Neonatal-perinatal medicine fellow procedural experience and competency determination: results of a national survey.
Ensuring that neonatal-perinatal medicine (NPM) fellows attain competency in performing neonatal procedures is a requirement of training-competent neonatologists. A survey of NPM fellows was performed to determine the procedural experience of current fellows, investigate techniques used to track procedural experience and examine the methods programs use to verify procedural competency. One hundred and sixty-three fellows in 57 accredited training programs responded to the survey. Reported number of procedures provide contemporary normative data on procedural experience during training. The majority of fellows reported using an online reporting system to track experience. The most common technique to verify procedural competency was supervised practice until an arbitrary number of procedures had been performed. NPM fellow procedural experience increases significantly for most, but not all, procedures duration training. We speculate that supplemental simulation training for rare neonatal procedures would help ensure the competency of graduating NPM fellows. Experience alone is insufficient to verify competency. Further work on the accurate tracking of experience and verification of procedural competency is needed.


Effectiveness and Safety of Resilient Hyaluronic Acid (RHA) Dermal Fillers for the Correction of Moderate-to-Severe Nasolabial Folds in People of Color: Post Hoc Subgroup Analyses of US Pivotal Clinical Data.
People of color (POC) are often underrepresented in clinical studies evaluating the safety and effectiveness of aesthetic products, including hyaluronic acid (HA) fillers, which to date have limited clinical data in POC. To assess the safety and effectiveness of a new line of dynamic HA fillers (RHA®, Revance, Nashville TN) for treating moderate-to-severe nasolabial folds (NLF) in POC versus non-POC. Post hoc subgroup analyses compared the efficacy and safety of POC versus non-POC subjects treated with RHA2, RHA3, or RHA4 for correction of moderate-to-severe nasolabial folds in the pooled Per Protocol population (N=217) in two clinical trials. Evaluated population cohorts were classified by Fitzpatrick Skin Type (FST) [high FST (IV-VI) versus low FST (I-III)] and by subject-reported race (non-White versus White) relative to baseline at 6, 9, 12, and 15 months. POC consistently showed greater improvement in wrinkle severity and higher responder rates compared to non-POC, which reached statistical significance at several measured time points. Global aesthetic improvement scores (GAIS) and subject satisfaction were similar for POC and non-POC and remained high throughout the course of the study. Treatment-related adverse event rates were generally lower for high FSTs versus low FSTs, with no reported cases of keloidal scarring. The RHA line of dynamic fillers is well tolerated and effective for the correction of moderate-to-severe nasolabial folds in POC and can be confidently used in this important and growing patient population.


Glassy cell carcinoma of the endometrium responsive to megestrol acetate.
A case of glassy cell carcinoma of the endometrium with pulmonary metastasis was responsive to treatment with a progestational agent. We believe this to be the first reported case of glassy cell carcinoma of the endometrium responsive to this form of therapy.


Atypical Palmar Involvement with Erythema Elevatum Diutinum as a Sole Manifestation: A Report of Two Cases.
Erythema elevated diutinum (EED) is a rare distinctive form of cutaneous leukocytoclastic vasculitis. EED typically presents with asymptomatic symmetrical erythematous-brown papules, nodules or plaques which favor the extensor aspect of extremities while distinctly sparing the palms. We report two cases of EED with a rare presentation limited to the palms.


Human cell-based estrogen receptor beta dimerization assay.
Estrogen is not only responsible for important functions in the human body, such as cell growth, reproduction, differentiation, and development, but it is also deeply related to pathological processes, such as cancer, metabolic and cardiovascular diseases, and neurodegeneration. Estrogens and other estrogenic compounds have transcriptional activities through binding with the estrogen receptor (ER) to induce ER dimerization. The two estrogen receptor subtypes, estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ), show structural differences and have different expression ratios in specific cells and tissues. Currently, the methods for confirming the estrogenic properties of compounds are the binding (Test guideline no. 493) and transactivation (Test guideline no. 455) assays provided by the Organization for Economic Co-operation and Development (OECD). In a previous study, we developed an ERα dimerization assay based on the bioluminescence resonance energy transfer (BRET) system, but there are currently no available tests that can confirm the effect of estrogenic compounds on ERβ. Therefore, in this study, we developed a BRET-based ERβ dimerization assay to confirm the estrogenic prosperities of compounds. The BRET-based ERβ dimerization assay was verified using nine representative ER ligands and the results were compared with the dimerization activity of ERα. In conclusion, our BRET-based ERβ dimerization assay can provide information on the ERβ dimerization potential of estrogenic compounds.


