicate a possible role of oxygen free radicals in the pathogenesis of Parkinson's disease.


Spontaneous occurrence of a potentially night blinding disorder in guinea pigs.
Several hereditary retinal disorders such as retinitis pigmentosa and congenital stationary night blindness compromise, sometimes exclusively, the activity of the rod pathway. Unfortunately, there are few animal models of these disorders that could help us better understand the pathophysiological processes involved. The purpose of this report is to present a pedigree of guinea pigs where, as a result of a consanguineous mating and subsequent selective breeding, we developed a new and naturally occurring animal model of a rod disorder. Analysis of the retinal function with the electroretinogram reveals that the threshold for rod-mediated electroretinograms (ERGs) is significantly increased by more than 2 log-units compared to that of normal guinea pigs. Furthermore, in response to a suprathreshold stimulus, also delivered under scotopic condition, which yield a mixed cone-rod response in normal guinea pigs, the ERG waveform in our mutant guinea pigs is almost identical (amplitude and timing of a- and b-waves) to that evoked in photopic condition. The above would thus suggest either a structural (abnormal development or absence) or a functional deficiency of the rod photoreceptors. We believe that our pedigree possibly represents a new animal model of a night blinding disorder, and that this condition is inherited as anautosomal recessive trait in the guinea pig population.


Biocompatibility and Structural Features of Biodegradable Polymer Scaffolds.
We performed a comparative analysis of physicochemical properties and biocompatibility of scaffolds of different composition on the basis of biodegradable polymers fabricated by casting and electrospinning methods. For production of polyhydroxyalkanoate-based scaffolds by electrospinning method, the optimal concentration of the polymer was 8-10%. Fiber diameter and properties of the scaffold produced by electrospinning method depended on polymer composition. Addition of polycaprolactone increased elasticity of the scaffolds. Bio- and hemocompatibility of the scaffolds largely depended on the composition formulation and method of scaffold fabrication. Polylactide introduced into the composition of polyhydroxybutyrate-oxyvalerate scaffolds accelerated degradation and increased adhesive properties of the scaffolds.


Molybdenum, nickel, cobalt, vanadium, and strontium in total diets.
The 234 foods from a 1984 collection of the Food and Drug Administration's Total Diet Study were analyzed for the trace elements molybdenum, nickel, cobalt, vanadium, and strontium by plasma emission spectrometry. Daily intakes of these elements were then estimated for eight age-sex groups on the basis of results from national food consumption surveys. The contribution of food commodity groups to the daily intake of the five elements and the distribution of the elements in the 234 foods were also determined. Results from this study were compared with those reported earlier from other laboratories.


Characteristics of pulmonary Mycobacterium avium complex disease diagnosed later in follow-up after negative mycobacterial study including bronchoscopy.
We occasionally experience cases suspected of pulmonary Mycobacterium avium complex (MAC) disease without positive bacterial cultures. To evaluate features of pulmonary MAC cases diagnosed later in the follow-up after negative intensive investigation. We defined and compared three groups; the first study negative (FSN) group, the first study positive (FSP) group, and MAC negative group. The FSN group consisted of patients negative for MAC isolation by bronchial washing performed between 2007 and 2011, but positive later. Patients with positive MAC cultures in the first study were incorporated into the FSP group. MAC negative group consisted of MAC suspects without MAC isolation in the follow-up. Twenty-four patients were classified as FSN group, 61 as MAC negative group and 265 as FSP group. FSN group exhibited more solitary nodule pattern (n = 7 in FSN, n = 6 in FSP; p < 0.001) and less nodular/bronchiectatic (NB) diseases (n = 17 in FSN, n = 245 in FSP; p < 0.001). When limited to NB type, the FSP group had more cavitations (6% in FSN, 32% in FSP; p = 0.028). Patients with more than three lung lobes involved were more frequent in the FSN group compared with FSP group with negative sputum cultures (65% vs 34%; p = 0.014) and with MAC negative group (65% vs 28%; p = 0.009). Patients diagnosed as pulmonary MAC disease in the follow-up duration tend to show solitary nodular pattern or NB pattern without cavitation. In FSN patients with NB pattern, more lung lobes were involved in the first study, suggesting subsequent MAC infection onto the underlying ectatic bronchi.


