Magnetic resonance imaging-based volumetry differentiates idiopathic Parkinson's syndrome from multiple system atrophy and progressive supranuclear palsy.
By using three-dimensional magnetic resonance imaging-based volumetry, we studied atrophy of the caudate nucleus, putamen, brainstem, and cerebellum in patients with idiopathic Parkinson's syndrome (IPS, n = 11), progressive supranuclear palsy (PSP, n = 6), and multiple system atrophy with predominant parkinsonism (MSA-P, n = 12) or ataxia (MSA-C, n = 17). Patients were compared with a total of 46 controls, of whom 16 were age matched. Mean striatal, cerebellar, and brainstem volumes were normal in patients with IPS. We found significant reductions in mean striatal and brainstem volumes in patients with MSA-P, MSA-C, and PSP, whereas patients with MSA-C and MSA-P also showed a reduction in cerebellar volume. On an individual basis, volumes of structures in patients with MSA and PSP showed an extensive overlap with the normal range with the exception of brainstem volumes in patients with MSA-C. Therefore, groups could not be discriminated on the basis of individual structure volumetry. Application of stepwise discriminant analysis, however, allowed discrimination of all 12 patients with MSA-P, 15 of 17 patients with MSA-C, and 5 of 6 patients with PSP from the normal and IPS cohorts. However, patients with IPS could not be separated from controls and patients with MSA-P could not be separated from patients with PSP. In conclusion, total intracranial volume-normalized magnetic resonance imaging-based volumetric measurements provide a sensitive marker to discriminate typical and atypical parkinsonism.


Translational properties of a non-polyadenylated oligo(U)-containing RNA fraction from wheat embryos.
A non-polyadenylated oligo(U)-containing RNA (poly(A)- . oligo(U)+ RNA) fraction was isolated from wheat embryo cytoplasm and its properties were compared with those of polyadenylated RNA (poly(A)+ RNA) from the same source. Both RNA preparations were highly heterogeneous and effectively stimulated [14C]leucine incorporation in a wheat germ cell-free translation system. Electrophoretic patterns of the translation products appearing in the non-polyadenylated RNA- and polyadenylated RNA-supplemented translation assays, respectively, differed from each other. The non-polyadenylated RNA-specific translation products included, in particular, a series of high molecular weight polypeptides. It is concluded that a specific class of non-polyadenylated oligo(U)-containing mRNA species (other than histone mRNAs) occurs in the wheat embryo cells.


Regional diastolic contour abnormalities during contrast stress echocardiography: improved detection of coronary artery disease.
Use of contrast improves detection of systolic regional wall motion abnormalities (RWMAs) during stress echocardiography. We evaluated regional diastolic contour abnormalities (RDCAs) that were associated with coronary artery disease (CAD). From August of 2003 to September of 2004, we evaluated 89 patients who underwent contrast stress echocardiography (CSE) and coronary angiography within a 3-month period ("invasive" group) and 17 patients with lower CAD risk who underwent CSE only ("reference" group). RDCAs were present in 73 patients in the invasive group and were associated with higher Framingham risk scores (relative risk, 3.6; 95% confidence interval, 1.9-6.6). RDCAs were present in 1 patient in the reference group. When combined with RWMA, RDCA improved sensitivity of CSE from 78% to 97% and specificity from 26% to 59% (diagnostic threshold for CAD was 70% stenosis). RDCAs were a novel observation associated with higher CAD risk and improved the diagnostic accuracy of CSE.


The challenge of a ban on animal testing for the development of a regulated legal market for new psychoactive substances (NPS) ('legal highs') in New Zealand: Issues and options for resolution.
In mid-July 2013, New Zealand passed the Psychoactive Substances Act (PSA), which allowed 'low risk' psychoactive products ('legal highs') to be approved for legal sale. In early May 2014, following public protest, the Psychoactive Substances Amendment Act (PSAA) was passed banning animal testing of psychoactive products, potentially making the new regime unworkable. To investigate strategies to overcome the impasse created by the animal testing ban. Solutions to the impasse were investigated using 'scenario' and 'stakeholder' analysis. Legislation, parliamentary debates, and regulatory statements related to the PSA and animal testing were reviewed. Strategies to resolve the impasse were discussed with stakeholders including the Psychoactive Substances Regulatory Authority (PSRA) officials, health officials, a legal high industry lawyer, and a leading legal highs manufacturer. This process generated six possible scenarios and five decision-making criteria of key importance to major stakeholders. Scenarios were then evaluated based on feedback from the industry and regulators. The six scenarios were: (1) pragmatic modification of the animal testing ban; (2) waiting until new non-animal test models are internationally accepted; (3) use of non-validated replacement test methods; (4) judicial challenge of the animal testing ban; (5) 'creative compliance' by only presenting human clinical trial results; and (6) philosophical re-conceptualisation of the 'benefits' from psychoactive products. Options 1 and 5 appear to be the most attractive overall solutions. However, both rely on a new political consensus and astute framing of the issues by political communicators. Political decision makers may be happy to accept Scenario 2 which would impose significant delays. A 'failed' pharmaceutical product with psychoactive effects may have the test data required to be approved under Scenarios 1 and 5. Ultimately, the pleasurable benefits from psychoactive products may need to be included in the debate.


Distinct patterns in homooligomer tract sequence context in prokaryotic and eukaryotic DNA.
The distributions of the junction sequences of homooligomer tracts of various lengths have been examined in prokaryotic DNA sequences and compared with those of eukaryotes. The general trends in the nearest and next to nearest neighbors to the tracts are similar for both groups. In both prokaryotes and eukaryotes A/T runs are preferentially flanked on either the 5' or the 3' ends by A and/or T. G/C runs are preferentially flanked by G and/or C. There is discrimination against A/T runs flanked by G or C and G/C runs flanked by A or T. However, whereas the distribution of prokaryotic homooligomer tract junction sequences was quite homogeneous, large variations were observed in the 5-fold larger eukaryotic database, increasing in magnitude from tracts of length 2 to 3 to 4 base pairs long. Possible DNA conformational implications and in particular DNA curvature and packaging aspects of prokaryotes and eukaryotes are discussed.


A systematic review: normative reference values of the median nerve cross-sectional area using ultrasonography in healthy individuals.
Median nerve cross-sectional area (CSA) was used for screening and diagnosis of neuropathy, but few studies have suggested reference range. Hence, this systematic review was performed to evaluate a normative values of median nerve CSA at various landmarks of upper limb based on ultrasonography. PubMed and Web of science were used to search relevant articles from 2000 to 2020. Forty-one eligible articles (2504 nerves) were included to access median nerve CSA at different landmarks (mid-arm, elbow, mid-forearm, carpal tunnel (CT) inlet and CT outlet). Data was also stratified based on age, sex, ethnicity, geographical location, and method of measurement. Random effects model was used to calculate pooled weighted mean (95% confidence interval (CI), [upper bound, lower bound]) at mid-arm, elbow, mid-forearm, CT inlet and outlet which found to be 8.81 mm2, CI [8.10, 9.52]; 8.57 mm2 [8.00, 9.14]; 7.07 mm2 [6.41, 7.73]; 8.74 mm2 [8.45, 9.03] and 9.02 mm2 [8.08, 9.95] respectively. Median nerve CSA varies with age, geographical location, and sex at all landmarks. A low (I2 < 25%) to considerable heterogeneity (I2 > 75%) was observed, indicating the variation among the included studies. These findings show that median nerve CSA is varying not only along its course but also in other sub-variables.


Low hematocrit during cardiopulmonary bypass is associated with increased risk of perioperative stroke in cardiac surgery.
The relationship between degree of hemodilution during cardiopulmonary bypass (CPB) and perioperative stroke has not been fully elucidated. The objective of this observational study was to evaluate the relationship between nadir hematocrit during CPB and perioperative stroke while adjusting for variables known to have an association with stroke and anemia. Perioperative data were prospectively collected on 10,949 consecutive patients who underwent cardiac surgery with CPB from 1999 to 2004 at a quaternary care hospital. Stroke was defined as a persistent neurologic deficit, consistent with a central nervous system lesion, occurring within 30 days of operation. Stroke was classified as perioperative if patients awoke from anesthesia with neurologic symptoms and postoperative if patients awoke without symptoms. Multivariable logistic regression analysis was used to control for confounding variables to obtain the independent relationship between nadir hematocrit during CPB and perioperative stroke. The prevalence of perioperative stroke was 1.0% (n = 110). An additional 50 patients had postoperative stroke. Nadir hematocrit during CPB was an independent predictor of perioperative stroke. After controlling for confounding variables, each percent decrease in hematocrit was associated with a 10% increase in the odds of suffering perioperative stroke (95% confidence interval, 4% to 18%; p = 0.002). The model was accurate (c-index = 0.85) and reliable (Hosmer-Lemeshow test p = 0.4). There is an independent, direct association between degree of hemodilution during CPB and risk of perioperative stroke. Prospective randomized clinical trials comparing different degrees of hemodilution during CPB are required to determine whether this is a cause-effect relationship or a simple association.


Delayed spinal extradural hematoma following thoracic spine surgery and resulting in paraplegia: a case report.
Postoperative spinal extradural hematomas are rare. Most of the cases that have been reported occured within 3 days of surgery. Their occurrence in a delayed form, that is, more than 72 hours after surgery, is very rare. This case is being reported to enhance awareness of delayed postoperative spinal extradural hematomas. We report a case of acute onset dorsal spinal extradural hematoma from a paraspinal muscular arterial bleed, producing paraplegia 72 hours following surgery for excision of a spinal cord tumor at T8 level. The triggering mechanism was an episode of violent twisting movement by the patient. Fresh blood in the postoperative drain tube provided suspicion of this complication. Emergency evacuation of the clot helped in regaining normal motor and sensory function. The need to avoid straining of the paraspinal muscles in the postoperative period is emphasized. Most cases of postoperative spinal extradural hematomas occur as a result of venous bleeding. However, an arterial source of bleeding from paraspinal muscular branches causing extradural hematoma and subsequent neurological deficit is underreported. Undue straining of paraspinal muscles in the postoperative period after major spinal surgery should be avoided for at least a few days.


Stupp-treated glioblastoma accompanied by EBV-positive primary CNS lymphoma.
We describe a patient who within 2 months of undergoing radio-chemotherapy for glioblastoma developed an Epstein-Barr virus-positive primary diffuse large B-cell CNS lymphoma. To our knowledge, this is the first such case reported in the literature showing that new tumefactions following aggressive treatment for glioblastomata might represent secondary malignancies.