Three membrane fusion pore families determine the pathway to pore dilation.
During exocytosis secretory vesicles fuse with a target membrane and release neurotransmitters, hormones, or other bioactive molecules through a membrane fusion pore. The initially small pore may subsequently dilate for full contents release, as commonly observed in amperometric traces. The size, shape, and evolution of the pore is critical to the course of contents release, but exact fusion pore solutions accounting for membrane tension and bending energy constraints have not been available. Here, we obtained exact solutions for fusion pores between two membranes. We find three families: a narrow pore, a wide pore, and an intermediate tether-like pore. For high tensions these are close to the catenoidal and tether solutions recently reported for freely hinged membrane boundaries. We suggest membrane fusion initially generates a stable narrow pore, and the dilation pathway is a transition to the stable wide pore family. The unstable intermediate pore is the transition state that sets the energy barrier for this dilation pathway. Pore dilation is mechanosensitive, as the energy barrier is lowered by increased membrane tension. Finally, we study fusion pores in nanodiscs, powerful systems for the study of individual pores. We show that nanodiscs stabilize fusion pores by locking them into the narrow pore family.


Clinical and immunological findings in 104 cases of paraneoplastic pemphigus.
Although there are many reports of sporadic patients with paraneoplastic pemphigus (PNP), only a few systematic studies on large cohorts of patients with PNP have been reported. To analyse the clinical and immunological findings in a large cohort of patients with PNP. This retrospective study consisted of 104 patients with PNP. Clinical and histopathological manifestations, associated neoplasms, complicating diseases, prognosis and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assays (ELISAs) were analysed. The clinical and histopathological findings in this study were generally similar to those in previous reports. The most common associated neoplasms included malignant lymphomas, malignant solid tumours and Castleman disease, in that order, while 12 patients had no detectable tumours. Novel ELISAs for desmocollins (Dscs) showed that 19 (18·6%), 42 (41·2%) and 62 (60·8%) of 102 patients with PNP showed antibodies to Dsc1, Dsc2 and Dsc3, respectively. Thirty-two (60%) of 53 patients had antibodies to alpha-2-macroglobulin-like protein 1 (A2ML1). We found statistically significant correlations between positive desmoglein 3 reactivity and genital lesions, and between positive desmoglein 3 reactivity and bronchiolitis obliterans. We consider that antibodies to Dscs and A2ML1 are useful for the diagnosis of PNP.


Environmental risk assessment of acid rock drainage under uncertainty: The probability bounds and PHREEQC approach.
Acid rock drainage (ARD) is a major environmental problem that poses significant environmental risks during and after mining activities. A new methodology for environmental risk assessment based on probability bounds and a geochemical speciation model (PHREEQC) is presented. The methodology provides conservative and non-conservative ways of estimating risk of heavy metals posed to selected endpoints probabilistically, while propagating data and parameter uncertainties throughout the risk assessment steps. The methodology is demonstrated at a minesite located in British Columbia, Canada. The result of the methodology for the case study minesite shows the fate-and-transport of heavy metals is well simulated in the mine environment. In addition, the results of risk characterization for the case study show that there is risk due to transport of heavy metals into the environment.


Considerations on mechanisms of focussed signal transmission in the multi-channel muscle stretch reflex system.
This paper presents theoretical considerations on the possibility of topographically ordered signal transmission in the control system of the muscle stretch reflex. It is investigated how correlations between Ia fibres from primary muscle spindle endings in conjunction with an appropriate connectivity of Ia fibres and motoneurones enable the stretch reflex system to trace local routes through the spinal cord. The complex data processing capabilities of the motoneuronal soma-dendritic membrane system are fully taken into account, and it is argued that correlations between inputs to this system may play an important role for signal transmission through the spinal cord.