Fear of COVID-19, mental health, and pregnancy outcomes in the pregnancy during the COVID-19 pandemic study: Fear of COVID-19 and pregnancy outcomes.
Sustained fear during pregnancy has the potential to increase psychological distress and obstetric risk. This study aimed to (1) identify factors and characteristics associated with fear of COVID-19, (2) investigate the relationship between fear of COVID-19 and maternal anxiety and depression, and (3) determine the relationship between fear of COVID-19 and pregnancy outcomes. 9251 pregnant Canadians were recruited between April - December 2020. Participants self-reported (scale of 0-100) the degree of threat they perceived from the SARS-CoV-2 virus in relation to themselves and their unborn baby. Mean fear scores indicated moderate to elevated concern. In multivariable linear regression, fear of COVID-19 was associated with food insecurity, ethnicity, geographic location, history of anxiety prior to pregnancy, having a chronic health condition, pre-pregnancy BMI, parity, and stage of pregnancy at study enrollment. Higher COVID-19 fear was associated with increased odds of depression, adjusted odds ratio (aOR) = 1.75, p < 0.001, 95% CI 1.66-1.85, and anxiety, aOR=2.04, p < 0.001, 95% CI 1.94-2.15). Furthermore, fear of COVID-19 was associated with a 192-gram reduction in infant birthweight, and a 6.1-day reduction in gestational age at birth. The sample has higher education compared to the Canadian population and cannot test causal effects. This study suggests that sociodemographic, health, and obstetric factors may contribute to increased fear of COVID-19 and associated adverse psychological and pregnancy outcomes.


The third histamine receptor. Highly potent and selective ligands.
The third histamine receptor was first identified on brain neurons and seems also to be present in other cells such as the lung mast cells. Hence the novel and potent H3 receptor agonist (R)-alpha-methylhistamine might find therapeutic applications in allergic diseases.


Differentiation of neurogenic tumours and pleomorphic adenomas in the parapharyngeal space based on texture analysis of T2WI.
The purpose of this study was to identify neurogenic tumours and pleomorphic adenomas of the parapharyngeal space based on the texture characteristics of MRI-T2WI. MR findings and pathological reports of 25 patients with benign tumours in the parapharyngeal space were reviewed retrospectively (13 cases with pleomorphic adenomas and 12 cases with neurogenic tumours). Using PyRadiomics, the texture of the region of interest in T2WI sketched by radiologists was analysed. By using independent sample t-tests and Mann‒Whitney U tests, the selected texture features of 36 Gray Level Co-Occurrence Matrix (GLCM) and Gray Level Dependence Matrix (GLDM) were tested. A set of parameters of texture features showed statistically significant differences between the two groups, which were selected, and the diagnostic efficiency was evaluated via the operating characteristic curve of the subjects. The differences in the three parameters - small dependence low level emphasis (SDLGLE), low level emphasis (LGLE) and difference variance (DV) of characteristics - between the two groups were statistically significant (P < 0.05). No significant difference was found in the other indices. ROC curves were drawn for the three parameters, with AUCs of 0.833, 0.795, and 0.744, respectively. There is a difference in the texture characteristic parameters based on magnetic resonance T2WI images between neurogenic tumours and pleomorphic adenomas in the parapharyngeal space. For the differential diagnosis of these two kinds of tumours, texture analysis of significant importance is an objective and quantitative analytical tool.


