Clinical phenotype and cytokine profile of adult IgA vasculitis with joint involvement.
Joint involvement can be observed during the course of adult IgA vasculitis (IgAV). However, clinical picture, prognosis, or pathophysiological data associated with this condition have been overlooked. We aimed to describe the clinical characteristics and outcome of IgAV patients with joint involvement and look to a specific cytokine profile. We analyzed clinical and biological data from a nationwide study that included adult IgAV patients. Presentation and outcomes of patients with or without joint involvement were compared at baseline and during follow-up. Plasma cytokine measurements of IgAV patients included in a prospective study were also analyzed using multiplex assays. Among 260 patients, 62% had joint involvement. Among them, rheumatological manifestations included arthralgia (100%) or arthritis (16%), mostly involving the knees and ankles. In multivariate analysis, patients with joint involvement, compared to those without, were younger (p = 0.002; OR 0.87; 95% CI 0.80-0.95) and showed more frequent gastrointestinal tract involvement (p = 0.012; OR = 2.08; 95% CI 1.18-3.67). However, no difference in terms of clinical response, relapse, end-stage renal disease, or death was observed between groups. Among 13 cytokines measured, plasma interleukin (IL)-1β level was higher in patients with joint involvement compared to those without (mean ± SEM IL-1β, 3.5 ± 1.2 vs. 0.47 ± 0.1 pg/ml; p = 0.024) or healthy controls (vs. 1.2 ± 0.5 pg/ml; p = 0.076). Joint involvement is frequent in adult IgAV and is associated with more frequent gastrointestinal involvement. Increased plasma IL-1β levels raise the question of targeting this cytokine in patients with chronic and/or refractory joint involvement. Key Points • Joint involvement in adult IgAV is a frequent manifestation. • Joint involvement is associated with more frequent gastrointestinal manifestations. • Interleukin-1β (IL-1β) might orchestrate joint inflammation in adult IgAV. • IL-1β might be a therapeutic target in patients with chronic and/or refractory joint involvement.


Cobiveco: Consistent biventricular coordinates for precise and intuitive description of position in the heart - with MATLAB implementation.
Ventricular coordinates are widely used as a versatile tool for various applications that benefit from a description of local position within the heart. However, the practical usefulness of ventricular coordinates is determined by their ability to meet application-specific requirements. For regression-based estimation of biventricular position, for example, a symmetric definition of coordinate directions in both ventricles is important. For the transfer of data between different hearts as another use case, the consistency of coordinate values across different geometries is particularly relevant. To meet these requirements, we compare different approaches to compute coordinates and present Cobiveco, a symmetric, consistent and intuitive biventricular coordinate system that builds upon existing coordinate systems, but overcomes some of their limitations. A novel one-way transfer error is introduced to assess the consistency of the coordinates. Normalized distances along bijective trajectories between two boundaries were found to be superior to solutions of Laplace's equation for defining coordinate values, as they show better linearity in space. Evaluation of transfer and linearity errors on 36 patient geometries revealed a more than 4-fold improvement compared to a state-of-the-art method. Finally, we show two application examples underlining the relevance for cardiac data processing. Cobiveco MATLAB code is available under a permissive open-source license.


Metacarpophalangeal joint injuries in fingers.
Although uncommon, injuries to the MP joints of fingers must not be ignored. A loss of function in even a single MP joint can seriously impair overall hand function. The potential dire consequences of these injuries can be avoided by an accurate diagnosis at the time of injury and the institution of appropriate treatment.


Gas chromatographic determination of D-/L-arabinitol ratio in healthy Polish children.
The D-/L-arabinitol enantiomers ratio (a marker of disseminated candidiasis of Candida species) in urine was determined by gas chromatography (GC) in 198 healthy Polish children ranging in age from 0 to 18 years. The urine samples were dry and trifluoroacetic anhydride (TFAA)-treated. Enantiomers derivatives were separated on a chiral column (beta-Dex 120, 60 m x 0.25 mm I.D.). A glass "solid-phase" injector and electron capture detector (ECD) were used. The ECD response was linear with correlation coefficients 0.999. The limit of detection was 0.02 micromol/l. Good results in terms of reproducibility, accuracy (RSD<10%, bias<6%), and linearity were obtained from real urine samples containing up to 400 micromol/l D-arabinitol. TFA-arabinitol derivatives in biological samples were stable from 1 to 5 days (depending on the arabinitol contents), while TFA-arabinitol standard derivatives were stable for 2 weeks. The identity of D- and L-arabinitol were confirmed by GC-MS analysis. The mean D-/L-arabinitol ratios ranged from 2.48 to 1.65 in the examined groups. The D-/L-arabinitol ratio was found to be exponentially regressive with age. A few cases of diagnosis of disseminated candidiasis by the GC method and confirmed by blood culture are described. The described GC method was also used for monitoring antifungal treatment of patients with disseminated candidiasis.


Rapid detection of rifampicin-resistant Mycobacterium tuberculosis by in-house, reverse line blot assay.
Drug resistance in tuberculosis is a significant problem in countries endemic for tuberculosis. A sensitive, specific, and high-throughput reverse line blot assay (RLBA) for the detection of genotypic resistance to rifampicin (RIF) was designed and evaluated. DNA sequencing done for 72 resistant isolates from Delhi, for baseline data, showed mutations within the rpoB core region in all RIF-resistant strains. The RLBA includes oligonucleotide probes specific for wild-type and mutant sequences, allowing sensitive detection of both genotypes in a single assay. The assay based on reverse hybridization principle simultaneously detects 13 different mutations affecting 6 independent codons, including the most prevalent mutations at positions 531 and 526. Application of the method to a panel of 292 MDR TB isolates and susceptible strains from 5 different cities in India showed 98% concordance with the sequencing results. This rapid, simple, economical, and highly sensitive assay provides a practical alternative to sequencing for genotypic evaluation of RIF resistance in Mycobacterium tuberculosis.


Physiology and methodology of chromium toxicity using alga Scenedesmus quadricauda as model object.
Physiological responses of Scenedesmus quadricauda to Cr(VI) and Cr(III) excess were studied in buffer with circumneutral pH (6.5). Total Cr content was similar in low (1 μM of both oxidation states) but higher in 10 μM Cr(VI) treatment and high accumulation potential was detected (80-82% and 41-65% in 1 and 10 μM treatments, respectively). Specific fluorescence indicator (6-((anthracen-9-yl) methyleneamino)-2H-chromen-2-one) confirmed partial reduction of Cr(VI) to Cr(III) under exposure conditions. Viability and chlorophyll autofluorescence were more depleted by Cr(VI) while Cr(III) stimulated increase in ROS and lipid peroxidation. Antioxidative enzyme activities showed significantly higher values in 10 μM treatments of both Cr oxidation states. Depletion of mitochondrial proteins was not reflected in alteration of total soluble proteins indicating sensitivity of this organelle to Cr and TTC test showed no clear oxidation state-related effect. In this view, "Cr(VI) is not more toxic than Cr(III)" at least for some parameters. Subsequent study with the application of 10 μM Cr(VI) confirmed that HEPES buffer is more suitable exposure solution for toxicological studied than water or inorganic salts (higher chlorophyll autofluorescence was observed) and pH 6.5 is more suitable than low or high pH (4.5 or 8.5) in terms of Cr uptake. Another known Cr(III) fluorescence indicator (naphthalimide-rhodamine) also confirmed partial reduction of Cr(VI) to Cr(III) at acidic pH but only traces were seen at alkaline pH.


Secretory autophagy-induced bladder tumour-derived extracellular vesicle secretion promotes angiogenesis by activating the TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis.
Tumour angiogenesis is an independent risk factor for bladder cancer (BCa) progression, but viable and promising antiangiogenic targets are understudied. Secretory autophagy has received increasing interest recently, while the roles and executing mechanisms in the tumour microenvironment (TME) remain unclear. Herein, we found that active cathepsin B (CTSB) was upregulated in tumour tissues and serum EVs of 241 BCa patients from four cohorts and was significantly associated with poor prognosis. Starving TME (STME)-induced conventional autophagy in BCa cells elevated active CTSB levels by facilitating the expression and nuclear translocation of NFATC2. In addition, STME-induced secretory autophagy simultaneously led to markedly increased secretion of LC3-conjugated EVs loaded with active CTSB (EV-CTSB) into the TME. The increased exogenous active CTSB in endothelial cells by directly ingesting EV-CTSB prominently activated the TPX2-mediated phosphorylation of the AURKA-PI3K-AKT axis, increased VEGFA expression, and promoted angiogenesis. Our findings not only verify that EV-CTSB can be a promising target for antiangiogenic strategies in bladder cancer, but also reveal a novel action pattern based on secretory autophagy-induced EV secretion which is enlightening to explore crosstalk in the TME from various perspectives.


Role of pneumolysin for the development of acute lung injury in pneumococcal pneumonia.
Acute respiratory failure is a significant complication of severe pneumococcal pneumonia. In a mouse model, we observed early-onset lung microvascular leakage after pulmonary infection with Streptococcus pneumoniae, and we hypothesized that the important virulence factor pneumolysin may be the direct causative agent. Controlled, in vivo, ex vivo, and in vitro laboratory study. Laboratory. Female mice, 8-12 wks old. Ventilated and blood-free perfused murine lungs were challenged with recombinant pneumolysin via the airways as well as via the vascular bed. In addition, we analyzed the impact of pneumolysin on electrical cell impedance and hydraulic conductivity of human umbilical vein endothelial cell (HUVEC) and alveolar epithelial cell (A549) monolayers. Aerosolized pneumolysin dose-dependently increased capillary permeability with formation of severe lung edema but did not affect pulmonary vascular resistance. Intravascular pneumolysin caused an impressive dose-dependent increase in pulmonary vascular resistance and in lung microvascular permeability. By immunohistochemistry, pneumolysin was detected mainly in endothelial cells of pulmonary arterial vessels, which concomitantly displayed strong vasoconstriction. Moreover, pneumolysin increased permeability of HUVEC and A549 monolayers. Interestingly, immunofluorescence of endothelial cell monolayers exposed to pneumolysin showed gap formation and moderate stress fiber generation. Pneumolysin may play a central role for early-onset acute lung injury due to severe pneumococcal pneumonia by causing impairment of pulmonary microvascular barrier function and severe pulmonary hypertension.