Clinicians' perceived value and demographic factors that predict the utilisation of patient reported outcome measures for low back pain amongst chiropractors in Australia.
Factors that influence utilisation rates of patient reported outcome measures (PROMs) for low back pain (LBP) within the chiropractic profession of Australia are currently unknown. This study aimed to examine whether factors, including age, sex, experience level, clinical title (principal vs associate), or a clinicians' perceived value of PROMs, are predictive of the frequency and/or type of PROMs used by chiropractors in the management of LBP. A cross sectional online survey was distributed to members of the Chiropractic Association of Australia (CAA now known as Australian Chiropractors Association-ACA) and Chiropractic Australia (CA). 3,014 CAA members and 930 CA members were invited to participate totaling 3,944, only respondents that were using PROMs were included in the analysis (n = 370). Ordinal logistic regression was used to examine associations between clinician demographics and perceived value of PROMs, and the frequency of pain, health, and functional patient reported outcome measure (PROM) usage by chiropractors. Principal chiropractors were more likely (Wald = 4.101, p = 0.04, OR = 1.4 (1.0-2.1)) than associate chiropractors to frequently use pain-related PROMs for the management of patients with LBP. The remaining demographic factors (age, sex, and experience level) were not associated with the frequency of PROM usage; nor were the perceived value clinicians place on PROMs in clinical practice. Principal chiropractors were more likely to frequently use pain-related PROMs for the management of patients with LBP when compared to associate chiropractors. Demographic factors, appear to have little influence on PROM usage. While chiropractors place high value on PROMs, these beliefs are not associated with increased frequency of PROM usage for the management of LBP.


Morphologically distinctive forms of cutaneous mast cell degranulation induced by cold and mechanical stimuli: an ultrastructural study.
To determine whether morphological differences in the response of cutaneous mast cells characterize clinically distinct forms of urticaria, we used ultrastructural techniques to examine skin biopsy specimens from three patients with cold-induced urticaria and four patients with dermographism. Biopsy specimens were obtained before application of the stimulus and at the time of lesion formation. Patients with cold-induced urticaria exhibited morphological alterations only after stimulus application consisting of enlargement and uniform disorganization of some, but not all, granules, fusion of the membranes of adjacent granules, fusion of granule membranes with mast cell membranes, and discharge of electron-lucent and disorganized granule contents into the extracellular space. Mast cells from patients with immediate as well as delayed dermographism exhibited alterations before and after stimulus application consisting of enlargement of most granules, nonuniform (zonal) disorganization or solubilization of granule contents, fusion of granule membranes with mast cell membranes, and extracellular discharge of granule contents. Small cytoplasmic vesicles containing disorganized granular material were associated with the degranulation process. Endothelial cells lining nearby postcapillary venules exhibited prominent perinuclear condensation of contractile microfilaments during degranulation in both groups. Both before and after application of the stimulus, the walls of the superficial dermal vessels of the patients with dermographism were thinner and contained less extracellular matrix material than vessel walls of the patients with cold-induced urticaria. The morphologically distinctive types of mast cell degranulation that characterize these two clinically separable urticarial disorders may indicate different pathogenic mechanisms of lesion formation.


Modulation of the tetrameric I-motif folding of C-rich Tetrahymena telomeric sequences by hexitol nucleic acid (HNA) modifications.
I-motifs are non-canonical DNA structures consisting of two parallel strands held together by hemiprotonated cytosine-cytosine+ base pairs, which intercalate to form a ordered column of stacked base pairs. This unique structure covers potential relevance in various fields, including gene regulation and biotechnological applications. A unique structural feature of I-motifs (iM), is the presence of sugar-sugar interactions through their extremely narrow minor grooves. Consistently, oligonucleotides containing pentose derivatives such as ribose, 2'-deoxyribose, arabinose, and 2'-deoxy-2'-fluoroarabinose highlighted a very different attitude to fold into iM. On the other hand, there is significant attention focused on exploring sugar-modifications that can increase nucleic acids resistance to nuclease degradation, a crucial requirement for therapeutic applications. An interesting example, not addressed in the iM field yet, is represented by hexitol nucleic acid (HNA), a metabolically stable six-membered ring analogue compatible with A-like double helix formation. Herein, we selected two DNA C-rich Tetrahymena telomeric sequences whose tetrameric iMs were already resolved by NMR and we investigated the iM folding of related HNA and RNA oligonucleotides by circular dichroism, differential scanning calorimetry and NMR. The comparison of their behaviours vs the DNA counterparts provided interesting insights into the influence of the sugar on iM folding. In particular, ribose and hexitol prevented iM formation. However, by clustering the hexitol-containing residues at the 3'-end, it was possible to modulate the distribution of the different topological species described for the DNA iMs. These data open new avenues for the exploitation of sugar modifications for I-motif characterization and applications.


Long-term subthreshold electrical stimulation of the left stellate ganglion and a canine model of sudden cardiac death.
We sought to develop a high-yield canine model of sudden cardiac death (SCD). Because electrical stimulation is a powerful means to elicit nerve sprouting, we hypothesize that subthreshold electrical stimulation is more effective than nerve growth factor (NGF) infusion in inducing nerve sprouting and SCD in dogs with myocardial infarction (MI) and complete atrioventricular block (CAVB). We gave subthreshold electrical stimulation to the left stellate ganglion (LSG) in six normal dogs for 41 +/- 9 days (protocol 1) and to six dogs with MI and CAVB for 41 +/- 29 days, while continuously monitoring their cardiac rhythm (protocol 2). We also monitored the rhythm of two dogs with MI, CAVB, and NGF infusion to the LSG and determined the ventricular nerve density in six healthy control dogs. In protocol 1, the hearts from dogs with LSG electrical stimulation had a higher density of nerve fibers immunopositive to tyrosine hydroxylase, synaptophysin, and growth-associated protein-43 than those of normal control dogs (p < 0.01). In protocol 2, there was a high magnitude of cardiac nerve sprouting in all dogs studied. Ventricular tachycardia > or =8 beats and > or =20 beats was more frequent in dogs with electrical stimulation than in dogs with NGF infusion to the LSG (36 +/- 60 and 11 +/- 17 vs. 4.7 +/- 6.1 and 0.1 +/- 0.33 episodes per day, p < 0.05 and p < 0.03, respectively). Four of six dogs in protocol 2 had SCD. Subthreshold electrical stimulation of the LSG induces cardiac nerve sprouting and sympathetic hyperinnervation and facilitates the development of a high-yield canine model of ventricular arrhythmia and SCD.


The female paraplegic: a statistical survey.
From November 1969 to December 1979, 1234 patients with spinal cord lesions were treated at the Henry Gabrielle Hospital. Of these 386 were from medical causes and 848 from trauma. The computer study of these cases brings out statistical differences between the sexes as the overall incidence in females is 30 per cent and even lower if one considers traumatic cases only 22.4 per cent out of the 848 cases. Furthermore, the average female paraplegic is two years older and it was noted that more females are married. In females the causes of spinal cord injuries are more frequently car accidents and suicidal falls from high places, whereas in males the causes are related to direct blows, that is sport injuries, motorcycle accidents and industrial falls. Clinical symptoms are similar in the two groups with the exception that there is less heterotopic ossifications and fewer bladder stones in females. The duration of hospitalisation is shorter in females. A well equipped household is more important for the handicapped females than for males.


Transcriptional activation of the Drosophila melanogaster glucose-6-phosphate dehydrogenase gene by insertion of defective P elements.
Tandem insertions of defective P elements (1.15 kb KP and 0.6 kb core P) accelerate the transcription rate of the glucose-6-phosphate dehydrogenase (G6PD) gene in Drosophila melanogaster. In this report, we have analyzed the activation mechanism of the G6PD promoter by in vitro transcription and gel retardation assays. Results showed that one cis-acting region in the core P and two such regions in the KP are associated with activation of the G6PD promoter, and that putative transcriptional regulatory protein(s) which specifically bind to each of the cis-acting regions are present in nuclear extracts of Canton S embryos. On the other hand, the P elements do not activate the normal actin 5C promoter, but activate the promoter when the 20 bp sequence around the G6PD transcription start site is placed in front of the promoter. It appears that the GC-rich region in this 20 bp sequence is required for the activation.


The impact of age and BMI on Eating Disorder Examination Questionnaire (EDE-Q) scores in a community sample.
The primary objectives for this study were to establish normative data for the EDE-Q in a nationally representative sample of women and to investigate the unique and relative effects of age and BMI. A community sample of 3000 women aged 16-50 was randomly selected from the Norwegian National Population Register. Mean global EDE-Q was 1.27 (SD=1.19). EDE-Q scores decreased significantly with age yet increased with BMI. In the regression model, BMI and age accounted for 19% versus 2%, respectively, of the global EDE-Q. Extreme shape and weight concerns appeared to drive the higher global EDE-Q scores for individuals with overweight or obesity, with 30-40% scoring above the recommended clinical cut-off for Shape and Weight Concern. Higher EDE-Q scores, largely driven by elevated shape and weight concerns, appear normative among individuals with obesity in a nationally representative population. BMI should be routinely considered when establishing criteria for defining recovery and determining clinical significance using the EDE-Q.


A simple protocol for expression of isotope-labeled proteins in Escherichia coli grown in shaker flasks at high cell density.
Protein expression in E. coli grown in shaker flasks is a routine and pivotal tool in many research laboratories. To maximize protein yields, cells are normally induced in the middle of the linear growth phase, typically at an OD600 of ≤ 1 for cells grown in Luria-Bertani (LB) medium at 37 °C. We recently showed that the E. coli linear growth phase can be extended to higher cell density when cells are cultured under less than optimal conditions such as in minimal medium and/or at lower temperatures. Maximizing the yield of protein per unit volume of culture is important for reducing the costs, especially when isotopically labeling is required. Here, we present a modified minimal medium and a simple protocol that can increase the protein yield up to fourfold in a pH-stabilized LB medium and up to sevenfold in a modified M9+ medium (M9++). When M9++ medium coupled with the high density (OD600 ~ 6) cell growth protocol are used to express uniformly 15N- or 15N/13C-labeled proteins, the amount of 15NH4Cl and 13C6-glucose for a given cell mass is reduced by 50% and ~ 65%, respectively, relative to the traditional low density (OD600 ~ 1) cell growth protocol with M9 medium; the inclusion of 0.1% LB in the minimal medium permits a reduction in the concentration of both the trace element solution and MgCl2, which can cause precipitation. Mass data indicate that inclusion of 0.1% LB does not significantly affect the isotope enrichment level.