Breast cancer cells induce osteoclast formation by stimulating host IL-11 production and downregulating granulocyte/macrophage colony-stimulating factor.
Breast cancer cells frequently metastasize to the skeleton, where they induce OCL formation and activity, resulting in extensive bone destruction. However, the mechanisms by which breast cancer cells mediate increased osteolysis remain unclear. To elucidate this point, we investigated how 3 human breast cancer cell lines, MDA-MB-231, MDA-MB-435 and MCF-7, induce OCL formation using a murine osteoblast-spleen cell coculture system and compared their effects with a human colorectal cancer cell line, HCT-15; a human lung cancer cell line, HT-1080; and a normal human breast cell line, HME. The breast cancer cell lines supported OCL formation only when osteoblasts were present in spleen cell cocultures, whilst the non-breast cancer cell lines and the normal breast cell line, HME, had no effect. Fractionation of BCCM by ultrafiltration established that osteoclastogenic activity was associated with factors having m.w. >3 kDa. Breast cancer cell lines produced primarily PTHrP, with lesser amounts of IL-6, IL-11 and TNF-alpha. The effect of BCCM on OCL formation in osteoblast-spleen cell cocultures was partially prevented by a neutralising antibody to human PTHrP and completely prevented by a neutralising antibody to either murine IL-11 or the murine IL-11 receptor; neutralising antibodies to human IL-6, IL-11 or TNF-alpha were without effect. BCCM or human PTHrP induced an increase in murine osteoblast IL-11 mRNA and protein production, effects that were prevented in the presence of a neutralising antibody to human PTHrP. The osteoclastogenic activity of IL-11 was mediated by enhancing osteoblast production of PGE(2) effects, which were abrogated by an inhibitor of cyclooxygenase. PGE(2) apparently enhanced OCL formation by downregulating GM-CSF production by spleen cells since recombinant murine GM-CSF inhibited OCL formation and a neutralising antibody to murine GM-CSF blocked these inhibitory effects. We conclude that breast cancer cells induce OCL formation by stimulating osteoblastic production of IL-11. The subsequent release of PGE(2) followed by inhibition of GM-CSF production by cells within the bone microenvironment plays an important part in mediating the effects of breast cancer cells on OCL formation and their resorptive activity.


Structural analysis and biosynthesis gene cluster of an antigenic glycopeptidolipid from Mycobacterium intracellulare.
Mycobacterium avium-Mycobacterium intracellulare complex (MAC) is the most common isolate of nontuberculous mycobacteria and causes pulmonary and extrapulmonary diseases. MAC species can be grouped into 31 serotypes by the epitopic oligosaccharide structure of the species-specific glycopeptidolipid (GPL) antigen. The GPL consists of a serotype-common fatty acyl peptide core with 3,4-di-O-methyl-rhamnose at the terminal alaninol and a 6-deoxy-talose at the allo-threonine and serotype-specific oligosaccharides extending from the 6-deoxy-talose. Although the complete structures of 15 serotype-specific GPLs have been defined, the serotype 16-specific GPL structure has not yet been elucidated. In this study, the chemical structure of the serotype 16 GPL derived from M. intracellulare was determined by using chromatography, mass spectrometry, and nuclear magnetic resonance analyses. The result indicates that the terminal carbohydrate epitope of the oligosaccharide is a novel N-acyl-dideoxy-hexose. By the combined linkage analysis, the oligosaccharide structure of serotype 16 GPL was determined to be 3-2'-methyl-3'-hydroxy-4'-methoxy-pentanoyl-amido-3,6-dideoxy-beta-hexose-(1-->3)-4-O-methyl-alpha-L-rhamnose-(1-->3)-alpha-L-rhamnose-(1-->3)-alpha-L-rhamnose-(1-->2)-6-deoxy-alpha-L-talose. Next, the 22.9-kb serotype 16-specific gene cluster involved in the glycosylation of oligosaccharide was isolated and sequenced. The cluster contained 17 open reading frames (ORFs). Based on the similarity of the deduced amino acid sequences, it was assumed that the ORF functions include encoding three glycosyltransferases, an acyltransferase, an aminotransferase, and a methyltransferase. An M. avium serotype 1 strain was transformed with cosmid clone no. 253 containing gtfB-drrC of M. intracellulare serotype 16, and the transformant produced serotype 16 GPL. Together, the ORFs of this serotype 16-specific gene cluster are responsible for the biosynthesis of serotype 16 GPL.