Development of integrated microfluidic platform coupled with Surface-enhanced Raman Spectroscopy for diagnosis of COVID-19.
Corona Virus Disease 19 (COVID-19) pandemic has created an alarming situation across the globe. Varieties of diagnostic protocols are being developed for the diagnosis of COVID-19. Many of these diagnostic protocols however, have limitations such as for example unacceptable no of false-positive and false-negative cases, particularly during the early stages of infection. At present, the real-time (quantitative) reverse transcriptase-polymerase chain reaction (RT-PCR) is considered the gold standard for COVID-19 diagnosis. However, RT-PCR based tests are complex, expensive, time consuming and involve pre-processing of samples. A swift, sensitive, inexpensive protocol for mass screening is urgently needed to contain this pandemic. There is urgent need to harness new powerful technologies for accurate detection not only of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) but also combating the emergence of pandemics of new viruses as well. To overcome the current challenges, the authors propose a diagnostic protocol based on Surface-enhanced Raman Spectroscopy (SERS) coupled with microfluidic devices containing integrated microchannels functionalized either with vertically aligned Au/Ag coated carbon nanotubes or with disposable electrospun micro/nano-filter membranes. These devices have the potential to successfully trap viruses from diverse biological fluids/secretions including saliva, nasopharyngeal, tear etc. These can thus enrich the viral titre and enable accurate identification of the viruses from their respective Raman signatures. If the device is successfully developed and proven to detect target viruses, it would facilitate rapid screening of symptomatic as well as asymptomatic individuals of COVID-19. This would be a valuable diagnostic tool not only for mass screening of current COVID-19 pandemic but also in viral pandemic outbreaks of future.


The relationship between psychological distress during pregnancy and birth weight for gestational age.
Fetal growth may be determined by genetic as well as environmental factors. Whether psychological distress during pregnancy influences fetal growth is a matter of debate. A prospective population-based study with repeated measures of psychological distress (General Health Questionnaire) during pregnancy, based on the use of questionnaires. Danish speaking women with singleton pregnancies attending antenatal care between August 1, 1989 and September 30, 1991 were eligible to the study (n = 8719). Of these women 5868 women (67%) completed all questionnaires. The main outcome measure was fetal growth (assessed as birth weight for gestational age (continuous)) and birth weight below the 10th percentile of birth weight for gestational age (light for gestational age (LGA) (dichotomous). Gestational age was calculated primarily from an early ultrasound scan. Confounders were controlled using multivariate statistical methods. Birth weight for gestational age and risk of delivering a LGA baby were not associated with psychological distress, neither distress in 16th week nor in 30th week of pregnancy. To the extent that fetal growth can be explored at birth, the results indicate that psychological distress does not influence fetal growth.


Living arrangements, activity participation and depression among older Chinese adults.
We examined the relationship among living arrangements, activity participation and depression and the mediating effects of activity participation on the relationship between living arrangements and depression. This was a cross-sectional study based on nationally representative data. 9647 older adults aged 60 years and over were recruited from the 2018 Chinese Longitudinal Healthy Longevity Survey. Three-step regression and mediation analysis methods were used. Compared with older adults living with family members, those living in institutions attended fewer activities and experienced higher depression rates, and those living alone attended more activities and experienced higher depression rates. In the group living with family members, living with a spouse was an important way to increase activity participation and reduce depression. Mediation analysis suggested that activity participation mediated the impact of living arrangements on depression. Attending more activities could alleviate depression for older adults who are living alone, living in institutions and living without a spouse. Our findings suggest an emphasis on the role of spouses and activity participation during depression interventions among older adults.


Detubulation abolishes membrane potential stabilization in amphibian skeletal muscle.
A recently reported stabilization ('splinting') of the resting membrane potential ( Em) observed in amphibian skeletal muscle fibres despite extracellular hyperosmotic challenge has been attributed to high resting ratios of membrane Cl- to K+ permeability ( P Cl/ P K) combined with elevations of their intracellular Cl- concentrations, [Cl-]i, above electrochemical equilibrium by diuretic-sensitive cation-Cl-, Na-Cl (NCC) and/or Na-K-2Cl (NKCC), co-transporter activity. The present experiments localized this co-transporter activity by investigating the effects of established detubulation procedures on Em splinting. They exposed fibres to introduction and subsequent withdrawal of 400 mM extracellular glycerol, high divalent cation concentrations, and cooling. An abolition of tubular access of extracellularly added lissamine rhodamine fluorescence, visualized by confocal microscopy, and of the action potential afterdepolarization together confirmed successful transverse (T-) tubular detachment. Fibre volumes, V , of such detubulated fibres, determined using recently introduced confocal microscope-scanning methods, retained the simple dependence upon 1/[extracellular osmolarity], without significant evidence of the regulatory volume increases described in other cell types, previously established in intact fibres. However detubulation abolished the Em splinting shown by intact fibres. Em thus varied with extracellular osmolarity in detubulated fibres studied in standard, Cl(-)-containing, Ringer solutions and conformed to simple predictions from such changes in assuming that intracellular ion content was conserved and membrane potential change DeltaEm was principally determined by the K+ Nernst potential. Furthermore, cation--Cl- co-transport block brought about by [Cl-]o or [Na+]o deprivation, or inclusion of bumetanide (10 microM) and chlorothiazide (10 microM) in the extracellular fluid gave similar results. When taken together with previous reports of significant Cl- conductances in the surface membrane, these findings suggest a model that contrastingly suggests a T-tubular location for cation--Cl- co-transporter activity or its regulation.


Detection of apple chlorotic leaf spot virus using a 5' nuclease assay with a fluorescent 3' minor groove binder-DNA probe.
The development of a real-time 5' nuclease RT-PCR assay for the detection of apple chlorotic leaf spot virus (ACLSV) from infected plant material is described. A short fluorogenic 3' minor groove binder-DNA hydrolysis probe was used to circumvent genome variability between isolates and target a short conserved sequence. The covalent attachment of the minor groove binder moiety at the 3' end of the probe increased the probe/target duplex stability and raised the melting temperature to a range suitable for real-time analysis. The method is rapid, sensitive and takes place within a single tube without post-PCR handling of the amplification products.


Pharmacological profile of CR3465, a new leukotriene CysLT1 receptor antagonist with broad anti-inflammatory activity.
CR3465 (L-Tyrosine, N-[(2-quinolinyl)carbonyl]-O-(7-fluoro-2-quinolinylmethyl) sodium salt) is a potent antagonist of [3H]leukotriene D4 ([3H]LTD4) binding to guinea pig lung preparations, its Ki (4.7+/-0.7 nM) being comparable with that of montelukast (5.6+/-0.6 nM). In tracheal strips from standard or ovalbumin-sensitized guinea pigs, CR3465 caused parallel rightward shifts in the concentration-response curves obtained with either LTD4 or antigen (pA(2), 8.74 and 8.15). Intravenous (i.v.) administration of the agent both antagonized (ED50, 9.9+/-1.9 microg/kg) and reverted LTD4 -induced bronchoconstriction of anesthetized guinea pigs. CR3465 reduced inflammatory infiltrates in the bronchoalveolar lavage fluid after antigen challenge of sensitized animals, and proved also active in inhibiting phosphodiesterase 3 (PDE3) and phosphodiesterase 4 (PDE4) activities exhibited by human platelets and neutrophils (IC50, 2.01+/-0.07 and 4.7+/-0.5 microM). In line with properties shown by phosphodiesterase inhibitors, CR3465 reduced the contractile response of guinea pig airways to histamine and decreased N-formyl-Met-Leu-Phe (fMLP)-induced degranulation of human neutrophils (IC50, 13.8 microM). Oral administration (20 mg/kg) of the compound in rats produced a significant (37%) ex vivo inhibition of tumor necrosis factor-alpha (TNF-alpha) release from lipopolysaccharide-stimulated whole blood. Pharmacokinetic data in the rat demonstrated approximately 100% bioavailability of the agent. We conclude that CR3465 represents a potent leukotriene CysLT1 receptor antagonist with enhanced effects, being also useful for counteracting spasmogenic and inflammatory stimuli other than those elicited by cysteinyl-leukotrienes (Cys-LTs).


[User perceptions of a public health program to reduce disability among Chilean older adults].
The Program "Más Adultos Mayores Autovalentes" (Más AMA) started in 2015 as a strategy for the prevention of disability among older adults. To describe the health benefits, from user's perspective, of the Functional Stimulation Component of the Más AMA program. Eleven focus groups including 97 participants of the Más AMA program were conducted in Northern Metropolitan Santiago municipalities. The benefits perceived by Más AMA participants were a reduction in loneliness and isolation, physical reactivation, engagement in activities, and the use of support resources within the community. The relationship with professionals working at Más AMA was described as highly satisfactory. The benefits of attending the Más AMA program from the point of view of their users are mainly related with social and affective dimensions, which contrast with the emphasis in physical and cognitive dimensions given by the technical orientation of the Más AMA program.


Exercise increases solid meal gastric emptying rates in men.
Gastric emptying rates of radiolabeled beef stew meals were measured in 10 healthy, young (median age = 27 years) male subjects on each of three randomly chosen study days. The subjects either (1) stood at rest, (2) walked on an exercise treadmill at 3.2 km/hr, or (3) at 6.4 km/hr during the study while gastric emptying was being monitored by externally positioned gamma cameras. Compared to the standing at rest study, exercise significantly increased gastric emptying (at rest emptying half-time (t1/2) = 72.6 +/- 7.6 (SEM) min; 3.2 km/hr t1/2 = 44.5 +/- 3.9 min, P = 0.0051; 6.4 km/hr t1/2 = 32.9 +/- 1.9 min, P = 0.0051). The 6.4 km/hr emptying time was significantly (P = 0.0249) faster than the 3.2 km/hr emptying time. Thus, the amount of exercise is a physiological factor that alters solid meal gastric emptying rates.


Structural Insights into the Mechanisms and Pharmacology of K2P Potassium Channels.
Leak currents, defined as voltage and time independent flows of ions across cell membranes, are central to cellular electrical excitability control. The K2P (KCNK) potassium channel class comprises an ion channel family that produces potassium leak currents that oppose excitation and stabilize the resting membrane potential in cells in the brain, cardiovascular system, immune system, and sensory organs. Due to their widespread tissue distribution, K2Ps contribute to many physiological and pathophysiological processes including anesthesia, pain, arrythmias, ischemia, hypertension, migraine, intraocular pressure regulation, and lung injury responses. Structural studies of six homomeric K2Ps have established the basic architecture of this channel family, revealed key moving parts involved in K2P function, uncovered the importance of asymmetric pinching and dilation motions in the K2P selectivity filter (SF) C-type gate, and defined two K2P structural classes based on the absence or presence of an intracellular gate. Further, a series of structures characterizing K2P:modulator interactions have revealed a striking polysite pharmacology housed within a relatively modestly sized (~70 kDa) channel. Binding sites for small molecules or lipids that control channel function are found at every layer of the channel structure, starting from its extracellular side through the portion that interacts with the membrane bilayer inner leaflet. This framework provides the basis for understanding how gating cues sensed by different channel parts control function and how small molecules and lipids modulate K2P activity. Such knowledge should catalyze development of new K2P modulators to probe function and treat a wide range of disorders.