Effect of hyperglycemia on all-cause mortality from pediatric brain injury: A systematic review and meta-analysis.
This study aimed to assess the effect of hyperglycemia on all-cause mortality in pediatric patients with brain injury, based on currently available evidence. We systematically searched the PubMed, Embase, and Cochrane Library databases with the keywords "hyperglycemia", "brain injury", and "pediatrics". The retrieved records were screened by title, abstract, and full-text to include original articles assessing the effects of hyperglycemia on pediatric brain injury. The extracted data were assessed by a fixed-effects model. The risk of bias in the eligible studies was evaluated with the Newcastle-Ottawa Scale. Publication bias was visually examined with a funnel plot. Begg and Egger tests, respectively, were used to identify small-study effects. Sensitivity analysis was performed to evaluate the robustness of the original effect size. Nine observational studies were identified from 1439 primary hits. A total of 970 pediatric patients, including 304 with hyperglycemia and brain injury, were included for meta-analysis. Hyperglycemia was strongly associated with a higher risk of all-cause mortality in pediatric patients (odds ratio = 11.60, 95% confidence interval [CI] 7.88-17.08; I = 0%). The overall quality of eligible studies was low, but the funnel plot indicated no publication bias. Hyperglycemia is significantly associated with high all-cause mortality in pediatric patients with brain injury. However, the relationship should be confirmed by larger-scale observational studies and randomized controlled trials.


Secondary zoonotic dog-to-human transmission of SARS-CoV-2 suggested by timeline but refuted by viral genome sequencing.
The risk of secondary zoonotic transmission of SARS-CoV-2 from pet animals remains unclear. Here, we report on a 44 year old Caucasian male presenting to our clinic with COVID-19 pneumonia, who reported that his dog displayed respiratory signs shortly prior to his infection. The dog tested real-time-PCR (RT-PCR) positive for SARS-CoV-2 RNA and the timeline of events suggested a transmission from the dog to the patient. RT-PCR and serological assays were used to confirm SARS-CoV-2 infection in the nasopharyngeal tract in the dog and the patient. We performed SARS-CoV-2-targeted amplicon-based next generation sequencing of respiratory samples from the dog and patient for sequence comparisons. SARS-CoV-2 infection of the dog was confirmed by three independent PCR-positive pharyngeal swabs and subsequent seroconversion. Sequence analysis identified two separate SARS-CoV-2 lineages in the canine and the patient's respiratory samples. The timeline strongly suggested dog-to-human transmission, yet due to the genetic distance of the canine and the patient's samples paired-transmission was highly unlikely. The results of this case support current knowledge about the low risk of secondary zoonotic dog-to-human transmissions of SARS-CoV-2 and emphasizes the strength of genomic sequencing in deciphering viral transmission chains.


Australian national birthweight percentiles by sex and gestational age for twins, 2001-2010.
Birthweight remains one of the strongest predictors of perinatal mortality and disability. Birthweight percentiles form a reference that allows the detection of neonates at higher risk of neonatal and postneonatal morbidity. The aim of the study is to present updated national birthweight percentiles by gestational age for male and female twins born in Australia. Population data were extracted from the Australian National Perinatal Data Collection for twins born in Australia between 2001 and 2010. A total of 43,833 women gave birth to 87,666 twins in Australia which were included in the study analysis. Implausible birthweights were excluded using Tukey's methodology based on the interquartile range. Univariate analysis was used to examine the birthweight percentiles for liveborn twins born between 20 and 42 weeks gestation. Birthweight percentiles by gestational age were calculated for 85,925 live births (43,153 males and 42,706 females). Of these infants, 53.6% were born preterm (birth before 37 completed weeks of gestation) while 50.2% were low birthweight (<2500 g) and 8.7% were very low birthweight (<1500 g). The mean birthweight decreased from 2462 g in 2001 to 2440 g in 2010 for male twins, compared with 2485 g in 1991-94. For female twins, the mean birthweight decreased from 2375 g in 2001 to 2338 g in 2010, compared with 2382 g in 1991-94. The birthweight percentiles provide clinicians and researchers with up-to-date population norms of birthweight percentiles for twins in Australia.