XIPP: multi-dimensional NMR analysis software.
Here we present the XIPP (eXtensible Interactive Peak Picker) NMR software for analyzing multidimensional NMR data of proteins, DNA, RNA and protein-nucleic acid complexes. XIPP organizes experiments into pre-defined studies and replaces our original PIPP software suite which is no longer supported. Default study types exist for backbone assignment, sidechain assignment, NOE assignment and several relaxation series experiments, used in solution NMR studies. XIPP is written in Java and Jython. The default study types are defined in Jython which can be modified and extended to create new types of studies.


Abuse of a newborn - the need for professional awareness of this increasingly common social problem.
Child abuse, whether physical, sexual, or psychological, is a health and social problem both globally and regionally. During the examination and diagnostic treatment of a child due to trauma, it is necessary to take into account physical abuse as a possible cause of trauma. We present the case of a female newborn referred from the General Hospital due to inconsolable crying and poor mobility of the left leg. According to the anamnesis, clinical examination, and diagnostic processing, physical violence was highly suspected. Specific fractures were verified by X-ray and computed tomography, and after excluding possible other causes, the case was reported to the competent institutions that excluded the child from the family. Given the increase in domestic violence, healthcare professionals must be aware of the fact that they must pay extra attention to certain indicators and act accordingly. When abuse is suspected, such children require a multidisciplinary approach by several specialists to minimize the possibility of error in the final diagnosis.


Craniotomy for recurrent glioblastoma: Is it justified? A comparative cohort study with outcomes over 10 years.
The role of repeat resection for recurrent glioblastoma multiforme (rGBM) is unclear. This large comparative cohort study assessed overall survival (OS), survival since recurrence (SSR), quality of life, and complications in reoperated versus non-reoperated patients for rGBM. All patients with rGBM between 2005 and 2015, who were discussed by our institution's multi-disciplinary team, and who either did or did not undergo reoperation, were prospectively followed up with data collected and compared. Survival and prognostic factors were analysed using Kaplan-Meier and Cox regression methods. 312 patients (reoperated, n = 145; non-reoperated, n = 167) were analysed. Median SSR was 10.8 months and 6.9 months in the reoperated and non-reoperated groups respectively (Log-rank test: p = 0.02). Median OS was 24.1 months and 20.4 months in the reoperated and non-reoperated groups, respectively (Log-rank test: p = 0.04). Quality of life as measured by Short Form 36 scores were 59 versus 54 at baseline and 62 versus 51 at four-month follow-up for re-operated and non-reoperated groups, respectively (p < 0.05). Age < 60 years, Karnofsky Performance Status (KPS) ≥ 80, recurrence ≥ 9 months from initial diagnosis, methylguanine methyltransferase (MGMT) promoter methylation, and extent of resection (EOR) > 80 %, each were significant predictors of SSR and OS. Complication rates were 5.5 % and 6.2 % following repeat resection and primary resection, respectively (p > 0.05). This is the first large prospective comparative cohort study of rGBM and demonstrates that repeat resection confers a small but significant benefit in survival and quality of life over non-operative treatment. Best prognosis is associated with: younger age, KPS ≥ 80, late recurrence, MGMT promoter methylation and EOR > 80 %.


ATP7A mutations in 66 Japanese patients with Menkes disease and carrier detection: A gene analysis.
Menkes disease (MNK; MIN 309400) is an X-linked recessive lethal disorder of copper metabolism caused by mutations in ATP7A (MIM 300011), which encodes a transmembrane copper-transporting P-type ATPase. This study assessed mutations in ATP7A in Japanese patients with MNK and their families using gene analysis. A total of 66 patients with MNK born between 1975 and 2013 in Japan were investigated in this study. Definite diagnosis of MNK was carried out on polymerase chain reaction (PCR) amplification and direct sequencing of each exon. Genetic analysis was also performed on 39 women for carrier diagnosis, and on nine fetuses and 10 neonates for the diagnosis of MNK. We detected 55 different mutations, of which 20 were de novo mutations. The mutations were located around the six copper binding sites, first to third and six transmembrane domains, and the ATP binding site. Of 30 mothers, 23 (76.7%) were carriers. Approximately half of the male siblings of patients with MNK were also diagnosed with MNK. Mutations in ATP7A varied widely across patients, although approximately half of the mutations were located in exons 4, 9, 10, and 15. Approximately 23% of patients did not inherit the mutations from their mothers, but had de novo mutations. An early definite diagnosis is necessary for the early treatment of MNK, and gene analysis serves as an effective method for detecting mutations in ATP7A.