["Art therapy could have the anthropological aim of opening up to the imagination, as a structuring and anticipatory future of a changing universe"].
Jean-Pierre Klein, honorary hospital psychiatrist and director of the French national institute of expression, creation, art and therapy, describes his discovery of art therapy or how the diversion of the imagination, through contact with the material, enables one to approach and symbolise one's problems without always being able to understand what the symbols evoke. Accompanied symbolisation in art therapy can indeed be sufficient. The evolution, from creation to creation, forms a transformation process without there necessarily being any interpretative deciphering. Interview with a pioneer of art therapy in France.


Production of collagenase by mouse peritoneal macrophages in vitro. Characterization of sites of cleavage of tropocollagen.
Macrophages from mineral oil-stimulated mice produce collagenase at a constant rate over several days in culture. Phagocytosis of latex does not increase production of enzyme. Gel electrophoretic and electron microscopic analyses indicate that the specificity of the macrophage enzyme is similar to that of other previously characterized mammalian collagenases.


Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93.
Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years. 1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy. Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three). Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer.


Doppler effect described by the solutions of the Cattaneo telegraph equation.
The Cattaneo telegraph equation for temperature with moving time-harmonic source is studied on the line and the half-line domain. The Laplace and Fourier transforms are used. Expressions which show the wave fronts and elucidate the Doppler effect are obtained. Several particular cases of the considered problem including the heat conduction equation and the wave equation are investigated. The quasi-steady-state solutions are also examined for the case of non-moving time-harmonic source and time-harmonic boundary condition for temperature.


Image-guided ovarian mass biopsy: efficacy and safety.
Image-guided needle biopsy represents a minimally invasive method for pathologic diagnosis of a mass. This study evaluates the diagnostic yield, accuracy, and safety of ovarian mass biopsy with combined core and fine-needle technique. Medical records of all women at least 18 years of age, referred from gynecologic oncology, who underwent image-guided ovarian mass biopsy from 2001 through 2011 were reviewed. Among 27 patients, ultrasound guidance was used in 13 (48%), six transabdominal and seven transvaginal; computed tomography guidance was used in 14 (52%), nine transabdominal and five transgluteal. Biopsy indications were suspected metastasis (n = 15; 56%), suspected ovarian cancer to be treated with neoadjuvant chemotherapy (n = 10; 37%), and relative contraindication to surgery (n = 2; 7%). Mean maximum lesion dimension was 9.9 cm (range, 2-23 cm), with solid composition in nine (33%), cystic in six (22%), and mixed in 12 (44%). Biopsy pathologic findings were compared versus those of the surgical specimen or, for masses that were not resected, versus the stability of benign masses and response to chemotherapy of malignant masses on follow-up. All biopsies yielded a diagnosis. No biopsy-related complications were noted. Eleven patients (41%) did not undergo lesion resection and were followed for an average of 28.8 months (range, 0.3-118.4 mo). In no patient did malignancy develop during clinical follow-up after a benign biopsy diagnosis. Sensitivity and specificity for diagnosis of malignancy were 100% ± 0 (19 of 19) and 88% ± 26 (seven of eight), respectively, for cancer detection. In nine patients (33%) with final pathologic diagnosis of epithelial ovarian cancer, tumor seeding was not observed during a mean follow-up of 44.6 months (range, 1.3-110.2 mo). Image-guided ovarian mass core needle biopsy results in a pathologic diagnosis of benign and malignant masses with high yield, accuracy, and safety.


Delaying anti-VEGF therapy during the COVID-19 pandemic: long-term impact on visual outcomes in patients with neovascular age-related macular degeneration.
To evaluate the outcomes of delayed intravitreal injections (IVIs) caused by the outbreak of coronavirus disease 2019 (COVID-19), in patients with neovascular age-related macular degeneration (nAMD). nAMD patients with scheduled IVIs between March 1st and April 30th, 2020 were stratified through a risk-based selection into a non-adherent group (NA-group) if they skipped at least one IVI and an adherent group (A-group) if they followed their treatment schedule. During the pandemic visit (v0), if a significant worsening of the disease was detected, a rescue therapy of three-monthly IVIs was performed. Multimodal imaging and best-corrected visual acuity (BCVA) findings were evaluated after 6 months (v6), compared between groups and with the visit prior the lockdown (v-1). Two hundred fifteen patients (132 females, mean age: 81.89 ± 5.98 years) delayed their scheduled IVI while 83 (53 females, mean age: 77.92 ± 6.06 years) adhered to their protocol. For both groups, BCVA at v0 was significantly worse than v-1 (mean 4.15 ± 7.24 ETDRS letters reduction for the NA-group and 3 ± 7.96 for the A-group) but remained stable at v6. The two groups did not significantly differ in BCVA trends after 6 months and neither for development of atrophy nor fibrosis. A risk-based selection strategy and a rescue therapy may limit the long-term outcomes of an interruption of the treatment protocol in patients with nAMD.


Molecular cloning and expression analysis of PDK family genes in Xenopus laevis reveal oocyte-specific PDK isoform.
Pyruvate dehydrogenase kinase (PDK) inactivates the multienzyme mitochondrial pyruvate dehydrogenase complex by the phosphorylation of three seryl residues in the pyruvate dehydrogenase moiety, and thus plays an important role in the control of glucose homeostasis. Genetically and biochemically distinct PDK family isozymes have been identified in mammalian species. In the present study, we demonstrate that the complete family of expressed PDK family genes in the tissues of the African clawed frog, Xenopus laevis, consists of four members, which are divided into two evolutionary groups. Xenopus PDKs (xPDKs) share an overall homology of about 70% to the human isoforms of PDK. The abundance of mRNAs for the four xPDK isoforms was analyzed by the real-time reverse transcriptase PCR technique in the various tissues of Xenopus laevis, including heart, lung, spleen, liver, kidney, skin, testis, oocytes, and eggs. Our data suggest that one of the xPDK isozymes can be referred to as an oocyte-specific xPDK. Functional differences between the xPDK isoforms are discussed, based on their different tissue-specific distributions and phylogenetic similarities to human PDKs.


Importance of plasma ghrelin levels with special reference to nutritional metabolism and energy expenditure in pediatric patients with severe motor and intellectual disabilities.
Nutritional metabolism is complex in pediatric patients with severe motor and intellectual disability (SMID), and therefore, appropriate estimation of the energy requirements is difficult. Focusing on ghrelin's role in energy metabolism regulation, we investigated plasma ghrelin levels in pediatric SMID patients and analyzed its nutritional significance as a regulatory marker of energy reserve. Fasting plasma total, acyl, and des-acyl ghrelin levels in 40 patients with SMID, including cerebral palsy (CP) (n = 20) and muscular disease (MD) (n = 8), and healthy controls (n = 13) were investigated. The correlations of plasma ghrelin levels with anthropometry, blood nutritional markers, energy intake, and resting energy expenditure (REE) measured with indirect calorimetry were analyzed. A p value < 0.05 was considered significant. SMID patients had significantly higher acyl ghrelin, and lower body mass index (BMI), z-scores of body weight (BW), body height and BMI, and albumin than controls. CP patients had significantly higher total and acyl ghrelin, z-score of the mid-upper arm circumference (MUAC), retinol-binding protein, transthyretin, creatinine, and glucose than MD patients. Total and acyl ghrelin in CP patients and des-acyl ghrelin in MD patients had significant negative correlations with MUAC and upper arm fat area. In CP patients, total and acyl ghrelin had significant positive correlations with REE/BW (kcal/kg), and total ghrelin was predictive of REE/BW (r2 = 0.625, p < 0.0001). An increase in acyl ghrelin observed in SMID patients possibly indicates energy reserve deficiency. In CP patients, total and acyl ghrelin inversely reflected total body fat mass, resulting in strongly positive correlations with REE/BW. The measurement of plasma ghrelin may be useful to assess nutritional metabolism and energy reserve in pediatric SMID patients, such as CP and MD patients.


Occupational Respiratory Allergy: Risk Factors, Diagnosis, and Management.
Occupational allergies are among the most common recorded occupational diseases. The skin and the upper and lower respiratory tract are the classical manifestation organs. More than 400 occupational agents are currently documented as being potential "respiratory sensitizers" and new reported causative agents are reported each year. These agents may induce occupational rhinitis (OR) or occupational asthma (OA) and can be divided into high-molecular weight (HMW) and low-molecular weight (LMW) agents. The most common occupational HMW agents are (glycol)proteins found in flour and grains, enzymes, laboratory animals, fish and seafood, molds, and Hevea brasiliensis latex. Typical LMW substances are isocyanates, metals, quaternary ammonium persulfate, acid anhydrides, and cleaning products/disinfectants. Diagnosis of occupational respiratory allergy is made by a combination of medical history, physical examination, positive methacholine challenge result or bronchodilator responsiveness, determination of IgE-mediated sensitization, and specific inhalation challenge tests as the gold standard. Accurate diagnosis of asthma is the first step to managing OA as shown above. Removal from the causative agent is of central importance for the management of OA. The best strategy to avoid OA is primary prevention, ideally by avoiding the use of and exposure to the sensitizer or substituting safer substances for these agents.