Percutaneous mechanical support for the failing right heart.
Right ventricular (RV) failure is an increasingly common clinical problem that may require mechanical support. In contrast to severe left ventricular failure, RV failure is typically more reversible. Therefore, application of shorter-term percutaneous support devices is potentially attractive. Current innovations promise greater availability of such percutaneous RV support devices. This article considers the available mechanical approaches to provide hemodynamic support to treat profound RV failure in the common clinical scenarios in which percutaneous mechanical RV support may be most beneficial.


Late effects of intracoronary streptokinase on regional wall motion, ventricular aneurysm and left ventricular thrombus in myocardial infarction: results from the Western Washington Randomized Trial.
To determine whether intracoronary streptokinase improves late regional wall motion or reduces left ventricular aneurysm or thrombus formation in patients with acute myocardial infarction, two-dimensional echocardiography was performed at 8 +/- 3 weeks after infarction in 83 patients randomized to streptokinase (n = 45) or standard therapy (n = 38) in the Western Washington Intracoronary Streptokinase Trial. Among the patients treated with streptokinase, the average time to treatment was 4.7 +/- 2.5 hours after the onset of chest pain, and 67% had successful reperfusion. Regional wall motion was assessed in nine left ventricular segments on a scale of 1 to 4 (normal, hypokinetic, akinetic and dyskinetic). Left ventricular thrombus formation was interpreted as positive, equivocal or negative. All patients received anticoagulant therapy in the hospital and 52 received such therapy after hospital discharge. The mean (+/- SD) global (1.5 +/- 0.4 in both groups) and regional wall motion scores in the streptokinase-treated and control groups were not significantly different. The prevalence of aneurysm was 16% in both groups. Left ventricular thrombus was identified in only five patients (positive identification in four, and equivocal in one), all in the streptokinase-treated group (p = NS). There were also no differences between streptokinase and control treatment in any of the echocardiographic variables in subgroups of patients with anterior infarction, inferior infarction, no prior infarction or reperfusion with streptokinase. It is concluded that intracoronary streptokinase given relatively late in the course of acute myocardial infarction does not result in improved global or regional wall motion or a reduction in left ventricular thrombus or aneurysm formation in survivors studied 2 months after myocardial infarction.


Effect of aspirin and acid on human jejunal mucosa. An ultrastructural study.
To determine the effects of aspirin and hydrochloric acid on human jejunal mucosa, three obese patients with a small intestinal bypass that opened on the abdominal wall as a mucous fistula were studied. An 80-mM solution of HCl, a 40-mM suspension of aspirin (equivalent to two tablets in a glass of water), and a combination suspension of 40 mM aspirin plus 40 mM HCl damaged a mean +/- SE of 26 +/- 13% (P less than 0.05), 24 +/- 5% (P less than 0.05), and 29 +/- 5% (P less than 0.05) of jejunal villi, respectively, 5 min after administration. By 60 min after instillation, considerable recovery had occurred. Scanning electron microscopy revealed focal villous tip erosion and erythrocyte extrusion after all test solutions. In conclusion, aspirin, 40 mM, physiologic concentration of hydrochloric acid, and the combination of acid plus aspirin are each capable of damaging human small intestinal mucosa on direct contact.


The effects of calcium2+ and magnesium2+ on the electrophoretic mobility of chromaffin granules measured by electrophoretic light scattering.
Electrophoretic light scattering was used to determine the electrophoretic mobility distributions of isolated bovine adrenal chromaffin granules as a function of divalent metal ion concentrations. Changes in the electrophoretic mobility reflected changes in the surface charge density of the granules. Ca2+ and Mg2+ (0.10--2.0 mM) were equally effective in reducing the electrophoretic mobilities. These findings are consistent with recent studies of the binding of Ca2+ and Mg2+ to the surface of chromaffin granules and are further evidence that the specific role of Ca2+ in exocytosis is due to effects other than the ability of Ca2+ to decrease the electrostatic repulsion between negatively charged membranes.


Histomorphometric analysis of osteocyte density and trabecular structure of 92 vertebral bodies of different ages and genders.
Knowledge of the histomorphometric structure of the vertebral body and factors influencing the structure is essential for a fundamental understanding of osteoporosis and osteoporotic fractures. The present study is focused on osteocyte density - a parameter seldom investigated so far - and trabecular width as well as bone area over tissue area in human vertebral bodies. Ninety-two vertebral body specimens (C5, C6, Th8, Th12, L1, L2) from 12 males and seven females were studied (Ethics Application Number A 2017-0072). The prepared vertebral specimens were extracted from the ventral aspect with a Jamshidi needle®. The punches were decalcified and subsequently H&E stained. Using the Fiji/Image J program (version 1.53 f, Wayne Resband, National Institute of Mental Health, USA), osteocyte numbers were counted per calcified bone surface, and the trabecular width and bone area of trabecular bone were measured. The collected data were analyzed using the statistical software package SPSS, version 23.0 (SPSS Inc., Chicago, USA). Pearson's correlation coefficient was used for correlation analyses. Multiple linear regression analyses were also performed. Osteocyte density did not differ significantly in comparisons based on gender and age (≤65 years; ≥66 years). Men had wider trabeculae (p < 0.001) and a higher bone area over tissue area (BA/TA, %) (p = 0.025) than women. Individuals over 65 years of age had thinner trabeculae (p < 0.001) and a smaller BA/TA (%) (p < 0.001) than younger individuals. Multiple linear regression analyses were performed to determine the influence of 'gender' and 'age' on trabecular width and bone area over tissue area. The R² was 0.388 for trabecular width and 0.227 for BA/TA (%). Per year of life, trabecular width decreases by 0.368 µm (β < 0.001) and BA/TA (%) by 0.001% (β = 0.001). Men have on average 8.2 µm wider trabeculae than women (β = 0.035). A negative correlation (r = -0.275) was observed between trabecular width and osteocyte density. The wider the trabeculae, the fewer osteocytes per mm² (p = 0.008). Surprisingly, we found no difference in osteocyte density with reference to age or gender. However, we did register significant age- and gender-related differences in bone area over tissue area and trabecular thickness. The age-related differences were more pronounced, implying that age-dependent loss of bone structure may be more important than differences between genders.


Intersection assistance: a safe solution for older drivers?
Within the next few decades, the number of older drivers operating a vehicle will increase rapidly (Eurostat, 2011). As age increases so does physical vulnerability, age-related impairments, and the risk of being involved in a fatal crashes. Older drivers experience problems in driving situations that require divided attention and decision making under time pressure as reflected by their overrepresentation in at-fault crashes on intersections. Advanced Driver Assistance Systems (ADAS) especially designed to support older drivers crossing intersections might counteract these difficulties. In a longer-term driving simulator study, the effects of an intersection assistant on driving were evaluated. 18 older drivers (M=71.44 years) returned repeatedly completing a ride either with or without a support system in a driving simulator. In order to test the intersection assistance, eight intersections were depicted for further analyses. Results show that ADAS affects driving. Equipped with ADAS, drivers allocated more attention to the road center rather than the left and right, crossed intersections in shorter time, engaged in higher speeds, and crossed more often with a critical time-to-collision (TTC) value. The implications of results are discussed in terms of behavioral adaptation and safety.


[Serum morphine concentrations and analgesia in epidural or subcutaneous morphine administration in obstetrics].
The analgesic effect of three mg morphine hydrochloride administered either epidurally or subcutaneously to 14 primiparae was compared. The maternal serum concentrations of morphine were determined in defined intervals over a period of four hours. Analgesia was significantly superior following epidural morphine, but unsatisfactory in both groups. Good pain relief was achieved by subsequent epidural administrations of bupivacaine.


Subsensory electrical noise stimulation applied to the lower trunk improves postural control during visual perturbations.
Low levels of sensory noise applied to the skin through electrical stimulation (ES) can improve balance control through a mechanism called stochastic resonance (SR). Little is known regarding the extent subsensory ES can improve reactive control of balance after unanticipated balance perturbations and the best location where to apply the stimulation. How efficient is subsensory ES in improving reactive control of balance following visual perturbations delivered in a virtual reality (VR) environment? 2) Does lower trunk stimulation have greater effects than lower legs stimulation? Eighteen healthy young adults stood on a force plate while wearing a Valve Index VR headset in eyes closed (EC), eyes open (EO), eyes open with anteroposterior visual perturbations (AP) and eyes open with mediolateral visual perturbations (ML) conditions. No-stimulation (NS), leg stimulation (LS), or trunk stimulation (TS) equal to 90% of the sensory threshold (ST) was applied. The 95% confidence ellipse area (95%EA), the lengths of AP and ML sway path (APPath, MLPath), and the AP and ML 50% and 95% power frequencies (APPF50, MLPF50, APPF95, and MLPF95) were calculated. Repeated-measures ANOVA and Tukey post-hoc tests were used to analyze the main and interaction effects of stimulation and visual conditions. During AP perturbations, participants showed higher frequencies, longer paths, and larger ellipse areas. TS caused lower APPF50, MLPF50, MLPF95, APPath and EA while LS caused lower MLPF50 and EA. During ML perturbations, TS reduced APPF50 and both LS and TS caused reduction of MLPF95. Higher instability following AP perturbations was associated with greater effects of TS and LS. The application of subsensory ES improved postural control during AP perturbations and TS reduced postural sway more effectively than LS. TS may be an effective strategy to enhance balance control during reactive postural tasks, thus potentially reducing fall risk.


Abdominal desmoid tumors.
Desmoid tumors are rare, benign, fibromatous lesions that are the result of abnormal proliferation of myofibroblasts. Desmoid tumors can be classified as extra-abdominal and abdominal. Abdominal desmoid tumors are either superficial or intraabdominal. These tumors are associated with a high recurrence rates, even if their microscopic characters indicate a benign disease; their biologic behavior often indicates rather a "malignant" disease, which can cause even the death. Intraabdominal desmoid tumors can engulf surrounding viscera and vessels, thereby greatly complicating their surgical treatment. Management is multidisciplinary. Simple observation is a reasonable management option for asymptomatic patients; spontaneous regression of these tumors may be observed. Complete excision is the treatment of choice for tumors causing symptoms or complications. Surgery should be minimized as much as feasible, while at the same time achieving free margins. Adjuvant therapy should be considered in selected cases; the role of other management options (including gene transfer therapy) is currently under intensive investigation.


Inhibition of CPEB3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory.
A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element binding protein 3 (CPEB3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozyme's self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the CPEB3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.