[Health status of the students of elementary mining and power engineering schools with special reference to arteriosclerosis and coronary disease risk factors].
The investigations were aimed at an evaluation of the health status of mining-and-power engineering school pupils from the viewpoint of classification to work at a strip mine and power station. Special attention was paid to the detection of possible causes of atherosclerosis and coronary heart disease 811 boys aged 14--20 were examined. Their physical development was good. No pathologies in the respiratory tract were found. Hands force was normal. Of six analysed risk factors most frequent were: hypertension and smoking habit. The percentage of pupils affected was increasing with age: arterial hypertension (from 5.5% to 15.7%) and smoking habit (from 6.1% to 43.3%).


[Genotoxicity risk assessment and oocytes: basis of genetic toxicology and application in reproductive science].
The aim of genotoxicity tests in germ cells is to assess the impact of exposure to environmental mutagens that may represent a risk for the fertility or for the offspring of exposed subject. The comet assay on mature mouse oocytes is a simple, reproductive and rapid test to study primary DNA damage in oocytes. This test is used to complete toxicology assays applied in first line to somatic cells, and could find many applications in reproductive toxicology to study impact of environmental factors on female germ cells. We describe a practical application of comet assay in reproductive biology to assess the genotoxicity of cryoprotectants used at high concentrations in oocyte vitrification protocols. This test allowed us to demonstrate that dimethylsulfoxide and ethylene glycol are non-genotoxic for the mouse oocytes and led us to hypothesize a genotoxic effect of 1,2-propanediol (PrOH) at high concentrations after having observed induction of significant DNA damage on CHO cell line and on mouse oocytes.


Adaptations in athletic performance and muscle architecture are not meaningfully conditioned by training free-weight versus machine-based exercises: Challenging a traditional assumption using the velocity-based method.
Although the superior effectiveness of free-weight over machine-based training has been a traditionally widespread assumption, longitudinal studies comparing these training modalities were scarce and heterogeneous. This research used the velocity-based method to compare the effects of free-weight and machine-based resistance training on athletic performance and muscle architecture. Thirty-four resistance-trained men participated in an 8-week resistance training program allocated into free-weight (n = 17) or machine-based (n = 17) groups. Training variables (intensity, intraset fatigue, and recovery) were identical for both groups, so they only differed in the use of a barbell or specific machines to execute the full squat, bench press, prone bench pull, and shoulder press exercises. The velocity-based method was implemented to accurately adjust the planned intensity. Analysis of covariance and effect size (ES) statistics were used to compare both training modalities on a comprehensive set of athletic and muscle architecture parameters. No between-group differences were found for any athletic (p ≥ 0.146) and muscle architecture (p ≥ 0.184) variable. Both training modalities significantly and similarly improved vertical jump (Free-weight: ES ≥ 0.45, p ≤ 0.001; Machine-based: ES ≥ 0.41, p ≤ 0.001) and lower limb anaerobic capacity (Free-weight: ES ≥ 0.39, p ≤ 0.007; Machine-based: ES ≥ 0.31, p ≤ 0.003). Additionally, the machine-based group meaningfully enhanced upper limb anaerobic power (ES = 0.41, p = 0.021), whereas the free-weight group significantly improved the change of direction (ES = -0.54, p = 0.003) and 2/6 balance conditions analyzed (p ≤ 0.012). Changes in sprint capacity (ES ≥ -0.13, p ≥ 0.274), fascicle length, and pennation angle (ES ≤ 0.19, p ≥ 0.129) were not significant for either training modality. Adaptations in athletic performance and muscle architecture would not be meaningfully influenced by the resistance modality trained.