Three-dimensional ultrasound features of the polycystic ovary and the effect of different phenotypic expressions on these parameters.
The aim of this study was to quantify the three-dimensional (3D) ultrasound characteristics of ovaries in Caucasian women with polycystic ovarian syndrome (PCOS) and to examine if these values differed between different phenotypic forms. 3D pelvic ultrasound was performed in 40 women with PCOS and in 40 controls. Total ovarian volume, stromal volume and echogenicity and antral follicle count (AFC) were measured and ovarian blood flow was quantified using both 3D power Doppler and two-dimensional pulsed-wave Doppler. Women with PCOS had a higher AFC (median 16.3 versus 5.5 per ovary, P < 0.001) and ovarian volume (12.56 versus 5.66 ml, P < 0.001). Stromal volume (10.79 versus 4.69 ml, P < 0.001) and stromal vascularization (VI: 3.85 versus 2.79%, P < 0.001; VFI: 1.27 versus 0.85, P < 0.001) were also increased in women with PCOS. There were no significant differences in stromal echogenicity or pulsed-wave Doppler indices between women with PCOS and the controls. Among the women with PCOS, ovarian vascularity was significantly higher in 30 women who were hirsute compared with normoandrogenic women (FI: 33.94 versus 29.30, P < 0.05) and in 14 women with PCOS who were of normal weight compared with obese women (VI: 4.51 versus 3.25%, P < 0.05; VFI: 1.56 versus 1.22, P < 0.05). Based on 3D ultrasound, women with PCOS have an increased stromal volume and vascularity. Stromal vascularity is significantly higher in women with PCOS who are hirsute and of normal weight.


The use of a simple barrier system to exclude murine pathogens.
A simple barrier system was used successfully to exclude Mycoplasma pulmonis and Sendai virus from a conventional mouse room. 49 weeks after introduction of the barrier system of management Pasteurella pneumotropica was first isolated from animals in the room.


Anemia is associated with worse symptoms, greater impairment in functional capacity and a significant increase in mortality in patients with advanced heart failure.
This study aimed to evaluate the relationship between anemia and heart failure (HF) prognosis. Although it is known that chronic diseases, including HF, may be associated with anemia, the impact of hemoglobin (Hb) level on symptoms and survival in HF has not been fully defined. We analyzed a cohort of 1,061 patients with advanced HF (New York Heart Association [NYHA] functional class III or IV and left ventricular ejection fraction [LVEF] <40%) referred to a single center for evaluation and management. The Hb level was drawn at time of initial evaluation. Patients were divided into quartiles of Hb: Hb <12.3; Hb 12.3 to 13.6; Hb 13.7 to 14.8; Hb >14.8 g/dl. Mean Hb was 13.6, and values ranged from 7.1 to 19.0 g/dl. The Hb groups were similar in age, medication profile, LVEF, hypertension, diabetes, smoking status and serum sodium. Lower Hb was associated with an impaired hemodynamic profile, higher blood urea nitrogen and creatinine, and lower albumin, total cholesterol and body mass index. Patients in the lower Hb quartiles were more likely to be NYHA functional class IV (p < 0.0001) and have lower peak oxygen consumption (PKVO(2)) (p < 0.0001). Survival at one year was higher with increased Hb quartile (55.6%, 63.9%, 71.4% and 74.4% for quartiles 1, 2, 3 and 4, respectively). On multivariate analysis adjusting for known HF prognostic factors, low Hb proved to be an independent predictor of mortality (relative risk 1.131, confidence interval 1.045 to 1.224 for each decrease of 1 g/dl). In chronic HF, relatively mild degrees of anemia are associated with worsened symptoms, functional status and survival.


AdipoR2 inhibits human glioblastoma cell growth through the AMPK/mTOR pathway.
AdipoR2, which belongs to the seven-transmembrane-domain receptor family, has been shown to play an important role in the development of human tumours, but the underlying mechanisms are poorly understood. In this study, we found that AdipoR2 expression correlates with glioma grade. In addition, we also investigated the mechanisms behind the antiproliferative effects of AdipoR2 in U251 cells (a human glioma cell line) using colony formation and WST-8 growth assays. The U251 cell line was cultured in vitro. Western blotting was used to detect the expression of relevant proteins. Quantitative RT-PCR was used to detect AdipoR1 and AdipoR2 expression. Flow cytometry was used to detect cell cycle assay results. The gene expression profiles of glioma samples from the CGGA database were analysed by MATLAB and GSEA software. The AMPK/mTOR pathway plays a central role in the regulation of cell proliferation, differentiation and migration and may promote tumorigenesis. Therefore, we can control cancer progression by modulating the AMPK/mTOR pathway. However, there is no information on the relationship between AdipoR and AMPK/mTOR in central nervous system tumours such as GBM. In this study. We found 648 upregulated genes and 436 downregulated genes correlated with AdipoR2 expression in 158 glioma samples. GSEA suggested that AdipoR2 is a cell cycle-associated gene. The results of the flow cytometry analysis indicated that AdipoR2 induced G0/G1 cell cycle arrest in U251 cells. Furthermore, we identified the AMPK/mTOR signalling axis to be involved in AdipoR2-induced cell cycle arrest. Our results suggest that AdipoR2 may represent a novel endogenous negative regulator of GBM cell proliferation. These findings also suggest that AdipoR2 may be a promising therapeutic target in GBM patients.


Acute and subacute myelopathy.
Myelopathy is a term referring to any pathologic process affecting the spinal cord, and encompasses a broad spectrum of etiologies. The first step is to categorize myelopathy, according to the time to reach maximum deficit. Myelopathies are commonly classified as acute, subacute or chronic, for which the etiologies are totally different. Myelopathy is considered acute when the symptoms progress to their nadir in maximum 21 days after onset. Due to heterogeneity in pathogenesis, and the overlap in the clinical and imaging presentation among etiologies, acute myelopathy is considered as a diagnostic dilemma. A simple and efficient algorithm for timely identification of the underlying cause is thus useful. In this review, we provide a simplified approach for the differential diagnosis among all causes of acute myelopathies, and describe the principal clinical and imaging features of the main etiologies in adults, including recently characterized antibody-mediated myelitis, and its mimics.


Long QT and ST-T change associated with organophosphate exposure by aerial spray.
The relation between the electrocardiographic manifestation and the subjective symptoms accompanying organophosphate pesticide exposure caused by aerial spray was investigated. The study included 39 patients with a diagnosis of organophosphate poisoning, who visited A-clinic within 24h of exposure to aerial spray of organophosphate pesticide in Gumma Prefecture, from July 2001 to September 2001. Ages ranged from 3 to 82 years. Thirty-five patients were female. Three were diagnosed as severe, 11 moderate, and 25 mild, judged from the score of subjective symptoms. Electrocardiographic abnormalities were bradycardia (<50) 2; prolonged PQ interval 4; prolonged QTc interval (>430ms) 22; nonspecific ST-T change 35; supraventricular arrhythmia 13; and ventricular premature complex with R on T 1. Prolonged QTc interval developed in 2-3 severe cases, 4-11 moderate cases, and 16-25 mild cases. QT prolongation, ST-T change and arrhythmia were detected for some patients exposed to organophosphate by aerial spray.


[Iontophoresis of noradrenaline on neurons of the septal, preoptic and anterior hypothalamic areas].
In the Guinea-Pig, iontophoretic application of noradrenaline to neurones in the rostral hypothalsmus has an exciting, inhibitory effect, or is without effect. Responses to noradrenaline of antidromically activated neurones by stimulation of arcuate nucleus-median eminence region are discussed in relation to the liberation of LH.


An RNA ligand inhibits hepatitis C virus NS3 protease and helicase activities.
The hepatitis C virus non-structural protein 3 (HCV NS3) possesses both protease and helicase activities that are essential for viral replication. In a previous study, we obtained RNA aptamers that specifically and efficiently inhibited NS3 protease activity (G9 aptamers). In order to add helicase-inhibition capability, we attached (U)14 to the 3'-terminal end of a minimized G9 aptamer, DeltaNEO-III. NEO-III-14U was shown to inhibit the NS3 protease activity more efficiently than the original aptamer and, furthermore, to efficiently inhibit the unwinding reaction by NS3 helicase. In addition, NEO-III-14U has the potential to diminish specific interactions between NS3 and the 3'-UTR of HCV-positive and -negative strands. NEO-III-14U showed effective inhibition against NS3 protease in living cells.


Direct evidence for a role of working memory in the attentional blink.
Theories of selective attention often have a central memory component, which is commonly thought to be limited in some way and is thereby a potential bottleneck in the attentional process. There have been only a few attempts to validate this assertion, and they have produced mixed results. This study presents a specific examination of the link between working memory and attention by engaging active rather than passive memory operations. Two experiments are reported that provide evidence for the involvement of working memory in the attentional blink (AB) phenomenon. Memory loads of increasing size had a detrimental effect on attentional performance within the blink-sensitive interval, but not beyond. Speeded response requirements proved to modulate the AB, but were independent from the memory load effect. Theoretical implications for current models of selective attention are discussed.


The use of phosphonates in agriculture. Chemical, biological properties and legislative issues.
The Phosphorus (III) derivatives, named Phosphonates, include congeners with properties as fungicides that are effective in controlling Oomycetes. Examples are organic compounds like Fosetyl-Al [Aluminium tris-(ethylphosphonate)] and salts formed with the anion of phosphonic acid [(OH)2HPO] and Potassium, Sodium and Ammonium cations. According to IUPAC, the correct nomenclature for these compounds is "phosphonates", but in common language and scientific literature they are often named "phosphites", creating ambiguity. The European legislation restricts the use of phosphonates, with the ban for application in organic agriculture. However, phosphonate residues were detected in some organic products due to their addition to fertilizers allowed in organic agriculture. The legitimacy of this addition is controversial, as it is not evident if phosphonates have also a nutritional role in addition to their fungicidal properties. The new European Directive EU 1009/2019 resolves the problem by banning the phosphonates addition to fertilizers and placing a limit of 0.5% by mass for unintentional addition. However, an official method is not available for phosphonates determination in fertilizers and approval by the European Committee for Standardization (CEN) is necessary in a short time. This review presents an overview about the chemical, biological, analytical and legislative aspects of phosphonates and aims at providing: clarity on the correct nomenclature to avoid misunderstandings; the evaluation of phosphonates properties with the absence of a nutritional role, justifying the ban on adding to fertilizers; a summary of analytical techniques that could be considered by CEN to complete the analytical background for the agricultural use of phosphonates.