Wavefront analysis of higher-order aberrations in patients with cataract.
To determine local refractive changes and higher-order aberrations in patients with nuclear or cortical cataract. Osaka University Medical School, Osaka, Japan. Wavefront analysis of both ocular and corneal aberrations was performed with the Hartmann-Shack aberrometer in 2 patients, a 22-year-old woman with bilateral developmental nuclear cataract and a 68-year-old woman with mild bilateral cortical cataract. Case 1 showed a delay in the wavefront that caused a myopic shift in the central pupillary area in both eyes, associated with the nuclear cataract. The spherical-like aberration (right eye, 36%; left eye, 21%) was greater than the coma-like aberration in both eyes. Case 2 showed an advancement of the wavefront that caused a hyperopic shift, especially in the lower temporal pupillary area, that was associated with the cortical cataract. The coma-like aberration (right eye, 63%; left eye, 52%) was greater than the spherical-like aberration in both eyes. The polarity of the third-order spherical aberration was negative in Case 1 and positive in Case 2. Corneal higher-order aberrations were small and had a different distribution than ocular higher-order aberrations in both patients. The Hartmann-Shack aberrometer was useful in detecting local refractive changes and higher-order aberrations in patients with mild cataract. The polarity and the absolute value of ocular higher-order aberrations may be useful parameters to characterize eyes with cataract.


Inhibition of rat alpha-fetoprotein-estrogen interaction by adult rat ovarian extracts--role of unsaturated fatty acids.
Thin layer chromatography with four different solvent systems enabled us to show that ovarian extracts contained nonesterified unsaturated fatty acids able to compete with estradiol on the alpha-fetoprotein binding site. Gas chromatography demonstrated a high level of oleic and linoleic acids and the presence of arachidonic acid, a strong competitor of the rat alpha-fetoprotein-estrogen interaction. Arachidonic acid is a precursor of prostaglandins thus we suggest that its binding to AFP might play a role in the AFP-mediated ovarian regulation previously demonstrated.


Role of Syndecan-4 in the cellular invasion of Orientia tsutsugamushi.
Cell surface heparan sulfate proteoglycans (HSPGs) play a critical role in the cellular invasion of intracellular bacteria and are presumed to have a role in the infection of host cells by Orientia tsutsugamushi. Previously, we showed that O. tsutsugamushi infection decreased markedly after treating host cells with heparinase, which suggests that HSPGs play an important role in oriential infection. We tested oriential infection in REF-Syn4 cells over-expressing syndecan-4, and in REF-Syn4AS cells in which the expression of syndecan-4 was down regulated by transfecting with anti-sense syndecan-4 cDNA. Oriential infection was found to be dependent on the expression level of syndecan-4 on the cell surface. Furthermore, the infectivity of O. tsutsugamushi was specifically reduced by treating O. tsutsugamushi with the purified recombinant core protein of syndecan-4 (Syn4E). These results suggest that the core protein of syndecan-4 and the heparin/heparan sulfate chain of syndecan play an important role in oriential infection by O. tsutsugamushi.


An asymmetric approach toward chiral multicyclic spirooxindoles from isothiocyanato oxindoles and unsaturated pyrazolones by a chiral tertiary amine thiourea catalyst.
The first organocatalytic Michael-cyclization cascade reaction between isothiocyanato oxindoles and unsaturated pyrazolones has been developed. The multicyclic spiro[oxindole/thiobutyrolactam/pyrazolone] core structures containing three contiguous stereogenic centers, including two spiro quaternary centers, were prepared with excellent diastereo- (up to >20 : 1) and enantioselectivities (up to 99% ee).


Localization of autosomal recessive early-onset parkinsonism to chromosome 1p36 (PARK7) in an independent dataset.
Two new loci, PARK6 and PARK7, for autosomal recessive early-onset parkinsonism have recently been identified on chromosome 1p, in single large pedigrees. Among 4 autosomal recessive early-onset families analyzed here, 2 supported linkage to PARK7, 1 with conclusive evidence. These data confirm localization of autosomal recessive early-onset parkinsonism to PARK7, suggesting it to be a frequent locus. Assignment of families to either PARK6 or PARK7 might be difficult because of the proximity of the two loci on chromosome 1p.


A Nanovaccine Based on Adjuvant Peptide FK-13 and l-Phenylalanine Poly(ester amide) Enhances CD8+ T Cell-Mediated Antitumor Immunity.
Cancer vaccines have shown promise as effective means of antitumor immunotherapy by inducing tumor antigen-specific T cell immunity. In this study, a novel peptide-based tumor nanovaccine that boosts antigen presentation and elicits effective antitumor immunity is developed. The adjuvant characteristics of an antimicrobial peptide-derived core peptide, FK-13, are investigated and used it to generate a fusion peptide named FK-33 with tumor antigen epitopes. l-phenylalanine-based poly(ester amide) (Phe-PEA), 8p4, is also identified as a competent delivery vehicle for the fusion peptide FK-33. Notably, the vaccination of 8p4 + FK-33 nanoparticles (8FNs) in vivo induces dendritic cell activation in the lymph nodes and elicits robust tumor antigen-specific CD8+ T cell response. The nanovaccine 8FNs demonstrate significant therapeutic and prophylactic efficacy against in situ tumor growth, effectively inhibit tumor metastasis, and significantly prolong the survival of tumor-bearing mice. Moreover, 8FNs can incorporate different tumor antigens and exhibit a synergistic therapeutic effect with antiprogrammed cell death protein 1 (PD-1) therapy. In summary, 8FNs represent a promising platform for personalized cancer vaccines and may serve as a potential combinational modality to improve current immunotherapy.


Suppression of lymphocyte mitogenesis by tamoxifen.
Tamoxifen (at 0.1-1 microM concentrations) inhibited significantly the response of rat spleen cells to phytohemagglutinin, concanavalin A, pokeweed mitogen and lipid A in a dose-dependent manner. To achieve this inhibition, it was sufficient to expose the lymphocytes for 4 h to tamoxifen prior to mitogenic stimulation. Estradiol did not have a consistent effect on lymphocyte mitogenesis under the same conditions and did not modify the suppressive effect of tamoxifen, even when the lymphocytes were treated first with estradiol followed by tamoxifen. It is suggested that the inhibitory effect of tamoxifen on these in vitro lymphocyte reactions is not mediated by the estrogen receptor.


Silent infection in male accessory genital organs and male infertility.
A silent infection of the male accessory genital organs was found in the semen of 78 patients (22,3%) of 350 infertile men. All the sperm characteristics (except agglutination) were significantly deteriorated in the infection group as compared to the sperm of 36 normal men. The volume was significantly larger than normal. In this group there was significant leukocytosis and, as a sign of prostatic hypofunction, reduced seminal acid phosphatase and citric acid activity. Chemotherapy for a period of two to four weeks improved leukocytosis and sperm transiently. Only acid phosphatase was normal three months after the treatment. Suggested reasons for the infertility of the silent infection group are: 1. hypofunction of the male genital organs, caused by a primary, strong infection suffered earlier. 2. The chronic, nonclinical infection of the male accessory genital organs, mainly as a complication of the primary infection. Chemotherapy for a period of four weeks seems to be too short to correct the silent infection as well as the infertility.


Quantum dot-based FRET for sensitive determination of hydrogen peroxide and glucose using tyramide reaction.
In this paper, we report a new strategy for detection of hydrogen peroxide and glucose using quantum dot (QD)-based fluorescence resonance energy transfer (FRET) and tyramide reaction. The principle of FRET is based on highly sensitive reaction of a carbocyanine dye (Cy5) labeled tyramide and hydrogen peroxide catalyzed by horseradish peroxidase (HRP), and the fluorescence spectrum of QDs (EXmax 605 nm) partially overlaps with the absorption bands of Cy5. We firstly conjugated HRP to QDs, and then demonstrated an efficient FRET between HRP conjugated QDs (as energy donors) and tyramide labeled Cy5 (as energy acceptors) due to the formation of Cy5-labeled HRP-QDs assemblies in the presence of H₂O₂. We observed that the fluorescence Cy5 depended linearly on the H₂O₂ concentration within a range of concentration from 10 to 100 nM and the detection limit of this assay was 10 nM. Based on the principle for determination of H₂O₂, we develop a new strategy for assay of glucose by coupling with glucose oxidase-mediated reaction. The established methods were successfully used for determination of glucose levels in human sera, and the results obtained were in good agreement with commercially available method. Our method is at least 1 order of magnitude more sensitive than in the commercially available method. More importantly, our method described here can be extended to other assay designs using different oxidase enzymes, energy donors and energy acceptors, such as near-infrared (NIR)-to-visible upconversion nanoparticles and silicon and carbon QDs.


Crystal structure of DnaK protein complexed with nucleotide exchange factor GrpE in DnaK chaperone system: insight into intermolecular communication.
The conserved, ATP-dependent bacterial DnaK chaperones process client substrates with the aid of the co-chaperones DnaJ and GrpE. However, in the absence of structural information, how these proteins communicate with each other cannot be fully delineated. For the study reported here, we solved the crystal structure of a full-length Geobacillus kaustophilus HTA426 GrpE homodimer in complex with a nearly full-length G. kaustophilus HTA426 DnaK that contains the interdomain linker (acting as a pseudo-substrate), and the N-terminal nucleotide-binding and C-terminal substrate-binding domains at 4.1-Å resolution. Each complex contains two DnaKs and two GrpEs, which is a stoichiometry that has not been found before. The long N-terminal GrpE α-helices stabilize the linker of DnaK in the complex. Furthermore, interactions between the DnaK substrate-binding domain and the N-terminal disordered region of GrpE may accelerate substrate release from DnaK. These findings provide molecular mechanisms for substrate binding, processing, and release during the Hsp70 chaperone cycle.


Gastrin induces heparin-binding epidermal growth factor-like growth factor in rat gastric epithelial cells transfected with gastrin receptor.
Parietal cells express heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF). However, it is unknown whether HB-EGF mediates the trophic action of gastrin. The purpose of this study was to determine whether gastrin modulates the expression of HB-EGF, which mediates the proliferative effects of gastrin on gastric epithelial cells. RGM1 cells, a rat gastric epithelial cell line, were transfected with a human gastrin receptor complementary DNA. Gastrin induction of messenger RNAs (mRNAs) for EGF-related polypeptides was assayed by Northern blotting. Processing of cell surface-associated proHB-EGF and secretion of HB-EGF were determined by flow cytometry and Western blotting, respectively. Tyrosine phosphorylation of the EGF receptor was assayed by immunoprecipitation and Western blotting with an antiphosphotyrosine antibody. Cell growth was evaluated by [3H]thymidine incorporation. Gastrin induced expression of HB-EGF mRNA, processing of proHB-EGF, release of HB-EGF into the medium, and tyrosine phosphorylation of the EGF receptor. The growth-stimulatory effects of gastrin were partly inhibited by anti-rat HB-EGF serum and completely blocked by AG1478, an EGF receptor-specific tyrphostin. The findings suggest that HB-EGF at least partially mediates the proliferative effects of gastrin on gastric epithelial cells.