[Using Liver Function Indicators to Predict Massive Blood Transfusion in Orthotopic Liver Transplantation].
To explore the predictive effect of preoperative liver function indicators for intraoperative massive blood transfusion in orthotopic liver transplantation and to establish a prediction model. We retrospectively analyzed the relevant data of 607 patients who underwent orthotopic liver transplantation in the Department of Liver Surgery, West China Hospital, Sichuan University between January 1, 2015 and June 30, 2021. According to the intraoperative transfusion volume of leukocyte-reduced red blood cells in additive solution, the patients were divided into a massive blood transfusion (MBT) group and a non-massive blood transfusion (NMBT) group. Univariate and multivariate logistic regressions were performed to analyze the risk factors of intraoperative MBT in orthotopic liver transplantation, the calibration of the predictive model was assessed by Hosmer-Lemeshow test, and the discrimination power of the predictive model was measured by area under the curve ( AUC) of the receiver operating characteristic (ROC) curve. According to the results of logistic regression, alanine transaminase (ALT), aspartate transaminase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), albumin (ALB), and Child-Pugh score showed no correlation with the risk of MBT in orthotopic liver transplantation operation. Platelet count (PLT) (odds ratio [ OR]=0.90, 95% confidence interval [ CI]: 0.09-0.19, P=0.02), international normalized ratio (INR) ( OR=19.43, 95% CI: 7.64-19.44, P<0.01), prothrombin time (PT) ( OR=1.43, 95% CI: 1.25-1.63, P<0.01), and activated partial thromboplastin time (APTT) ( OR=0.92, 95% CI: 0.90-0.95, P<0.01) were identified as the risk factors of intraoperative MBT in orthotopic liver transplantation. The Hosmer-Lemeshow test showed that the predictive model had good calibration ( χ 2=9.06, P=0.48) and discrimination power ( AUC=0.80, 95% CI 0.766-0.834, P<0.01). A predictive model based on the preoperative PLT, INR, PT, and APTT of patients undergoing orthotopic liver transplantation was established and can be used to predict the risk of intraoperative MBT in liver transplantation patients.


Human myeloma cells express the bone regulating gene Runx2/Cbfa1 and produce osteopontin that is involved in angiogenesis in multiple myeloma patients.
Osteopontin (OPN) is a multifunctional bone matrix glycoprotein that is involved in angiogenesis, cell survival and tumor progression. In this study we show that human myeloma cells directly produce OPN and express its major regulating gene Runx2/Cbfa1. The activity of Runx2/Cbfa1 protein in human myeloma cells has also been demonstrated. Moreover, using small interfering RNA (siRNA) to silent Runx2 in myeloma cells, we suppressed OPN mRNA and protein expression. OPN production in myeloma cells was stimulated by growth factors as IL-6 and IFG-1 and in turn OPN stimulated myeloma cell proliferation. In an 'in vitro' angiogenesis system we showed that OPN production by myeloma cells is critical for the proangiogenic effect of myeloma cells. The expression of OPN by purified bone marrow (BM) CD138(+) cells has also been investigated in 60 newly diagnosed multiple myeloma (MM) patients, finding that 40% of MM patients tested expressed OPN. Higher OPN levels have been detected in the BM plasma of MM patients positive for OPN as compared to controls. Moreover, significantly higher BM angiogenesis has been observed in MM patients positive for OPN as compared to those negative. Our data highlight that human myeloma cells with active Runx2/Cbfa1 protein directly produce OPN that is involved in the pathophysiology of MM-induced angiogenesis.