Modeling Human Volunteers in Multidirectional, Uni-axial Sled Tests Using a Finite Element Human Body Model.
A goal of the Human Research Program at National Aeronautics and Space Administration (NASA) is to analyze and mitigate the risk of occupant injury due to dynamic loads. Experimental tests of human subjects and biofidelic anthropomorphic test devices provide valuable kinematic and kinetic data related to injury risk exposure. However, these experiments are expensive and time consuming compared to computational simulations of similar impact events. This study aimed to simulate human volunteer biodynamic response to unidirectional accelerative loading. Data from seven experimental studies involving 212 volunteer tests performed at the Air Force Research Laboratory were used to reconstruct 13 unique loading conditions across four different loading directions using finite element human body model (HBM) simulations. Acceleration pulses and boundary conditions from the experimental tests were applied to the Global Human Body Models Consortium (GHBMC) simplified 50th percentile male occupant (M50-OS) using the LS-Dyna finite element solver. Head acceleration, chest acceleration, and seat belt force traces were compared between the experimental and matched simulation signals using correlation and analysis (CORA) software and averaged into a comprehensive response score ranging from 0 to 1 with 1 representing a perfect match. The mean comprehensive response scores were 0.689 ± 0.018 (mean ± 1 standard deviation) in two frontal simulations, 0.683 ± 0.060 in four rear simulations, 0.676 ± 0.043 in five lateral simulations, and 0.774 ± 0.013 in two vertical simulations. The CORA scores for head and chest accelerations in these simulations exceeded mean scores reported in the original development and validation of the GHBMC M50-OS model. Collectively, the CORA scores indicated that the HBM in these boundary conditions closely replicated the kinematics of the human volunteers across all loading directions.


[Evaluation of the aesthetic results perceived by patients after 3-port laparoscopic appendectomy].
The aesthetic result has lately been used in General Surgery as an argument for the development of new approaches. On numerous occasions attempts have been made to evaluate the perception that the patients themselves have after their operation by whatever approach, with the aim of finding where we differ and if there is a real option for improvement. The objective of this study was to analyse, using a simple questionnaire, the assessment of the aesthetic results as perceived by patients after appendectomy, and to attempt to determine what are the variables involved in an aspect so subjective as this. The variables collected were: age, sex, time since operation, infection of surgical wound, and presence of a drainage, as well as the responses on the aesthetic result of 70 patients who had a 3-port laparoscopic appendectomy. Infection of the surgical wound, as well as the age of the patients and the time since the operation determined statistically significant differences in their opinions as regards the number, size and overall aesthetic result of the laparoscopic appendectomy. The median overall satisfaction of the aesthetic result was 9 on a scale from 0 to 10. The assessment of the aesthetic result by patients after a 3-port laparoscopic appendectomy is good and is difficult to improve. It is recommended to prevent infection of the three ports after the intervention to obtain better results.


Eugenol alleviates Salmonella Typhimurium-infected cecal injury by modulating cecal flora and tight junctions accompanied by suppressing inflammation.
Salmonella enterica serovar Typhimurium (ST) mainly exists in poultry and poultry related products, which are common sources of human salmonellosis. So, ST is an important zoonotic pathogen that threatens public health and safety. Eugenol has been noted for its antibacterial and anti-inflammatory properties, and it is expected to develop into an antibacterial therapy in vivo. Herein, the effects of eugenol against ST infection in terms of intestinal flora, cecal tight junction, and cecal inflammation in broilers was evaluated in this study. The results showed that oral eugenol pretreatment obviously relieved the histopathological changes and ultrastructural injury of cecum caused by ST infection. Further analysis found that eugenol lessened the number of ST in the cecum, restrained Proteobacteria and Ruminococcus, and kept the ratio of Firmicutes to Bacteroidetes (F/B), improved the relative abundance of Alistipes compared to the infection control. Moreover, eugenol sustained the expression of ZO-1, claudin-1, and occluding tight junction proteins, reduced the mRNA levels of myeloid differentiation factor 88 (MyD88), toll-like receptor-4 (TLR4) and inducible nitric oxide synthesis (iNOS), suppressed the phosphorylation of p65 and IκBα in the NF-κB signaling pathway, as well as the mRNA levels of TNF-α, IL-1β, IL-2, and IL-18 in the cecum tissue. Taken together, eugenol could protect broilers against ST infection via maintaining intestinal flora, tight junctions involved in mucosal barrier function, then accordingly limiting the excessive inflammation, finally contributed to improving relative weight gains and survival rates of broilers.


[Clinical diagnosis of frequent skin tumors].
Some clinical differential diagnostic aspects of frequent or otherwise important skin tumors and precancerous lesions, grouped after their gross nodular or ulcerated, papillomatous or flat appearances, are compiled.


miR-196 regulates axial patterning and pectoral appendage initiation.
Vertebrate Hox clusters contain protein-coding genes that regulate body axis development and microRNA (miRNA) genes whose functions are not yet well understood. We overexpressed the Hox cluster microRNA miR-196 in zebrafish embryos and found four specific, viable phenotypes: failure of pectoral fin bud initiation, deletion of the 6th pharyngeal arch, homeotic aberration and loss of rostral vertebrae, and reduced number of ribs and somites. Reciprocally, miR-196 knockdown evoked an extra pharyngeal arch, extra ribs, and extra somites, confirming endogenous roles of miR-196. miR-196 injection altered expression of hox genes and the signaling of retinoic acid through the retinoic acid receptor gene rarab. Knocking down rarab mimicked the pectoral fin phenotype of miR-196 overexpression, and reporter constructs tested in tissue culture and in embryos showed that the rarab 3'UTR is a miR-196 target for pectoral fin bud initiation. These results show that a Hox cluster microRNA modulates development of axial patterning similar to nearby protein-coding Hox genes, and acts on appendicular patterning at least in part by modulating retinoic acid signaling.


Variation in Oophorectomy Rates for Children with Ovarian Torsion across US Children's Hospitals.
In this multicenter study of 1783 children diagnosed with ovarian torsion from 2012 to 2017, 402 children (22.5%) underwent oophorectomy. The odds of oophorectomy were higher in children under 11 years of age, children with public insurance, and children with complex chronic conditions. Future efforts should target a preservation-first approach.


[Population structure of Volga Tatars inferred from the mitochondrial DNA diversity data].
The data on mitochondrial DNA (mtDNA) variation in two populations of Volga Tatars, representing the population of Buinsk and Aznakaevo districts of the Republic of Tatarstan are presented. Comparative analysis of the data on mtDNA variation in the populations of Eastern Europe showed that Volga Tatars were characterized by low interpopulation differentiation (F(ST) = 0.33%), while the level of interethnic differentiation in Eastern Europe is 1.8%. Genetic similarity of Tatars from the eastern regions of Tatarstan to Bashkirs, as well as of Tatars from western regions to Chuvashes, with whom they share territorial borders, was revealed. Positive correlation between population genetic structure in Eastern Europe and linguistic affiliation of the ethnic groups studied was observed.


Effect of electroconvulsive shock on the somatosensory evoked potential in the rat.
The effect of electroconvulsive shock (ECS) on the cortical somatosensory evoked potential (SEP) was studied in 25 male rats. SEPs were recorded after stimulation of the contralateral forepaw. Animals were curarized and artificially ventilated but not anesthetized. The magnitude of the ECS was 80 mA for 600 ms which produced tonic-clonic convulsions lasting an average 54 s in noncurarized control animals. SEPs were recorded during the ictal period and then at intervals for 20 min. ECS initially caused the total abolition of all components of the SEP implying a significant but transient effect on activity propagated in specific and also possibly diffuse somatosensory pathways. The reappearance of the SEP coincided with the cessation of convulsive movements and the return of the corneal reflex. The return of the waveform to near baseline condition corresponded to the regaining of the righting reflex at approximately 3 min in the control animals. The most persisting change in the SEP waveform was in the shape of the late high-amplitude component (N2) which may reflect activity in the reticular formation. Following ECS, N2 reappeared with a peak latency notably decreased (approximately 1 ms) in comparison with the mean baseline recording. There was also an attenuation in the amplitude of N2 which remained significantly depressed (at less than 50% of mean baseline amplitude) throughout the post-ECS recording period. The results are compared with the relatively few studies of the acute effects of ECS on evoked potentials in psychiatric patients and also with a neuroendocrine theory which argues that the principal site and mode of action of ECS lies in the diencephalon.


Continuing the Original Stanford Sleep Surgery Protocol From Upper Airway Reconstruction to Upper Airway Stimulation: Our First Successful Case.
In 1993, a surgical protocol for dynamic upper airway reconstruction in patients with obstructive sleep apnea (OSA) was published, and it became commonly known as the Stanford phase 1 and 2 sleep surgery protocol. It served as a platform on which research and clinical studies have continued to perfect the surgical care of patients with OSA. However, relapse is inevitable in a chronic condition such as OSA, and a subset of previously cured surgical patients return with complaints of excessive daytime sleepiness. This report describes a patient who was successfully treated with phase 1 and 2 operations more than a decade previously. He returned at 65 years of age with relapse of moderate OSA, and after workup with polysomnography and drug-induced sleep endoscopy, he underwent upper airway stimulation of the hypoglossal nerve that resulted in a cure of OSA. This case shows why upper airway stimulation is an appropriate option for patients with OSA relapse, after previously successful maxillomandibular advancement.


Immune-Related Cerebellar Ataxia: A Rare Adverse Effect of Checkpoint Inhibitor Therapy.
Immune checkpoint inhibitors (ICIs) have led to a revolution in cancer management, mainly due to lasting long-term durable responses in a subset of patients with metastatic solid tumours (Gettinger et al. in JCO 36(17):1675-1684, 2018). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological immune-related adverse events (irAEs) has increased (2). Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs (Johnson et al. in J Immuno Cancer 7(1):134, 2019; Wang et al. in JAMA Oncol 4(12):1721, 2018). Small-cell lung cancer (SCLC) is common cause of neurologic paraneoplastic syndrome (Sebastian et al. in J Thorac Oncol 14(11):1878-1880, 2019). Nevertheless, the distinction between neurologic iRAEs and paraneoplastic neurological syndromes (PNSs) in patients with SCLC treated by ICIs remains challenging (Williams et al. JAMA Neurol 73(8):928, 2016). As immunotherapy is gradually being applied for the treatment of a large range of solid tumours, the incidence of neurological autoimmune adverse events has increased. Neurologic toxicities that result in high morbidity rates and even mortality have emerged as serious complications of ICIs and have yet to be fully understood. We report a case of an immune induced cerebellar ataxia in a 47 year-old small-cell neuroendocrine carcinoma patient undergoing checkpoint blockade by atezolizumab, a programmed cell death-1 ligand (PDL-1) inhibitor. After 4 cycles of immunotherapy, the patient presented with kinetic and static cerebellar syndrome leading to the diagnosis of TRIM9-Abs ICI-related cerebellar irAE. Therapeutic management was discussed in multidisciplinary meetings in the lack of therapeutic guidelines. There was no clinical improvement. Because of high morbidity and no treatment evidence, neurologic symptoms developing under ICI require early diagnosis and may indicate the need for definitive treatment discontinuation.