Author Correction: Elephant shark genome provides unique insights into gnathostome evolution.
An amendment to this paper has been published and can be accessed via a link at the top of the paper.


The normal limits, subclinical significance, related metabolic derangements and distinct biological effects of body site-specific adiposity in relatively healthy population.
The accumulation of visceral adipose tissue that occurs with normal aging is associated with increased cardiovascular risks. However, the clinical significance, biological effects, and related cardiometabolic derangements of body-site specific adiposity in a relatively healthy population have not been well characterized. In this cross-sectional study, we consecutively enrolled 608 asymptomatic subjects (mean age: 47.3 years, 27% female) from 2050 subjects undergoing an annual health survey in Taiwan. We measured pericardial (PCF) and thoracic peri-aortic (TAT) adipose tissue volumes by 16-slice multi-detector computed tomography (MDCT) (Aquarius 3D Workstation, TeraRecon, San Mateo, CA, USA) and related these to clinical characteristics, body fat composition (Tanita 305 Corporation, Tokyo, Japan), coronary calcium score (CCS), serum insulin, high-sensitivity C-reactive protein (Hs-CRP) level and circulating leukocytes count. Metabolic risk was scored by Adult Treatment Panel III guidelines. TAT, PCF, and total body fat composition all increased with aging and higher metabolic scores (all p<0.05). Only TAT, however, was associated with higher circulating leukocyte counts (ß-coef.:0.24, p<0.05), serum insulin (ß-coef.:0.17, p<0.05) and high sensitivity C-reactive protein (ß-coef.:0.24, p<0.05). These relationships persisted after adjustment in multivariable models (all p<0.05). A TAT volume of 8.29 ml yielded the largest area under the receiver operating characteristic curve (AUROC: 0.79, 95%CI: 0.74-0.83) to identify metabolic syndrome. TAT but not PCF correlated with higher coronary calcium score after adjustment for clinical variables (all p<0.05). In our study, we observe that age-related body-site specific accumulation of adipose tissue may have distinct biological effects. Compared to other adiposity measures, peri-aortic adiposity is more tightly associated with cardiometabolic risk profiles and subclinical atherosclerosis in a relatively healthy population.


Development of a Scale Based on Nursing Outcome Classification "Dignified Life Closure" (1307) to Assess End-of-Life Dignity of Patients in Care Homes for the Elderly.
To develop and pilot the DD-14 scale, a 14-indicator scale based on the Nursing Outcome Classification "Dignified life closure" (1307). Sixteen experts selected 14 indicators for Spanish populations. Six care home nurses piloted the scale in 50 terminal patients without cognitive impairment. Factorial and reliability analyses were performed and correlations were determined with dependency, symptomatology, and palliative care quality. DD-14 demonstrated high reliability (α = 0.916) and a stable factorial structure. It was not influenced by sex, age, or disease and correlated positively with the Barthel index (r = .622; p = .00) and negatively with the Palliative Outcome Scale (r = -.542;p = .00). DD-14 is a useful scale for evaluating end-of-life dignity. This instrument could be useful in planning nursing interventions.


Contribution of Carotid Bodies on Pulmonary Function During Normoxia and Acute Hypoxia.
Carotid bodies (CBs) are main peripheral chemoreceptors involved in breathing regulation. Despite the well-known role played by CBs on breathing control, the precise contribution of CBs on the regulation of lung mechanics remains controversial. Accordingly, we study changes in lung mechanics in normoxia (FiO2 21%) and hypoxia (FiO2 8%) in mice with or without functional CBs. For this, we used adult male mice that underwent sham or CB denervation (CBD) surgery. Compared to sham-operated mice, we found that CBD induced an increase in lung resistance (RL) while breathing normoxic air (sham vs. CBD, p < 0.05). Importantly, changes in RL were accompanied by an approximately threefold reduction in dynamic compliance (Cdyn). Additionally, end-expiratory work (EEW) was increased in normoxia in the CBD group. Contrarily, we found that CBD has no effect on lung mechanics during hypoxic stimulation. Indeed, RL, Cdyn, and EEW values in CBD mice were undistinguishable from the ones obtained in sham mice. Finally, we found that CBD induces lung parenchyma morphological alterations characterized by reduced alveoli space. Together our results showed that CBD progressively increases lung resistance at normoxic conditions and suggest that CB tonic afferent discharges are needed for the proper regulation of lung mechanics at rest.


Automatic detection of pulmonary nodules at spiral CT: clinical application of a computer-aided diagnosis system.
The aim of this study was to evaluate a computer-aided diagnosis (CAD) workstation with automatic detection of pulmonary nodules at low-dose spiral CT in a clinical setting for early detection of lung cancer. Eighty-eight consecutive spiral-CT examinations were reported by two radiologists in consensus. All examinations were reviewed using a CAD workstation with a self-developed algorithm for automatic detection of pulmonary nodules. The algorithm is designed to detect nodules with diameters of at least 5 mm. A total of 153 nodules were detected with at least one modality (radiologists in consensus, CAD, 85 nodules with diameter < 5 mm, 68 with diameter > or = 5 mm). The results of automatic nodule detection were compared to nodules detected with any modality as gold standard. Computer-aided diagnosis correctly identified 26 of 59 (38%) nodules with diameters > or = 5 mm detected by visual assessment by the radiologists; of these, CAD detected 44% (24 of 54) nodules without pleural contact. In addition, 12 nodules > or = 5 mm were detected which were not mentioned in the radiologist's report but represented real nodules. Sensitivity for detection of nodules > or = 5 mm was 85% (58 of 68) for radiologists and 38% (26 of 68) for CAD. There were 5.8+/-3.6 false-positive results of CAD per CT study. Computer-aided diagnosis improves detection of pulmonary nodules at spiral CT and is a valuable second opinion in a clinical setting for lung cancer screening despite of its still limited sensitivity.


Does initial and delayed heart rate predict mortality in patients with acute coronary syndromes?
Lower admission heart rate (HR) is known to predict favorable outcome in ST-elevation acute myocardial infarction. However, there are limited short-term and no long-term data available regarding the prediction value of the initial HR in patients with the full spectrum of acute coronary syndromes (ACS). In addition, it is unknown whether the HR obtained later during hospitalization for ACS (i.e., Day 2 or 3) remains prognostically valuable. The aim of this study was to investigate the utility of the initial and delayed HR in predicting outcome in patients with ACS. We examined mortality at 30 days and 10 months in 10,267 patients with ACS enrolled in the oral glycoprotein IIb/IIIa inhibition with Orofiban in Patients with Unstable coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 trial. Patients were stratified by HR and day from onset of ACS into the following groups: (1) HR < 60 beats/min, (2) HR 60-80 beats/min, (3) HR 80-100 beats/min, (4) HR > 100 beats/min; and HR obtained on (1) Day 1, (2) Day 2, and (3) Day 3. By univariate analysis, mortality at 30 days and at 10 months increased progressively with higher HR strata (1.4 vs. 1.6 vs. 2.3 vs. 5.6%, p < 0.001, and 2.6 vs. 4.2 vs. 6.5 vs. 11.8%, p < 0.001, respectively). Elevated HR remained associated with mortality irrespective of time from onset of ACS. Higher initial and delayed HR is highly predictive of higher short- and long-term mortality in patients with ACS. This is a simple marker that could be easily used in risk assessment.


Changes in the serum composition of free-fatty acids during an intravenous glucose tolerance test.
Recent studies suggest that measuring the free-fatty acids (FFA) during an intravenous glucose tolerance test (IVGTT) may provide information about the metabolic associations between serum FFA and carbohydrate and insulin metabolism. We evaluated the FFA profile during an IVGTT and determined whether this test changes the composition and concentration of FFA. An IVGTT was given to 38 severely obese persons before and 7 months after undergoing bariatric surgery and also to 12 healthy, nonobese persons. The concentration and composition of the FFA were studied at different times during the test. The concentration of FFA fell significantly faster during the IVGTT in the controls and in the severely obese persons with normal-fasting glucose (NFG) than in the severely obese persons with impaired-fasting glucose (IFG) or type 2 diabetes mellitus (T2DM) (P < 0.05). Significant differences were found in the time to minimum serum concentrations of FFA (control = NFG < IFG < T2DM) (P < 0.001). These variables improved after bariatric surgery in the three groups. The percentage of monounsaturated and n-6 polyunsaturated FFA in the control subjects and in the obese persons, both before and after surgery, decreased significantly during the IVGTT. In conclusion, during an IVGTT, severely obese persons with IFG or T2DM experienced a lower fall in the FFA than the severely obese persons with NFG and the controls, becoming normal after bariatric surgery.


Definition of carcinoma of the gastric cardia.
This study concerns the definition of carcinoma of the gastric cardia. The topography of the esophagogastric mucosal junction (mucosal EGJ) was investigated with an endoscope in 182 patients who were free of hiatal hernias, ulcers, and neoplasms in the esophagus and stomach. The relationship between the EGJ and the cardiac gland area was then examined histologically in 56 resected specimens containing intact EGJs and cardia gland areas. Furthermore the cancerous center was determined; the shortest distance between the cancerous center and the EGJ and the amount of esophageal invasion were measured in 102 resected carcinomas located close to the junction; the carcinomas contained the EGJ and were good enough for pathohistological examination. The EGJ was located 0.5 - 1.0 cm proximal to the His angle (the gastric cardia) in radiological and endoscopic examinations. Histologically the cardiac gland area was found to straddle the EGJ at a range of about 1 cm proximal and 2 cm distal to the junction. Among the upper stomach carcinomas, most of the tumors (87.5%) whose center was located within 2 cm from the EGJ invaded the esophagus. In conclusion, carcinoma of the gastric cardia is defined as a lesion with its center located within 1 cm proximal and 2 cm distal to the EGJ.


An alpha-numeric code for representing N-linked glycan structures in secreted glycoproteins.
Advances in high-throughput techniques have led to the creation of increasing amounts of glycome data. The storage and analysis of this data would benefit greatly from a compact notation for describing glycan structures that can be easily stored and interpreted by computers. Towards this end, we propose a fixed-length alpha-numeric code for representing N-linked glycan structures commonly found in secreted glycoproteins from mammalian cell cultures. This code, GlycoDigit, employs a pre-assigned alpha-numeric index to represent the monosaccharides attached in different branches to the core glycan structure. The present branch-centric representation allows us to visualize the structure while the numerical nature of the code makes it machine readable. In addition, a difference operator can be defined to quantitatively differentiate between glycan structures for further analysis. The usefulness and applicability of GlycoDigit were demonstrated by constructing and visualizing an N-linked glycosylation network.