Unconscious knowledge of rewards guides instrumental behaviors via conscious judgments.
The demonstration that unconscious learning supports instrumental behaviors (i.e., choosing the stimuli that lead to rewards) is central for the tenet that unconscious cognition sustains human adaptation. Recent studies, using reliable subliminal conditioning paradigms and improved awareness measurements have found evidence against unconscious knowledge sustaining accurate instrumental responses. The present preregistered study proposes a paradigm, in which unconscious processing is stimulated not by subliminally exposing the predictive (conditioned) stimuli, but by employing predictive regularities that are complex and difficult to detect consciously. Participants (N = 211) were exposed to letter strings that, unknown to them, were built from two complex artificial grammars: a "rewarded" or a "non-rewarded" grammar. On each trial, participants memorized a string, and subsequently had to discriminate the memorized string from a distractor. Correct discriminations were rewarded only when the identified string followed the rewarded grammar, but not when it followed the non-rewarded grammar. In a subsequent test phase, participants were presented with new strings from the rewarded and from the unrewarded grammar. Their task was now to directly choose the strings from the rewarded grammar, in order to collect more rewards. A trial-by-trial awareness measure revealed that participants accurately choose novel strings from the rewarded grammar when they had no conscious knowledge of the grammar. The awareness measure also showed that participants were accurate only when the unconsciously learned grammar led to conscious judgments. The present study shows that unconscious knowledge can guide instrumental responses, but only to the extent it supports conscious judgments.


Evaluation of Abbott anti-SARS-CoV-2 CMIA IgG and Euroimmun ELISA IgG/IgA assays in a clinical lab.
We report our findings of test performance especially specificity of a fully automated Abbott Architect anti-SARS-CoV-2 CMIA IgG and Euroimmun anti-SARS-CoV-2 ELISA IgA/IgG in human plasma. We used positive cohort of 97 samples from Covid-19 patients or healthcare workers, collected at late time points from symptom onsets. We also included another cohort of 215 samples as negative controls, 78 of which had positive serology test results of other infectious diseases or autoimmunity. Assay specificity was assessed by using a total of 847 anonymized samples which were collected before the Covid-19 pandemic from local patient populations seeking clinical care for rheumatoid diseases, thyroid cancer, and therapeutic drug monitoring. Abbott IgG, Euroimmun IgG/IgA had high precision, demonstrated by both intra- and inter-day CVs of <2%. There was no Abbott or Euroimmun IgG assay cross reactivity in the 78 samples with positive serology of non-SARS-CoV-2 infectious diseases and positive autoimmune antibodies. The Abbott IgG has specificity of 99.6%, while Euroimmun IgG and IgA were as high as 91.5% and 71.5%, respectively. Our evaluation confirmed high specificity of the Abbott IgG assay, while it was lower for Euroimmun IgG. Euroimmun IgA has suboptimal specificity which may limit its clinical use. Assay sensitivity was high for both Abbott and Euroimmun IgG assays.