Psychological distress and user experiences with health care provision in persons living with spinal cord injury for more than 20 years.
Descriptive cross-sectional and retrospective study. To gain more insight into the long-term health status in persons with traumatic spinal cord injury (SCI), especially perceived psychological distress as well as self-reports of utilization of healthcare services. Sunnaas Rehabilitation Hospital, Norway. In total, 147 persons with SCI were examined for more than 20 years and interviewed (in 2004/2005) using a self-administrated questionnaire and General Health Questionnaire (GHQ-20). Descriptive statistics and a logistic regression analysis were conducted to identify variables associated with psychological distress. Most participants had received SCI follow-up health services at least once after initial rehabilitation; 34% were satisfied, 51% neutral and 18% unsatisfied with the health services provided. Concerning psychological distress, 34 persons were cases according to the GHQ-20. The cases did not differ from non-cases concerning demography, time since injury, injury aetiology, injury severity, marital status or employment status. The regression analysis revealed that cases were associated (P<0.05) with more use of SCI-specific follow-ups. In a 20+ years' post-injury SCI population, psychological distress is common and associated with the use of follow-up services. The varying satisfaction of people with SCI about healthcare services is notable, as is the finding that 20% of people with paraplegia did not use specific SCI follow-up services. The experiences of people with SCI with healthcare services need further investigation, and there is also a need for studies that examine the effects of interventions aimed at improving services and patient satisfaction.


Mutations in the zinc-finger region of the yeast regulatory protein ADR1 affect both DNA binding and transcriptional activation.
The expression of the yeast ADH2 gene is controlled by the transcriptional activator ADR1, a zinc-finger protein that binds to an upstream activating sequence (UAS1) in the ADH2 promoter. We report here the isolation of seven mutations in the ADR1-5c allele, defining five different amino acid changes, that suppress the enhanced ADH2 expression caused by the ADR1-5c allele. Each of the mutations was shown to reduce the activation of ADH2 by a wild-type ADR1 gene, suggesting the mutations disrupt a domain important to the function of both the ADR1 and ADR1-5c proteins. All five amino acid changes occurred within the DNA-binding domain of ADR1 and were shown to severely inhibit the ability of ADR1 to bind UAS1 in vitro. These mutations were found, however, to also affect the ability of ADR1 to activate transcription independent of its ability to bind DNA. These results indicate that the DNA-binding region of ADR1 is involved in both transactivation and DNA binding.


Antenatal suspicion of ischemic placental disease and coexistence of maternal and fetal placental disease: analysis of over 500 cases.
To investigate the antenatal suspicion of placental disease and the coexistence of maternal and fetal placental ischemic disease. A prospective cohort study on normally formed singleton infants from 2000 to 2008 inclusive with placental ischemic disease. Uteroplacental ischemia or fetoplacental thrombotic vasculopathy was identified in 511 of 74,857 births (7/1000 births). Four hundred fifty-nine cases met the inclusion criteria. Maternal and fetal placental vascular disease coexisted in 9.2% (n = 42) of cases. Placental ischemic disease was suspected antenatally in 70% (324/459). Maternal placental disease occurred in 40% (184/459) and 30% (140/459) had fetal pathology. The perinatal mortality rate was 12.7/1000. Antenatal suspicion of placental disease led to increased obstetric intervention and delivery of small-for-gestational age infants. Maternal and fetoplacental vascular disease coexisted in 9.2%. Placental disease was suspected antenatally in 70% of cases and was associated with increased rates of obstetric intervention.


Are all parental experiences equal?: Cluster analysis of salivary cortisol and perception of parental stress in mothers of children with autism spectrum disorder.
Many parents of children with autism spectrum disorder (ASD) report high stress levels related to their parenting role. The experience of stress is reflected in physical symptoms and well-being, as observed by abnormal patterns of cortisol regulation. However, it may be a mistake to conceive parenthood as unilaterally stressful as diverse experiences are possible. Mothers of children with ASD provided salivary cortisol samples and self-rated parental stress. The area under the curve with respect to ground was calculated in regard to three daily collection time points. As a group, mothers reported average levels of parenting stress and flat daily cortisol output. The current age of the child and age at the time of diagnosis moderately predicted overall daily cortisol. Hierarchical clusters analysis identified four distinct profiles of stress regulation based on daily cortisol regulation and perception of parental stress. Groups did not differ based on the severity of symptoms related to autism or demographic information. We suggest that other variables, such as stress mediators and secondary stressors, may explain variability in stress regulation. Future research and intervention should perceive the parental experience as heterogeneous and focus on individualizing the support offered in light of diverse experiences.