Regioselective synthesis of 2-chloroquinoline based ethyl 4-(3- hydroxyphenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3- carboxylates and their in-silico evaluation against P. falciparum lactate dehydrogenase.
The reaction of various substituted 2, 4-dichloroquinolines with ethyl 4-(3-hydroxyphenyl)- 2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate was carried out in the presence of K2CO3 as a mild and efficient base at controlled temperature leading to novel 2-chloroquinoline based polyhydroquinoline with high regioselectivity. All the synthesized compounds were characterized using IR, NMR, Mass spectral data and then subjected to an in-silico analysis against P. falciparum lactate dehydrogenase.


Comparison of the prognostic factors of total en bloc spondylectomy and total piecemeal spondylectomy in patients with Enneking stage III giant cell tumor in the thoracic and lumbar spine.
To compare total en bloc spondylectomy with marginal margins against piecemeal spondylectomy with intralesional margins in the surgical treatment of Enneking stage III spinal giant cell tumor (GCT) in terms of local recurrence. A retrospective survival analysis of patients with Enneking stage III GCT who underwent TES with marginal margins or total piecemeal spondylectomy with intralesional margins was performed between January 2006 and April 2020. Local recurrence-free survival (LRFS) was the time between the date of surgery and recurrence. Factors with p-values < 0.05 in the univariate analysis were included in the multivariate analysis using proportional hazard analysis. Sixty patients (25 men and 35 women) with a mean age of 35.6 (range 11-71) years were included. The mean follow-up duration was 93 (range 24-198) months. Two patients were lost to follow-up 6 and 14 years after the procedure. Over a 10-year period, the recurrence rate was 13.3%. The 2-, 5-, and 10-year LRFS rates were 95%, 88%, and 78%, respectively. Univariate analysis identified total piecemeal spondylectomy and no adjuvant radiotherapy as prognostic factors for LRFS. Multivariate Cox-regression models showed a significant association between local recurrence and total piecemeal spondylectomy and no adjuvant radiotherapy. TES with marginal margins is better than total piecemeal spondylectomy with intralesional margins owing to its lower postoperative recurrence rate. Adjuvant radiotherapy should be administered to reduce postoperative recurrence rates.


An algebraic approach to the detection of multiple markers in complex neuronal systems.
An important class of neuroanatomical problems requires identification of neurons that contain two or more substances. Based on the additivity of neuronal elements that are independently labeled, a simple numerical approach may be applied to these problems. This approach provides a sensitive and viable alternative to direct multiple labeling of endogenous or transported neuronal markers.


The role of reactive phosphate species in the abatement of micropollutants by activated peroxymonosulfate in the treatment of phosphate-rich wastewater.
This study investigated the mechanisms of forming reactive species to degrade micropollutants through the activation of peroxymonosulfate (PMS) by phosphate, a prevalent ion in wastewater. Considering the density functional theory results, the formation of hydrogen bonds between phosphate and PMS molecules might be the crucial step in the overall reactions, which prefers producing ⋅OH and reactive phosphate species (RPS, namely H2PO4⋅, HPO4⋅-, and PO4⋅2-) to yielding SO4⋅-. Besides, in the phosphate (5 mM)/PMS system at pH = 8, HPO4⋅- was modeled to be the dominant radical with a steady-state concentration of 3.6 × 10-12 M, which was 666 and 773 times higher than those of ⋅OH and SO4⋅-. The contributions of 1O2, ⋅OH, SO4⋅-, and RPS to the micropollutant decomposition in phosphate/PMS were studied, and RPS were found to be selective for micropollutants with electron-donating moieties (such as phenolic and aniline groups). Additionally, the degradation pathways of bisphenol A, diclofenac, ibuprofen, and atrazine in phosphate/PMS were proposed according to the detected transformation products. Cytotoxicity analysis was carried out to evaluate the potential environmental impacts resulting from the degradation of micropollutants by phosphate/PMS. This study confirmed the significance of RPS for micropollutant degradation during PMS-based treatment in phosphate-rich scenarios.


Transcatheter Mitral Valve Repair-Beyond the EVEREST and COAPT Criteria.
Transcatheter mitral valve repair (TMVr) has emerged as a safe and effective alternative to conventional surgery in patients with primary and secondary mitral regurgitation, especially those at high surgical risk. This review summarises alternative indications for TMVr outside of the traditional criteria derived from the major randomised trials and focusses on less common mitral valve anatomies such as commissural prolapse and bileaflet prolapse, patients with mitral annuloplasty rings, as well as acutely unwell patients with papillary muscle rupture and/or cardiogenic shock. Specific technical challenges involved in treating such patient groups are summarised and described.


Young key populations left behind: The necessity for a targeted response in Mozambique.
The first exposure to high-risk sexual and drug use behaviors often occurs during the period of youth (15-24 years old). These behaviors increase the risk of HIV infection, especially among young key populations (KP)-men how have sex with men (MSM), female sex workers (FSW), and people who inject drugs (PWID). We describe the characteristics of young KP participants in the first Biobehavioral Surveillance (BBS) surveys conducted in Mozambique and examine their risk behaviors compared to adult KP. Respondent-driven sampling (RDS) methodology was used to recruit KP in three major urban areas in Mozambique. RDS-weighted pooled estimates were calculated to estimate the proportion of young KP residing in each survey city. Unweighted pooled estimates of risk behaviors were calculated for each key population group and chi-square analysis assessed differences in proportions between youth (aged less than 24 years old) and older adult KP for each population group. The majority of MSM and FSW participants were young 80.7% (95% CI: 71.5-89.9%) and 71.9% (95% CI: 71.9-79.5%), respectively, although not among PWID (18.2%, 95% CI: 13.2-23.2%). Young KP were single or never married, had a secondary education level or higher, and low employment rates. They reported lower perception of HIV risk (MSM: 72.3% vs 56.7%, p<0.001, FSW: 45.3% vs 24.4%, p<0.001), lower HIV testing uptake (MSM: 67.5% vs 72.3%, p<0.001; FSW: 63.2% vs 80.6%; p<0.001, PWID: 53.3% vs 31.2%; p = 0.001), greater underage sexual debut (MSM: 9.6% vs 4.8%, p<0.001; FSW: 35.2% vs 22.9%, p<0.001), and greater underage initiation of injection drug use (PWID: 31.9% vs 7.0%, p<0.001). Young KP also had lower HIV prevalence compared to older KP: MSM: 3.3% vs 27.0%, p<0.001; FSW: 17.2% vs 53.7%, p<0.001; and PWID: 6.0% vs 55.0%, p<0.001. There was no significant difference in condom use across the populations. There is an immediate need for a targeted HIV response for young KP in Mozambique so that they are not left behind. Youth must be engaged in the design and implementation of interventions to ensure that low risk behaviors are sustained as they get older to prevent HIV infection.


Discovery of small molecule inhibitors of ubiquitin-like poxvirus proteinase I7L using homology modeling and covalent docking approaches.
Essential for viral replication and highly conserved among poxviridae, the vaccinia virus I7L ubiquitin-like proteinase (ULP) is an attractive target for development of smallpox antiviral drugs. At the same time, the I7L proteinase exemplifies several interesting challenges from the rational drug design perspective. In the absence of a published I7L X-ray structure, we have built a detailed 3D model of the I7L ligand binding site (S2-S2' pocket) based on exceptionally high structural conservation of this site in proteases of the ULP family. The accuracy and limitations of this model were assessed through comparative analysis of available X-ray structures of ULPs, as well as energy based conformational modeling. The 3D model of the I7L ligand binding site was used to perform covalent docking and VLS of a comprehensive library of about 230,000 available ketone and aldehyde compounds. Out of 456 predicted ligands, 97 inhibitors of I7L proteinase activity were confirmed in biochemical assays ( approximately 20% overall hit rate). These experimental results both validate our I7L ligand binding model and provide initial leads for rational optimization of poxvirus I7L proteinase inhibitors. Thus, fragments predicted to bind in the prime portion of the active site can be combined with fragments on non-prime side to yield compounds with improved activity and specificity.


Elevated serum uric acid level is associated with adverse reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles: a retrospective cohort study.
Serum uric acid levels are elevated in polycystic ovary syndrome, however, the relationship between serum uric acid level and reproductive outcomes in women with polycystic ovary syndrome remains unclear. This study aimed to investigate the association between serum uric acid level and the reproductive outcomes in women with polycystic ovary syndrome undergoing in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles. This was a retrospective cohort study performed at a university-affiliated reproductive medicine center. A total of 1903 women with polycystic ovary syndrome undergoing their first in vitro fertilization or intracytoplasmic sperm injection embryo transfer cycles between January 2010 and January 2021 were initially included. The trends for reproductive outcomes in polycystic ovary syndrome across quartiles of serum uric acid levels were assessed. A logistic regression analysis was performed to obtain the odds ratios for in vitro fertilization outcomes based on the quartiles of serum uric acid with or without adjusting for potential confounding variables. Using generalized additive models, serum uric acid was further treated as its original continuous property to visualize its nonlinear relationship with in vitro fertilization outcomes. The live birth rate was the main outcome. After exclusions, a total of 883 women with polycystic ovary syndrome with their first fresh-embryo transfer cycles were included. In quartiles of serum uric acid levels, there was a significant decreasing trend in the live birth rate from the lowest quartile (Q1: 61.8%) to the highest (Q4: 45.9%) (Ptrend=.002). The percentage of low birthweight increased from Q1 (22.3%) to Q4 (31.7%) (Ptrend=.049). Compared with those in Q1, women in Q4 showed a significant lower probability of live birth and clinical pregnancy and a higher risk for low birthweight (all P<.05). Both the unadjusted and adjusted generalized additive models indicated that as the serum uric acid level increased, the probability of clinical pregnancy and the live birth rate exhibited an overall decreasing profile, and the risk for low birthweight showed an increasing profile. An elevated serum uric acid level is associated with decreased probabilities of live birth and clinical pregnancy and an increased risk for low birthweight in women with polycystic ovary syndrome. However, these associations may be confounded by other factors and more well-designed studies are needed to confirm these findings in the future.