Patterns of Pediatric Palliative and End-of-Life Care in Neonatal Intensive Care Patients in the Southern U.S.
Despite high rates of mortality among infants in the Southern U.S., little is known about the timing of pediatric palliative care (PPC), the intensity of end-of-life care, and whether there are differences among sociodemographic characteristics. To describe PPC patterns and treatment intensity during the last 48 hours of life among neonatal intensive care unit (NICU) patients in the Southern U.S. who received specialized PPC. Medical record abstraction of infant decedents who received PPC consultation in two NICUs (in Alabama and Mississippi) from 2009 to 2017 (n = 195) including clinical characteristics, palliative and end-of-life care characteristics, patterns of PPC, and intensive medical treatments in the last 48 hours of life. The sample was racially (48.2% Black) and geographically (35.4% rural) diverse. Most infants died after withdrawal of life-sustaining interventions (58%) and had do not attempt resuscitation orders documented (75.9%); very few infants enrolled in hospice (6.2%). Initial PPC consult occurred a median of 13 days after admission and a median of 17 days before death. Infants with a primary diagnosis of genetic or congenital anomaly received earlier PPC consultation (P = 0.02) compared to other diagnoses. In the last 48 hours of life, NICU patients received intensive interventions including mechanical ventilation (81.5%), CPR (27.7%) and surgeries or invasive procedures (25.1%). Black infants were more likely to receive CPR compared to White infants (P = 0.04). Overall, PPC consultation occurred late in NICU hospitalizations, infants received high-intensity medical interventions in the last 48 hours of life, and there are disparities in intensity of treatment interventions at end of life. Further research is needed to explore if these patterns of care reflect parent preferences and goal concordance.


Bile plug syndrome: successful management with a mucolytic agent.
Common bile duct obstruction, in an infant with bile plug syndrome, was relieved at surgery with a mucolytic agent, after an unsuccessful attempt at clearing the biliary tree with saline irrigation. This procedure obviated choledochotomy in this patient, and may be of use in other infants with ductal obstruction complicating the inspissated bile, associated with gut rest, parenteral nutrition, or diuretic therapy.


New technologies for burn wound closure and healing--review of the literature.
Methods for handling burn wounds have changed in recent decades. Increasingly, aggressive surgical approach with early tangential excision and wound closure is being applied leading to improvement in mortality rates of burn victims. Autografts from uninjured skin remain the mainstay of treatment. Autologous skin graft, however, has limited availability and is associated with additional morbidity and scarring. Severe burn patients invariably lack sufficient adequate skin donor sites requiring alternative methods of skin replacement. The present review summarizes available replacement technologies.


Antenatal education to increase exclusive breastfeeding: a randomized controlled trial.
To evaluate the effectiveness of a professional one-to-one antenatal breastfeeding support and education intervention on the exclusivity and duration of breastfeeding. A total of 469 primiparous women who attended the antenatal clinics of two geographically distributed public hospitals in Hong Kong were randomized to receive either standard antenatal care or a one-to-one antenatal breastfeeding support and education session. The primary outcome was the prevalence of exclusive breastfeeding at 6 weeks postpartum. Secondary outcomes were the prevalence of exclusive breastfeeding at 3 and 6 months postpartum as well as the overall duration of any and exclusive breastfeeding across the first 6 months postpartum. The exclusive breastfeeding rate in the intervention group was 37.8% at 6 weeks postpartum compared with 36.4% in the standard care group (P=.77; 95% confidence interval [CI] -0.08 to 0.11). There were no significant differences between the two treatment groups in exclusive breastfeeding rates at 3 and 6 months or in the overall duration of any (hazard ratio [HR] 1.11, 95% CI 0.88-1.40] or exclusive breastfeeding (HR 0.96, 95% CI 0.79-1.17). The study had a least 80% power to detect a 50% increase in the rate of exclusive breastfeeding at 6 weeks postpartum. In a setting with a high breastfeeding initiation rate, one-to-one antenatal breastfeeding support and education did not increase the exclusivity or duration of breastfeeding. ClinicalTrials.gov, www.clinicaltrials.gov, NCT01648114.


TFP5 attenuates cyclin-dependent kinase 5-mediated islet β-cell damage in diabetes.
Islet β-cell damage and dysfunction represent the pathophysiological basis of diabetes. Excessive activation of cyclin-dependent kinase 5 (CDK5) is involved in the pathogenesis of type 2 diabetes mellitus (T2DM), although the exact mechanism remains unclear. Therefore, this study investigated the role of a CDK5 inhibitor (TFP5) in islet β-cell damage under diabetic conditions by regulating the expression of CDK5 in vitro and in vivo. CDK5 was upregulated under high glucose conditions in vivo and in vitro, which resulted in inflammation, oxidative stress, and apoptosis of islet β-cells, thereby decreasing insulin secretion. However, TFP5 treatment inhibited the overexpression of CDK5; reduced the inflammatory response, oxidative stress, and apoptosis of islet β cells; and restored insulin secretion. In conclusion, CDK5 is involved in islet β-cell damage under high glucose conditions, and TFP5 may represent a promising candidate for the development of treatments for T2DM.


Bifunctional Z-Scheme Ag/AgVO3/g-C3N4 photocatalysts for expired ciprofloxacin degradation and hydrogen production from natural rainwater without using scavengers.
To maximize the employment of sustainable solar energy in treating the recalcitrant pollutant and hydrogen energy production, the development of a highly efficient photocatalyst is desirable. Herein, a Z-scheme Ag/AgVO3/g-C3N4 photocatalyst was synthesized via a wet-impregnation method. The amount of Ag/AgVO3 deposited onto g-C3N4 has a significant effect on the photocharge carrier separation and migration of the as-developed Z-scheme photocatalyst. It was found that 0.5 wt % Ag/AgVO3/g-C3N4 photocatalyst exhibited a profound photocatalytic degradation performance with 82.6% ciprofloxacin removal and 3.57 mmol/h of hydrogen produced from natural rainwater under visible-light irradiation. Additionally, the apparent quantum efficiency (AQE) of this sample was 9.95% at 420 nm which is four times higher than the pure sample. The remarkable photocatalytic performance was attributed to the enhanced crystallographic structure, evidently from the XRD and XPS analysis. Moreover, the intimate contact between Ag/AgVO3 and g-C3N4 nanoparticles allows the smooth photocharge carrier separation and migrations, resulting in superior photocatalytic performance in comparison to the pure samples. Interestingly, the profound photocatalytic activity demonstrated here was achieved without the addition of any sacrificial reagents. This work demonstrates the feasibility of utilizing visible-light-driven photocatalysts in treating the recalcitrant antibiotic pollutants and producing hydrogen from natural rainwater.


Molecular characterisation and morphological description of two new species of Hepatozoon Miller, 1908 (Apicomplexa: Adeleorina: Hepatozoidae) infecting leukocytes of African leopards Panthera pardus pardus (L.).
The African leopard Panthera pardus pardus (L.) is currently listed as a vulnerable species on the IUCN (International Union for the Conservation of Nature) red list of threatened species due to ongoing population declines. This implies that leopard-specific parasites are also vulnerable to extinction. Intracellular apicomplexan haemoparasites from the genus Hepatozoon Miller, 1908 have been widely reported from wild carnivores in Africa, including non-specific reports from leopards. This paper describes two new haemogregarines in captive and wild leopards from South Africa and provides a tabular summary of these species in relation to species of Hepatozoon reported from mammalian carnivores. Blood was collected from nine captive and eight wild leopards at various localities throughout South Africa. Thin blood smears were Giemsa-stained and screened for intraleukocytic haemoparasites. Gamont stages were micrographed and morphometrically compared with existing literature pertaining to infections in felid hosts. Haemogregarine specific primer set 4558F and 2733R was used to target the 18S rRNA gene for molecular analysis. Resulting sequences were compared to each other and with other available representative mammalian carnivore Hepatozoon sequences from GenBank. Two species of Hepatozoon were found in captive and wild leopards. Of the 17 leopards screened, eight were infected with one or both morphologically and genetically distinct haemogregarines. When compared with other species of Hepatozoon reported from felids, the two species from this study were morphometrically and molecularly distinct. Species of Hepatozoon from this study were observed to exclusively parasitize a particular type of leukocyte, with Hepatozoon luiperdjie n. sp. infecting neutrophils and Hepatozoon ingwe n. sp. infecting lymphocytes. Phylogenetic analysis showed that these haemogregarines are genetically distinct, with Hepatozoon luiperdjie n. sp. and Hepatozoon ingwe n. sp. falling in well supported separate clades. To our knowledge, this is the first morphometric and molecular description of Hepatozoon in captive and wild African leopards in South Africa. This study highlights the value of using both morphometric and molecular characteristics when describing species of Hepatozoon from felid hosts.


Assessing subclinical inflammation by peroxidase detection in patients with pressure ulcers.
This study aimed to examine the superiority of peroxidase detection of macroscopic observations using rat wounds, and to test the external validity of the peroxidase analysis in pressure ulcers (PU) in humans. In the animal study, rat wounds were analysed. A cross-sectional study analysed, by wound blotting, exudate samples from full-thickness PUs. Peroxidase activity was divided into two groups (ring and non-ring signals). Scores in the 'inflammation/infection' and 'necrotic tissue' components of DESIGN, a classification tool of PUs, were compared between the groups. In the animal study, 20 rat wounds were assessed and in the clinical study, 62 samples were collected from 26 full-thickness PUs of 21 patients aged ≥ 65 years. In the animal study, five of six wounds with clinical inflammation signs showed ring signal (defined as a signal on the wound edge and no signal on the wound bed). While the tissue sections of three wounds with a ring signal showed inflammatory features, they showed no clinical signs of 'inflammation/infection'. In the clinical study, which analysed 630 ring and 32 non-ring signals, 13 samples in the ring signal group and five in the non-ring signal group had 'inflammation/infection; scores of ≥1 (p=0.016). Despite having no clinical signs, 17 samples showed the ring signal. This study revealed the external validity of the wound blotting analysis of peroxidase and demonstrated its use to detect subclinical inflammation.


Different modalities of invasive neurostimulation for epilepsy.
Epilepsy affects 1% of the general population, about one-third of which is pharmacologically resistant. Uncontrolled seizures are associated with an increased risk of traumatic injury and sudden unexpected death of epilepsy. There is a considerable psychological and financial burden on caregivers of patients with epilepsy, particularly among pediatric patients. Epilepsy surgery, when indicated, is the most promising cure for epilepsy. However, when surgery is contraindicated or refused by the patient, neurostimulation is an alternative palliative approach, albeit with a lower chance of entirely curing patients of seizures. There are many options for neurostimulation. The three most commonly used invasive neurostimulation procedures that consistently show evidence of being safe and efficacious are vagal nerve stimulation, responsive neuro stimulation, or anterior thalamic nucleus deep brain stimulation. The goal of this review is to summarize the current evidence supporting the use of these three techniques, which are approved by most regulatory bodies, and discuss different factors that may enable epilepsy surgeons to choose the most appropriate modality for each patient.