A national survey of practice patterns: temporal artery biopsy.
To assess current clinical practice patterns for temporal artery biopsy (TAB) among clinicians in establishing the diagnosis of giant cell arteritis. A survey was sent via e-mail using the Survey Monkey website (www.surveymonkey.com; accessed January 24, 2013). The survey initially was sent in July 2010 and continued through October 2010. The survey was sent via e-mail to the members and affiliates of the American Society of Ophthalmic Plastic and Reconstructive Surgery, the North American Neuro-Ophthalmology Society, and the American College of Rheumatology. Data from the survey were collected via Survey Monkey and data analysis was performed using the Fisher exact test and Wilcoxon rank-sum test. Response to the survey questions on primary unilateral versus bilateral biopsy, performing second-side biopsy if first side results were negative, and the duration for which biopsy findings are reliable after initiating immunosuppressive therapy. The self-described primary subspecialty of the 1074 respondents was as follows: oculoplastic surgery (n = 127), neuro-ophthalmology (n = 119), rheumatology (n = 799), and other (n = 28). Overall, 66% of respondents advocated initial unilateral TAB, 18% advocated bilateral biopsy in all cases, and 16% recommended either unilateral or bilateral TAB depending on the degree of clinical suspicion. Rheumatologists were 4.5 times more likely to advocate initial bilateral biopsy than neuro-ophthalmologists or oculoplastic surgeons (P<0.0001, Fisher exact test). Most respondents believed that biopsy results were accurate for more than 14 days. These results were not affected by stratification of years in practice by the Kruskal-Wallis rank-sum test. Temporal artery biopsy practices vary greatly among treating physicians. This lack of consensus underscores the need for a systematic assessment of varying practice patterns. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Lipid peroxidation: a mechanism involved in acute ethanol toxicity as demonstrated by in vivo pentane production in the rat.
The effect of a single dose of ethanol on lipid peroxidation in three groups of rats fed different amounts of vitamin E was determined by the measurement of pentane in the breath. All rats had increased pentane production above basal levels by 15 min following oral administration of 6 g ethanol/kg body wt. The increase in total pentane production during a 13-hr test period after intragastric administration of ethanol was greater in the rats fed the vitamin E-deficient diet than in the rats fed vitamin E-supplemented diets (alpha = 2P = 0.02). The results support the hypothesis that acute ethanol toxicity involves lipid peroxidation and further demonstrate the usefulness in toxicological studies of monitoring pentane as an index of lipid peroxidation in vivo.


Covariance regression with random forests.
Capturing the conditional covariances or correlations among the elements of a multivariate response vector based on covariates is important to various fields including neuroscience, epidemiology and biomedicine. We propose a new method called Covariance Regression with Random Forests (CovRegRF) to estimate the covariance matrix of a multivariate response given a set of covariates, using a random forest framework. Random forest trees are built with a splitting rule specially designed to maximize the difference between the sample covariance matrix estimates of the child nodes. We also propose a significance test for the partial effect of a subset of covariates. We evaluate the performance of the proposed method and significance test through a simulation study which shows that the proposed method provides accurate covariance matrix estimates and that the Type-1 error is well controlled. An application of the proposed method to thyroid disease data is also presented. CovRegRF is implemented in a freely available R package on CRAN.


Analysis of gated membrane currents and mechanisms of firing control in the rapidly adapting lobster stretch receptor neurone.
1. The gated membrane currents (a tetrodotoxin-sensitive Na+ current and a tetraethylammonium- and 4-aminopyridine-sensitive K+ current) of the rapidly adapting stretch receptor neurone of lobster were investigated with respect to their kinetic properties using electrophysiological, pharmacological, and mathematical techniques. 2. The currents were found to be controlled by slow inactivations as well as by fast Hodgkin-Huxley (1952) gating processes. They could be described by kinetic expressions which differed from those inferred for the slowly adapting receptor (Gestrelius & Grampp, 1983a; Gestrelius, Grampp & Sjölin, 1983) only with respect to some of the parameter values. 3. With these expressions, and additional equations for the cell's pump and leak current components (Edman, Gestrelius & Grampp, 1986), a mathematical receptor model was formulated which accurately predicts the impulse activity of the living preparation in different functional circumstances and which, therefore, was adopted as an appropriate theory of firing regulation. 4. From a model analysis it appeared (a) that the 'rapid' adaptation of the receptor's impulse activity is mainly an effect of slow Na+ current inactivation starting a regenerative process of accommodation which, basically, is due to a small ratio of subthreshold Na+ to K+ currents; (b) that, because of the transmembrane Na+ influx being limited by accommodation, impulse firing is only little affected by a Na+-dependent pump current activation; and (c) that the phenomenon of increased firing frequency initially during prolonged stimulation ('negative adaptation') is an effect of the slow K+ current inactivation being faster than the slow Na+ current inactivation at comparable degrees of membrane polarization. 5. From further model studies it also appeared that, during depolarizations between successive action potentials evoked by constant stimulation, the membrane behaves like a high-resistance constant-current generator feeding into a short-circuiting capacitor. In consequence, the cell's stimulus sensitivity (change in firing frequency with stimulation strength) is, at functionally relevant stimulation intensities, mainly determined by the membrane capacitance and by the amplitude of the interspike membrane depolarization while, at higher stimulation intensities and firing frequencies, it becomes more and more a function of the spike duration itself.