Enhancing anaerobic methane production in integrated floating-film activated sludge system filled with novel MWCNTs-modified carriers.
Conductive materials can enhance anaerobic methane production by accelerating interspecies electron transfer between electroactive bacteria and methanogens. However, the daily loss or less specific surface area of small/big size of conductive materials always limits their application in anaerobic digestion. In this study, the conductive multi-walled carbon nanotubes (MWCNTs) (15 wt% and 20 wt%) were mixed with high-density polyethylene (HDPE) and novel conductive suspended carriers were prepared. Results showed the conductivity of the novel conductive suspended carriers increased by 1-2 orders of magnitude comparing with HDPE carriers, as well as the attached biomass improved from 3.93 g/m2 (HDPE carriers) to 5.82 g/m2 (15 wt% MWCNTs-modified carriers) and 6.67 g/m2 (20 wt% MWCNTs-modified carriers). Integrated floating-film activated sludge (IFFAS) filled with MWCNT-modified carriers showed significant advantages in chemical oxygen demand (COD) removal (removal efficiency increased by 3.6-37.2%) and methanogenic performance (cumulative methane increased by 12.28-62.91%) compared with the control reactor filled with conventional HDPE carriers when treating sodium propionate wastewater at the organic loading rates (OLR) of 11.3-26.3 kg COD/(m³∙d). SEM images and high-throughput sequencing results proved potential direct interspecies electron transfer (DIET) had been established successfully on the MWCNTs-modified carriers. The syntrophic electroactive bacteria (Geobacter, Thauera) and Methanotrix were enriched by 2.28-4.58% and 9.41-16.80% respectively owning to the addition of novel conductive carriers. This study proved IFFAS process filled with novel MWCNTs-modified suspended carriers showed great potential in establishing DIET to enhance anaerobic digestion in practical application.


The utilization of atrial sensing dipole in single lead implantable cardioverter defibrillator for detection of new-onset atrial high-rate episodes or subclinical atrial fibrillation: A systematic review and meta-analysis.
This meta-analysis aims to evaluate the performance of atrial sensing dipole in single lead implantable cardioverter defibrillator (VDD-ICD) recipients in particular diagnosing new-onset atrial high-rate episodes (AHREs) defined as rate threshold of 200 beats per minute, or subclinical atrial fibrillation (SCAF) defined as device-detected AF without symptoms. We comprehensively searched PubMed, Embase, and ClinicalTrials.gov. Studies comparing contemporary single- and dual-chamber ICD (VVI-/DDD-ICD) versus VDD-ICD were included. Restricted maximum likelihood method for random effect model and Mantel-Haenszel method for fixed effect model were used to estimate the effect size of new-onset AHREs, or SCAF detection in each group. Three prospective studies were identified and total of 991 participants were included. There were 330 (33.3%) in VDD-ICD and 661 (66.7%) in VVI-/DDD-ICD. Most (78%) participants were men. Median follow-up was from 365 days to 847 days. VDD-ICD has a higher likelihood of detecting AHREs or SCAF as compared to VVI-/DDD-ICD [(OR random effect : 2.6; 95% CI: 1.2, 5.8; p = .018); I-squared = 67.8%, p = .019]. This difference was more apparently seen in the comparison between VDD-ICD and VVI-ICD [(OR random effect: 3.8; 95% CI: 2.1, 6.6, p < .001), I-squared = 0.0%, p = .518]. The result is same as fixed effect. Rate of AHREs detection observed in VDD-ICD was not statistically different when compared to the only group with DDD-ICD from SENSE trial. In conclusion, this meta-analysis reveals that the use of floating atrial sensing dipole in VDD-ICD increases the detection of new-onset AHREs or SCAF when compared to VVI-ICD, with similar atrial sensing performance to DDD-ICD.


Immune-mediated disorders.
Paraneoplastic and autoimmune encephalitis comprise a group of immune-mediated disorders that are associated with different immune effector mechanisms. Classic paraneoplastic neurologic syndromes are triggered by an antitumor immune response. The disease is considered to result from a T-cell response; in addition, patients harbour high titers of autoantibodies against intracellular antigens that are considered as epiphenomenon but are useful diagnostic markers. Neuropathology consists of T-cell-dominated inflammation, marked neuronal loss, and microglial activation with upregulation of HLA-DR. In the last decade, an increasing number of diseases associated with autoantibodies against neuronal surface antigens have been described. There is strong evidence that these autoantibodies are pathogenic and the associated syndromes are generally termed as antineuronal autoimmune encephalitis. Patients typically present with limbic, multifocal, or diffuse encephalitis and respond to immunotherapy. Neuropathologic descriptions are restricted to few biopsy and autopsy specimens and show mild inflammatory infiltrates and microglial activation, together with reduced expression of the respective target antigens, immunoglobulin deposits, and a variable degree of complement activation. Other putative autoimmune disorders of the central nervous system include, among others, Rasmussen encephalitis, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS), acute cerebellitis, Susac syndrome, and Hashimoto encephalitis. While pathologic studies suggest an immune-mediated disease for Rasmussen encephalitis, CLIPPERS, acute cerebellitis, and Susac syndrome, neuropathologic descriptions of Hashimoto encephalitis are rare and the pathogenesis deserves further study.


Peptide Effectors in Phytonematode Parasitism and Beyond.
Peptide signaling is an emerging paradigm in molecular plant-microbe interactions with vast implications for our understanding of plant-nematode interactions and beyond. Plant-like peptide hormones, first discovered in cyst nematodes, are now recognized as an important class of peptide effectors mediating several different types of pathogenic and symbiotic interactions. Here, we summarize what has been learned about nematode-secreted CLAVATA3/EMBRYO SURROUNDING REGION-RELATED (CLE) peptide effectors since the last comprehensive review on this topic a decade ago. We also highlight new discoveries of a diverse array of peptide effectors that go beyond the CLE peptide effector family in not only phytonematodes but in organisms beyond the phylum Nematoda.


Three heritable responses to alcohol in a heterogeneous randomly mated mouse strain. Inferences for humans.
Alcohol-induced heart-rate change, open-field activity changes and sleeping time were found to be significantly heritable in mice. Heart rate and sleeping time may have parallels in man and mouse in their alcohol responses and genetics.


The interaction of Aβ42 peptide in monomer, oligomer or fibril forms with sphingomyelin/cholesterol/ganglioside bilayers.
Aβ42 peptide binds neuronal membranes and aggregates into plaques that are characteristic of Alzheimer's disease. Aβ42 peptide has been proposed to be generated in membrane (nano) domains in the liquid-ordered phase, ganglioside GM1 being a major facilitator of peptide binding to the membrane. The peptide exists in solution in various degrees of aggregation, either monomers, oligomers or fibrils, of which oligomers appear to be particularly toxic. The present study reports on the binding of Aβ42 peptide, in monomer, oligomer or fibril form, to model membranes (lipid vesicles or monolayers), composed of sphingomyelin and cholesterol in equimolar ratios, to which 1-5 mol% of different gangliosides were incorporated. Thermodynamic binding parameters obtained from calorimetric data indicate a strong tendency to bind the membrane (ΔG ≈ 7 kcal/mol peptide), in a process dominated in most cases by the increase in entropy. ΔG was virtually invariant with the ganglioside species and the aggregation state of the peptide. The Langmuir balance demonstrated the capacity of all peptide preparations to become inserted in lipid monolayers of any composition and initial π in the range 10-30 mN/m, although fibrils were less capable to do so than oligomers or monomers, their maximum initial π being ≈25 mN/m.


[Pelvic irradiation and hematopoietic toxicity: A review of the literature].
Pelvic bone marrow is the site of nearly 50% of total hematopoiesis. Radiation therapy of pelvic lymph node areas, and cancers located near the bony structures of the pelvis, exposes to hematological toxicity in the range of 30 to 70%. This toxicity depends on many factors, including the presence or absence of concomitant chemotherapy and its type, the volume of irradiated bone, the received doses, or the initial hematopoietic reserve. Intensity modulated radiation therapy allows the optimisation of dose deposit on at risk organs while providing optimal coverage of target volumes. However, this suggests that dose constraints should be known precisely to limit the incidence of radiation side effects. This literature review focuses firstly on pelvic lymph node areas and bony volumes nearby, then on the effects of irradiation on bone marrow and the current dosimetric constraints resulting from it, and finally on hematological toxicities by carcinologic location and progress in reducing these toxicities.


Aicardi-Goutières syndrome (AGS).
In 1984, Jean Aicardi and Françoise Goutières described 8 children showing both severe brain atrophy and chronic cerebrospinal fluid lymphocytosis, with basal ganglia calcification in at least one member of each affected family. The course was rapid to death or a vegetative outcome. Aicardi and Goutières correctly predicted that the disorder would be genetic, but emphasised that "some features, especially the pleocytosis, may erroneously suggest an inflammatory condition". The increased interferon-alpha in affected children (Pierre Lebon, Paris) mimicked congenital viral infection, but the associated chilblains (pernio) pointed to lupus erythematosus and an autoimmune mechanism. Genetic research led by Yanick Crow has clarified these puzzling relationships in Aicardi-Goutières syndrome, a syndrome that now includes conditions previously known as microcephaly-intracranial calcification syndrome, pseudo-TORCH and Cree encephalitis. At the time of writing, Crow's team has discovered that over 80% of families with Aicardi-Goutières syndrome have mutations in one of four nuclease genes, the exonuclease TREX1 and the genes for all three subunits of the ribonuclease H2 enzyme complex. Aicardi-Goutières syndrome is both genetically and phenotypically heterogeneous, with a range of severity from life-threatening perinatal illness to mild late infancy onset. All infants of whatever genotype have increased interferon-alpha in the first year of life and this appears to be the final common pathway that links Aicardi-Goutières syndrome, congenital virus infection and systemic lupus erythematosus.


Study of the pyrolysis of sludge and sludge/disposal filter cake mix for the production of value added products.
Slow and fast pyrolysis of sludge and sludge/disposal filter cake (FC) mix are performed to investigate the liquid and solid products for their use as value added products. The obtained slow pyrolysis liquid products separate in an oil, a water rich fraction and a valuable crystalline solid 5,5-dimethyl hydantoin. During fast pyrolysis, mainly an oil fraction is formed. Aliphatic acids and amides present in the water rich fractions can be considered as value added products and could be purified. The oil fractions have properties which make them promising as fuel (25-35 MJ/kg, 14-20 wt% water content, 0.2-0.6 O/C value), but upgrading is necessary. Sludge/FC oils have a lower calorific value, due to evaporation of alcohols present in FC. ICP-AES analyses reveal that almost none of the metals present in sludge or sludge/FC are transferred towards the liquid fractions. The metals are enriched in the solid fractions.