Psychological states and coping strategies after bereavement among spouses of cancer patients: a quantitative study in Japan.
The purposes of this study were (1) to characterize psychological states and coping strategies after bereavement among spouses of cancer patients in Japan and (2) to explore the factors associated with psychological states in oncology settings. In March 2009, questionnaires to assess spouses' psychological states, coping strategies, and mental health states (GHQ-28) were sent after patients died at the National Cancer Center of Japan. To address the first purpose, exploratory factor analysis, gender comparison, and calculation of correlation with age, time since bereavement, and mental health states were conducted. Hierarchical regression analysis was conducted to address the second purpose. A total of 821 spouses experiencing bereavement for 7 months to 7 years participated in the study. Psychological states revealed three factor structures: "Anxiety/Depression/Anger", "Yearning", and "Acceptance/Future-Oriented Feelings". Coping strategies also revealed three factor structures: "Distraction", "Continuing Bonds", and "Social Sharing/Reconstruction". Coping strategies represented 18 % to 34 % of each factor associated with psychological states, whereas the characteristics of bereaved spouses and deceased patients represented 6 % and less than 6 %, respectively. More "Distraction and Social Sharing/Reconstruction" and less "Continuing Bonds" were significantly associated coping strategies for achieving "Acceptance/Future-Oriented Feelings" (p < 0.01). Both psychological states and coping strategies after bereavement revealed three factor structures. Coping strategies was the primary, bereaved spouses' characteristics was the secondary, and deceased patients' characteristics was the tertiary factor associated with psychological states. Enhancing "Distraction" and "Social Sharing/Reconstruction", and reducing "Continuing Bonds" might be promising strategies for achieving positive psychological states of the bereaved.


T1D -weighted ihMT imaging - Part I. Isolation of long- and short-T1D components by T1D -filtering.
To identify T1D -filtering methods, which can specifically isolate various ranges of T1D components as they may be sensitive to different microstructural properties. Modified Bloch-Provotorov equations describing a bi-T1D component biophysical model were used to simulate the inhomogeneous magnetization transfer (ihMT) signal from ihMTRAGE sequences at high RF power and low duty-cycle with different switching time values for the dual saturation experiment: Δt = 0.0, 0.8, 1.6, and 3.2 ms. Simulations were compared with experimental signals on the brain gray and white matter tissues of healthy mice at 7T. The lengthening of Δt created ihMT high-pass T1D -filters, which efficiently eliminated the signal from T1D components shorter than 1 ms, while partially attenuating that of longer components (≥ 1 ms). Subtraction of ihMTR images obtained with Δt = 0.0 ms and Δt = 0.8 ms generated a new ihMT band-pass T1D -filter isolating short-T1D components in the 100-µs to 1-ms range. Simulated ihMTR values in central nervous system tissues were confirmed experimentally. Long- and short-T1D components were successfully isolated with high RF power and low duty-cycle ihMT filters in the healthy mouse brain. Future studies should investigate the various T1D -range microstructural correlations in in vivo tissues.


Disruption of the autism-related gene Pak1 causes stereocilia disorganization, hair cell loss, and deafness in mice.
Several clinical studies have reported that hearing loss is correlated with autism in children. However, little is known about the underlying mechanism between hearing loss and autism. p21-activated kinases (PAKs) are a family of serine/threonine kinases that can be activated by multiple signaling molecules, particularly the Rho family of small GTPases. Previous studies have shown that Pak1 mutations are associated with autism. In the present study, we take advantage of Pak1 knockout (Pak1-/-) mice to investigate the role of PAK1 in hearing function. We find that PAK1 is highly expressed in the postnatal mouse cochlea and that PAK1 deficiency leads to hair cell (HC) apoptosis and severe hearing loss. Further investigation indicates that PAK1 deficiency downregulates the phosphorylation of cofilin and ezrin-radixin-moesin and the expression of βII-spectrin, which further decreases the HC synapse density in the basal turn of cochlea and disorganized the HC stereocilia in all three turns of cochlea in Pak1-/- mice. Overall, our work demonstrates that the autism-related gene Pak1 plays a crucial role in hearing function. As the first candidate gene linking autism and hearing loss, Pak1 may serve as a potential target for the clinical diagnosis of autism-related hearing loss.


Copper-Catalyzed Three-Component Reactions of α-Ketoaldehyde, 1,3-Dicarbonyl Compound, and Organic Boronic Acid in Water: A Route to 1,4-Diketones.
A novel three-component reaction of α-ketoaldehydes, 1,3-dicarbonyl compounds, and organic boronic acids catalyzed by CuO in water has been developed to give a wide range of products containing 1,3/1,4-diketones. The method has some advantages such as the use of readily available starting materials, wide substrate scopes, excellent yields, gram-scale synthesis, and mild reaction conditions.


Cytologic findings in effusions from patients with SARS-CoV-2 infection.
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with "flu-like" upper respiratory tract symptoms and pneumonia. Body cavity effusions develop in a subset of patients with advanced disease. Although SARS-CoV-2 is known to be present in certain body fluids (eg, blood) of COVID patients, it remains unclear if body cavity fluids are sites of infection. Our aim was to characterize the cytologic and clinical findings in COVID-19 patients with effusions. A record search for all cases of body cavity effusion cytology in SARS-CoV-2 positive patients from March 1, 2020, to September 1, 2020, was performed. Clinical history, fluid chemical analysis, cytologic findings, and patient outcomes were recorded. All cytology slides were reviewed. In situ hybridization (ISH) targeting SARS-CoV-2 spike protein transcript (V-nCoV2019-S) was performed on cell block material in all cases. A total of 17 effusion cytology cases were identified among 15 COVID patients, including 13 pleural, 2 pericardial, and 2 peritoneal. Most (13 of 15) patients were hospitalized for COVID complications. Eight patients died during hospitalization, 7 from COVID complications. All fluids were transudative by protein criteria. Lymphocytic or histiocytic inflammation predominated in 12 of 17 cases. Five exhibited hemophagocytosis. No viral cytopathic changes or extra-medullary megakaryocytes were seen. Viral RNA was not detected in any case by ISH. Body cavity effusion is an ominous finding in patients with advanced COVID-19 disease. Such effusions tend to be transudative with lymphohistiocytic inflammation, and commonly exhibit hemophagocytosis, an otherwise rare finding in effusion cytologies. No direct infection of cellular elements by SARS-CoV-2 was identified by ISH.


Mitral valve "anular" calcium forming a complete circle or "O" configuration: clinical and necropsy observations.
Attention is called to the occurrence of a complete circle or "O"-shaped ring of calcium at the mitral anular region in each of two women, aged 67 and 82 years. Extension of mitral anular calcium from behind the posterior mitral leaflet across the ventricular aspect of the anterior mitral leaflet to form a complete circle has not been reported previously.


Adaptation and negative aftereffect to lateral optical displacement in newly hatched chicks.
Chicks wearing hoods containing 8.5-degree wedge prisms from the day of hatching showed both significant reduction in the average lateral displacement of pecking (adaptation) and significant pecking overcompensation in the direction opposite to the original displacement (negative aftereffect) when matched 0-degree plates were substituted for the prisms on the 8th day.


Silencing susceptibility genes in potato hinders primary infection of Phytophthora infestans at different stages.
Most potato cultivars are susceptible to late blight disease caused by the oomycete pathogen Phytophthora infestans. A new source of resistance to prevent or diminish pathogen infection is found in the genetic loss of host susceptibility. Previously, we showed that RNAi-mediated silencing of the potato susceptibility (S) genes StDND1, StDMR1 and StDMR6 leads to increased late blight resistance. The mechanisms underlying this S-gene mediated resistance have thus far not been identified. In this study, we examined the infection process of P. infestans on StDND1-, StDMR1- and StDMR6-silenced potato lines. Microscopic analysis showed that penetration of P. infestans spores was hampered on StDND1-silenced plants. On StDMR1- and StDMR6-silenced plants, P. infestans infection was arrested at a primary infection stage by enhanced cell death responses. Histochemical staining revealed that StDMR1- and StDMR6-silenced plants display elevated ROS levels in cells at the infection sites. Resistance in StDND1-silenced plants, however, seems not to rely on a cell death response as ROS accumulation was found to be absent at most inoculated sites. Quantitative analysis of marker gene expression suggests that the increased resistance observed in StDND1- and StDMR6-silenced plants relies on an early onset of SA- and ET-mediated signalling pathways. Resistance mediated by silencing StDMR1 was found to be correlated with the early induction of SA-mediated signalling. These data provide evidence that different defense mechanisms are involved in late blight resistance mediated by functional impairment of different potato S-genes.


Immuno-detection of Staphylococcus aureus biofilm on a cochlear implant.
A 46-year-old man suffering from progressive deafness since childhood received a Clarion 90 K cochlear implant with the HiRes preformed electrode in his left ear in October 2006. A persistent Staphylococcus aureus infection failed to be treated with corticoids, amoxicillin/ clavulanate, ciprofloxaxin, and rifampin. The processor was removed on July 2007. The removed cochlear implant processor was treated with different reagents, with the aim of detecting a S. aureus and S. aureus biofilm: (1) fluorescein-coupled Fc of anti-human serum, (2) polyclonal anti-polysaccharide intercellular adhesion antibodies coupled to Alexa Fluor 568 goat anti-rabbit immunoglobulin (Ig)G, (3) crystal violet, (4) methylene blue, (5) acridine orange, (6) Gram stain, and (7) live/dead fluorescent stain. S. aureus and the major constituent of the S. aureus biofilm, the polysaccharide intercellular adhesion, were detected on the surface of the implant. S. aureus was isolated after a simple contact between the implant and a solid growth medium. The ability of the isolated S. aureus strain to produce biofilm in vitro was confirmed. S. aureus biofilm was documented on the implant. Initial bacterial colonization could be related to the pocket of the removable magnet. Colonies of S. aureus without biofilm were found attached to the electrode wire. We report one case of a S. aureus biofilm infection documented on a cochlear implant, as assessed by immuno-microscopy. The biofilm was likely responsible for the persistent infection which manifested for many months after the implant surgery and could explain the unusual bacterial phenotypic resistance against administered antimicrobial agents.