Spectrometric and voltammetric investigation of interaction of neutral red with calf thymus DNA: pH effect.
The interaction of neutral red (NR) with calf thymus DNA (CT DNA) was investigated by spectrometric (UV-vis, circular dichroism and fluorescence) and voltammetric techniques. It was shown that the interaction of NR with DNA depended on the values of R (R is defined as the ratio of the concentration of NR to that of CT DNA) and pH of the solution. NR intercalated into CT DNA base pairs at lower R value (R < 2.4) and following by NR aggregating along the helical surface of DNA at higher R value (R > 2.4) in pH 6.0 solution. Interestingly, we found that at lower R value, NR intercalated into CT DNA with its long axis perpendicular or parallel to the dyad axis of DNA in the solution of pH 6.0. While in pH 7.0 solution, NR bound with CT DNA through intercalation and electrostatic interactions. The electrochemical inactive complexes, NR-2CT DNA, 3NR-CT DNA, and NR-CT DNA were formed when NR interacted with nucleic acids in pH 6.0 and 7.2 solutions, respectively. The corresponding intrinsic binding constants for these complexes were obtained by UV-vis and fluorescence spectrometric methods, respectively. The CD spectra showed that the conformation of CT DNA was converted from right-handed B-DNA to left-handed Z-DNA due to the aggregating of NR along the surface of DNA in pH 6.0 solution, whereas a conversion from B-DNA to C-DNA was induced due to the interaction of DNA with NR in pH 7.2 solution. Finally, two binding modes of NR with CT DNA in aqueous with different values of pH were shown in the scheme.


Emissive ZnO@Zn3 P2 nanocrystals: synthesis, optical, and optoelectrochemical properties.
ZnO@Zn3 P2 quantum dots (QDs) are synthesized, with emission from yellow to red. Photoelectrochemical investigations reveal that the current and voltage of the QD-derivatized electrodes show a response upon illumination. A photocurrent of ca. 8 nA cm(-2) for a monolayer of ZnO@Zn3 P2 QDs deposited on indium tin oxide (ITO) electrode is recorded.


Tousled homolog, TLK1, binds and phosphorylates Rad9; TLK1 acts as a molecular chaperone in DNA repair.
The Tousled-like kinases are involved in chromatin assembly, DNA repair, transcription, and chromosome segregation. In this work, we show that overexpression of TLK1B hastens repair of double strand breaks (DSBs) in mouse cells. We have identified Rad9 as a protein interacting tightly with TLK1B. TLK1B phosphorylates hRad9 at S328, and the significance of this phosphorylation was addressed by expressing wild-type (WT) or mutant (S328A) hRad9 in mouse Rad9-null cells. Complementation with WT or mutant Rad9 restored the ability to survive ionizing radiation and doxorubicin, but the effect was greater for the WT protein. The S328A mutation had little effect on the level of 9-1-1 complex, but evidence shows that TLK1/1B functions to modulate the amount of 9-1-1 at DSBs. Rad9 competed with the chromatin assembly factor Asf1 for binding to TLK1B. TLK1B hastened the reassembly of nucleosomes adjacent to a DSB introduced with HO nuclease. This effect was also seen in cells expressing a kinase-dead TLK1B (KD), implicating that the kinase activity is dispensable for stimulation of chromatin remodeling at DSBs. Likewise, chromatin assembly on a plasmid was stimulated by addition of either TLK1B or KD. After the induction of DSB, occupancy of Rad9 adjacent to the break increased during repair while that of Asf1 decreased, and the effect was more pronounced in TLK1B-overexpressing cells. We propose that following genotoxic stress, TLK1/1B is first recruited to the DSB in a complex with Rad9. It then exchanges with Asf1 to promote nucleosomes eviction at the DSB and access of the repair machinery to unencumbered DNA.


Management of chest trauma in children.
Chest trauma in children is caused by high-energy blows, due in general to traffic accidents, that involve several other body regions. They occur mainly in the first decade of life and can be penetrating but are more often non-penetrating. Rib fractures and lung contusions, sometimes associated with pneumothorax or haemothorax, are the more usual injuries, but tracheobronchial rupture, cardiac, oesophageal or diaphragmatic injuries may also occur. These injuries are treated with supportive respiratory and haemodynamic measures, drainage of air or blood from the pleural space and, at times, surgical repair of the injured organ(s). Ruptures of the airway may be difficult to treat and occasionally require suture, anastomosis or resection. Oesophageal injuries can be treated conservatively with antibiotics, drainage and parenteral nutrition. Diaphragmatic tears should be repaired operatively. Overall mortality ranges from 6 to 20%. Mortality is high but this is mainly due to the associated presence of extra-thoracic trauma, and particularly to head injuries.


Degradation of polyethylene by Klebsiella pneumoniae Mk-1 isolated from soil.
The massive accumulation of polyethylene (PE) in the natural environment has caused persecution to the ecological environment. At present, the mechanism of microbial degradation of PE remains unclear, and the related enzymes for degrading PE need to be further explored. In this study, a strain of Klebsiella pneumoniae Mk-1 which can effectively degrade PE was obtained from the soil. The degradation performance of the strains was evaluated by weight loss rate, SEM, ATR/FTIR, WCA, and GPC. The key gene of PE degradation in the strain was further searched, which may be the laccase-like multi-copper oxidase gene. Then, the laccase-like multi-copper oxidase gene (KpMco) was successfully expressed in E.coli and its laccase activity was verified, which reached 85.19 U/L. The optimum temperature and pH of the enzyme are 45 °C and 4.0, respectively; it shows good stability at 30-40 °C and pH 4.5-5.5; Mn2+ and Cu2+ can activate the enzyme effect. After the enzyme was applied to the degradation of PE film, it was found that the laccase-like multi-copper oxidase did have a certain degradation effect on PE film. This study provides new strain and enzyme gene resources for the biodegradation of PE, thereby promoting the process of PE biodegradation.


Clinical efficacy and biomarker analysis of neoadjuvant atezolizumab in operable urothelial carcinoma in the ABACUS trial.
Antibodies targeting PD-1 or its ligand 1 PD-L1 such as atezolizumab, have great efficacy in a proportion of metastatic urothelial cancers1,2. Biomarkers may facilitate identification of these responding tumors3. Neoadjuvant use of these agents is associated with pathological complete response in a spectrum of tumors, including urothelial cancer4-7. Sequential tissue sampling from these studies allowed for detailed on-treatment biomarker analysis. Here, we present a single-arm phase 2 study, investigating two cycles of atezolizumab before cystectomy in 95 patients with muscle-invasive urothelial cancer (ClinicalTrials.gov identifier: NCT02662309). Pathological complete response was the primary endpoint. Secondary endpoints focused on safety, relapse-free survival and biomarker analysis. The pathological complete response rate was 31% (95% confidence interval: 21-41%), achieving the primary efficacy endpoint. Baseline biomarkers showed that the presence of preexisting activated T cells was more prominent than expected and correlated with outcome. Other established biomarkers, such as tumor mutational burden, did not predict outcome, differentiating this from the metastatic setting. Dynamic changes to gene expression signatures and protein biomarkers occurred with therapy, whereas changes in DNA alterations with treatment were uncommon. Responding tumors showed predominant expression of genes related to tissue repair after treatment, making tumor biomarker interpretation challenging in this group. Stromal factors such as transforming growth factor-β and fibroblast activation protein were linked to resistance, as was high expression of cell cycle gene signatures after treatment.


Statins in nonalcoholic fatty liver disease and steatohepatitis: updated review.
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that refers to the presence of hepatic steatosis without significant intake of alcohol. NAFLD is an asymptomatic disease that can progress to nonalcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma. The most common cause of mortality in patients with NAFLD or NASH is cardiovascular disease (CVD). Currently, the treatment of NAFLD focuses on gradual weight loss and life style modifications. However, multifactorial treatment of NAFLD or NASH risk factors may be needed to reduce the likelihood of these patients developing CVD. This review discusses the mechanisms that link hyperlipidemia and NAFLD. In addition, the review focuses on the safety and efficacy of statins in patients with NAFLD or NASH, and their effect on the extent of hepatic steatosis and fibrosis based on human studies.


Synergistic effects of combined treatment of 1,2-dichloroethane and high-dose ethanol on liver damage in mice and the related mechanisms.
Our previous studies have shown that the metabolism of 1,2-dichloroethane (1,2-DCE) mediated by CYP2E1 could result in oxidative damage in the liver of mice. In the current study, we further investigated the effects of combined treatment with 1,2-DCE and high dose ethanol on liver and the mechanisms since both of them can be metabolized by CYP2E1 in the liver. There are several novel findings in the current study. First, combined treatment of mice with 1,2-DCE and high-dose ethanol could synergistically upregulate both protein and mRNA levels of CYP2E1, which might aggravate liver damage through CYP2E1-mediated oxidative stress. Second, the combined treatment could also synergistically trigger NLRP3 inflammasome activation and inflammatory responses in the liver. Third, the combined treatment synergistically upregulated the antioxidant defence systems in response to oxidative stress, however the compensatory mechanisms of antioxidant defence systems appeared to be insufficient to protect liver damage in the mice. Finally, the upregulated CYP2E1 expression was confirmed by using its specific inhibitor to play the crucial roles in liver damage in the mice during the combined treatment.


Saints, demons, and faith - A review of the historical interaction between Christianity and epilepsy.
The view that epilepsy is caused by demonic possession prevailed throughout the Middle Ages and re-emerges in rare cases of misguided exorcisms even in modern Western societies. This review reflects on the biblical sources of the demonic understanding of seizures and the subsequent marginalization of people with epilepsy. While the development of science led to a decline in beliefs of supernatural causes of seizures, the link between Christianity and epileptology is sustained through recurrent considerations of epileptic phenomena among religious figures. The influence of epilepsy on the legacy of historical persons of Christianity should be regarded with caution because of limited clinical evidence in historical documents. However, it should be acknowledged that religious experiences, as well as general religiosity, can be important in modern-day epilepsy care as they are shown to have psychological, societal, and even clinical implications. Further studies should expand our knowledge on the contemporary importance of the Christian tradition for people with epilepsy.


A computerized analysis of the entire retinal ganglion cell population and its spatial distribution in adult rats.
In adult albino (SD) and pigmented (PVG) rats the entire population of retinal ganglion cells (RGCs) was quantified and their spatial distribution analyzed using a computerized technique. RGCs were back-labelled from the optic nerves (ON) or the superior colliculi (SCi) with Fluorogold (FG). Numbers of RGCs labelled from the ON [SD: 82,818+/-3,949, n=27; PVG: 89,241+/-3,576, n=6) were comparable to those labelled from the SCi [SD: 81,486+/-4,340, n=37; PVG: 87,229+/-3,199; n=59]. Detailed methodology to provide cell density information at small scales demonstrated the presence of a horizontal region in the dorsal retina with highest densities, resembling a visual streak.