Neuronal expression of mRNAs for complement proteins of the classical pathway in Alzheimer brain.
To determine possible sources of complement proteins in the brain, we investigated by in situ hybridization expression of the mRNAs of C1q, C2, C3, C4, C5, C6, C7, C8 and C9 in postmortem Alzheimer disease (AD) and control brain tissue. We found detectable hybridization for all these components in the temporal cortex and hippocampus, with significantly higher levels being found in AD tissue. Hybridization signals were strongest over pyramidal neurons. Low or absent hybridization was seen in the visual cortex or cerebellum. These results suggest that the activated complement components found in association with AD lesions may be, in part, derived from neurons.


Medium- and long-term reproducibility of self-reported exposure to physical ergonomics factors at work.
The literature is sparse on reproducibility of self-reported exposure to physical ergonomics risk factors for musculoskeletal disorders (MSDs). Aims of this study were to evaluate, in a cohort of workers interviewed up to three times: 1-year test-retest reliability; and 5- and 6-year recall of physical exposures. We also examined whether reproducibility was influenced by the presence of UE MSD or by technological changes introduced between the last two surveys. A cohort of automobile manufacturing employees was interviewed at baseline, one and six years later about work history, physical and psychosocial exposures at work, upper limb symptoms, injury and medical history, and demographics. Agreement between interviews was evaluated by intraclass correlation and Spearman coefficients. Differences in exposure between 1- and 6-year follow-up were analyzed by Wilcoxon matched-pairs signed-ranks test. Large and significant decreases in work pace and physical effort were observed from baseline, although an upper extremity composite index was quite stable in the total population. One-year test-retest reliability was fair to good for the composite exposure index (ICC=0.58), whole-body vibration, handling parts, and tool use, but poor for the other variables considered. Long-term reproducibility, from baseline or 1-year follow-up to 6-year follow-up, was poor for the composite index and almost all single items. UE MSD case status influenced 1-year test-retest reliability, with subjects who changed case status from baseline displaying higher reliability, but not reproducibility of recalled exposures. A strong regression to the mean effect was observed on exposures reported at follow-up surveys. Recalled ergonomics exposures could be employed in retrospective cohort studies as a somewhat reliable and unbiased estimate of the self-reported exposures that would have been obtained up to one year earlier, but not over a longer period (5-6 years). These longer-term results may have been limited by difficulty in matching jobs between interviews; also the regression to the mean effect likely contributed to reduce agreement. Changes in production technology and work organization produced a decrease in physical workload intensity and job pace, but did not have a substantial impact on an exposure index for the upper limb.


Absence of measles virus receptor (CD46) in lesions of subacute sclerosing panencephalitis brains.
In this study we investigated pathological changes of the expression of the measles virus (MV) receptor, CD46, in subacute sclerosing panencephalitis (SSPE) brains. We analyzed CD46 expression in lesions of brain specimens from five SSPE patients in comparison to uninfected regions of the same brains and to normal human brains. The correlation between CD46 and MV infection, in individual cells in SSPE brains, was analyzed by double-staining procedures using monoclonal antibodies (mAbs) and in situ hybridization to detect MV-specific mRNAs. We found that CD46 was expressed at relatively low levels by neurons and astrocytes in normal brains in comparison to neuroblastoma and astrocytoma cell lines. Within heavily infected (MV-positive) brain lesions of all five SSPE cases, CD46 was either not detected or was expressed to a lesser degree by neural cells, irrespective of whether MV antigens were detectable or not. In contrast, normal levels of CD46 were found in SSPE brain tissue distant from the lesion. Using in situ hybridization, mRNAs of both MV nucleocapsid and MV hemagglutinin (MV-H) were detected in all SSPE lesions, while no or only small amounts of MV-H protein were detected. MV-infected neurons were never found to express CD46. Although a strict correlation between levels of the MV-H protein and the absence CD46 could not be seen, these findings suggest that the CD46 expression is reduced by the MV infection in lesions of SSPE brains.


Comparison between anti-vascular endothelial growth factor therapy and photodynamic therapy for myopic choroidal neovascularization.
To compare the efficacy of anti-vascular endothelial growth factor (VEGF) therapy versus photodynamic therapy (PDT) for myopic choroidal neovascularization (mCNV). This study is a retrospective interventional study. Forty-two eyes from 42 patients with mCNV (36 subfoveal, 4 juxtafoveal, and 2 extrafoveal) treated and followed up for more than 6 months were included. Twenty eyes from 20 patients were treated by PDT (PDT group) at 1.5 ± 0.9 months after the symptoms and 22 eyes from 22 patients were treated by anti-VEGF therapy (anti-VEGF group) at 0.9 ± 0.8 months after the symptoms. Photodynamic therapy was performed, followed up, and retreated by standard procedures. Anti-VEGF therapy was repeated as needed. Gender, age, best-corrected visual acuity (BCVA), greatest linear dimension (GLD), central retinal thickness (CRT), and outer nuclear layer (ONL) thickness at the fovea were then compared between the anti-VEGF and PDT groups. No differences were detected in baseline parameters between the anti-VEGF and PDT groups. The mean BCVA (logMAR) at month 3 and 6 after the initial treatment was improved (-0.30 and -0.29) from baseline in the anti-VEGF group, which was statistically significant (p=0.0048 and 0.021, respectively). In the PDT group, modest improvements were observed in the mean BCVA at the same time periods (-0.05 and -0.10) with no statistical significance (p=0.79 and 0.90, respectively). The mean CRT was significantly reduced from baseline to month 6 in the anti-VEGF and PDT groups. The ONL thickness was significantly reduced in both groups, although the magnitude was significantly greater in the PDT group than the anti-VEGF group. Treatment with anti-VEGF therapy had significantly better visual outcomes than PDT for mCNV.


Differential expression of microRNAs and their targets reveals a possible dual role in physiological bark disorder in rubber tree.
Trunk phloem necrosis (TPN), a physiological bark disorder of the rubber tree (Hevea brasiliensis), is a serious problem that affects the yield of natural rubber. The resultant bark dryness occurs in up to half of a plantation's trees in almost every rubber tree plantation region, causing a great annual loss of dry rubber for natural rubber production. Different types of injury and physical damage caused by mechanical activation as well as environmental stresses cause physiological bark disorder in tree. Due to the essential role of miR166, miR393 and miR167 in vascular development and abiotic stress response in diverse plant species, it was interesting to investigate the role of these miRNAs in rubber trees, particularly during development of a physiological bark disorder. In this study, the expression pattern of miR166, miR393 and miR167; and their target genes, HD-ZIP III; TIR1 and ARF8, respectively; was demonstrated in healthy tree and different TPN trees. Their existence and function in vivo was validated using RNA ligase-mediated 5' rapid amplification of cDNA ends. Taken together, the results suggest a possible dual role of these three miRNAs in maintaining normal bark regeneration in healthy trees, coping with overtapping by affecting the wound healing system leading to abnormal bark regeneration in overtapped-TPN trees, and act as additional forces that enhance the attenuation of vascular development resulting in bark necrosis and cell death in the natural-TPN tree. This is the first study to address the molecular events of miRNAs involved in the physiological bark disorder TPN in rubber tree. Further study will open the possibility to better understanding of physiological and molecular perspectives during TPN development, and lead to improvement of monitoring the exploitation of rubber tree plantations.


Crossing the Boundaries within Computational Chemistry: From Molecular Dynamics to Cheminformatics and back.
The research in the group for computational chemistry at the ETH Zurich focuses on the development of methods and software for classical molecular dynamics simulations and cheminformatics, and their application to biological and chemical questions. Here, important advances and challenges in these subfields of computational chemistry are reviewed and potential opportunities for cross-fertilization are outlined.


Multi-analyte screening of small peptides by alkaline pre-activated solid phase extraction coupled with liquid chromatography-high resolution mass spectrometry in doping controls.
Peptidic drugs with wide spectrum of physiological activity are of interest for cheating athletes and can be misused as doping in sports. A growing number of small peptide drugs capable of enhancing performance are included in the prohibited list issued by World Anti-Doping Agency (WADA), therefore the improvement of the detection methods is constantly needed. In the present study, a screening assay was developed comprising 54 prohibited small peptides and the related substances in urine by means of the alkaline pre-activated weak cation exchange-solid phase extraction (WCX-SPE) with liquid chromatography-high resolution mass spectrometry (LCHRMS). This method performed good enrichment and purification effect of traditional WCX for basic peptides, and also improve the purification power of acidic peptides, which significantly expanded the coverage of detection substances. The method was validated in accordance with WADA relevant criteria and validated with a main focus on qualitative parameters including selectivity, limits of detection (0.02-0.2 ng/mL), linearity (0.1-20 ng/mL for 46 analytes and 0.2-20 ng/mL for 9 analytes), accuracy and precision (RE% and RSD% < 20% at 1, 5 and 10 ng/mL), recovery (39.2%-100.1% except for the TB500(1-2) free acid: 9.2%), matrix effects (ion suppression effect: 0 to 49.4% and ion enhancement effect: 100% and 264.6%), carryover, reliability and sample extract stability. As a proof-of-principle, urine samples from two patients received a single injection of leuprorelin acetate microspheres (3.75 mg) 30 days before were analyzed and the results proved the applicability of the method.


Secularity, abortion, assisted dying and the future of conscientious objection: modelling the relationship between attitudes.
Controversies arise over abortion, assisted dying and conscientious objection (CO) in healthcare. The purpose of the study was to examine the relationship between attitudes towards these bioethical dilemmas, and secularity and religiosity. Data were drawn from a 2017 web-based survey of a representative sample of 1615 Norwegian adults. Latent moderated structural equations modelling was used to develop a model of the relationship between attitudes. The resulting model indicates that support for abortion rights is associated with pro-secular attitudes and is a main "driver" for support for assisted dying and opposition to conscientious objection. This finding should be regarded as a hypothesis which ought to be tested in other populations. If the relationship is robust and reproduced elsewhere, there are important consequences for CO advocates who would then have an interest in disentangling the debate about CO from abortion; and for health systems who ought to consider carefully how a sound policy on CO can safeguard both patient trust in the services and the moral integrity of professionals. It is suggested that if religiosity wanes and pro-secular and pro-abortion attitudes become more widespread, support for CO might decline, putting into question whether present policies of toleration of conscientious refusals will remain acceptable to the majority.