Motor performance decrement by midazolam: antagonism by Ro 15-1788 and CGS 8216.
Rats were trained in a fine motor control performance that required operation by a paw of a force transducer so that it remained between upper and lower limits of a force band for a continuous 1.5-sec period to deliver each food pellet. Acute doses of midazolam (0.75-3.0 mg/kg, SC) impaired indices of motor performance in a graded, dose-related fashion. When administered alone, Ro 15-1788 (0.1-5.0 mg/kg, SC) had no effect on motor behavior while CGS 8216 (0.5 and 1.0 mg/kg, IP) alone had small effects. In general, the motor performance decrements produced by midazolam were antagonized in a dose-related fashion by both Ro 15-1788 and CGS 8216.


Binding of [3H]substance P to putative substance P receptors in rat brain membranes.
[3H]Substance P was used to label putative substance P receptors in rat brain membranes. [3H]Substance P binding was saturable, reversible, and displaceable by non-radioactive substance P. Association, dissociation and saturation experiments suggest a single site interaction of [3H]substance P to its binding site (k-1/k+1 = 0.56 nM; KD = 0.9 nM, Bmax 86.5 fmol/mg protein.


Highly crystalline {010} facet grown α-MoO3 nanobelts for resistive sensing of n-butanol vapor at room temperature.
The present work is aimed at developing an n-butanol sensor based on the chemi-resistive principle using MoO3 nanostructures as a sensing element. Highly ordered free-standing α-MoO3 nanobelts were synthesized using hydrothermal technique. The synthesis parameters adapted in the present work have paved a way in obtaining distinct MoO3 nanostructure with minimal process time as compared with the earlier reports. Initially, the formation of monoclinic crystals with an end centered lattice of β-Mo9O26 was observed, which then is transformed into orthorhombic α-MoO3 on calcination at 450 °C for 5 h. XPS profiles of the nanobelts revealed the presence of molybdenum and oxygen in a stoichiometric ratio of 2.6. Penta- and hexa-coordinated defect centers of Mo5+ and oxygen vacancies were observed from the photoluminescence spectra. The nanobelts respond to n-butanol vapors at room temperature with a 75-fold signal increase and response-recovery times of 17 & 10 s, respectively. The lowest detection limit is 1 ppm. The influence of relative humidity on the sensing response was also studied. Graphical abstract.


The role of protein structure in the mitochondrial import pathway. Unfolding of mitochondrially bound precursors is required for membrane translocation.
In order to examine the influence of protein structure on the post-translational import of a protein into mitochondria, the carboxyl-terminal 129 residues of F1-ATPase beta-subunit precursor (511aa) have been replaced with 61 residues of yeast copper metallothionein. Import of the F1 beta-copper metallothionein (beta CuMT) hybrid into mitochondria was as efficient as that of the F1 beta precursor in the absence of copper. Addition of copper to mitochondrial import reactions, which had no significant effect on import of the F1 beta-subunit precursor, blocked import of the beta CuMT protein. This copper-dependent transport block for the beta CuMT precursor occurred after the precursor was bound to mitochondria. Expression of the beta CuMT protein in vivo revealed that beta CuMT would bind copper and allow growth of a copper-sensitive yeast host on an otherwise inhibitory level of the cation as long as it was localized in the cytoplasm. These data indicate that the binding of copper by beta CuMT renders it refractile for partial unfolding which is necessary for its translocation into mitochondria. These observations provide an alternative scheme for the selection of mutants defective in mitochondrial import.


Trigger wrist and flexor tenosynovitis.
We report a case of a profundus tendon sheath fibroma which initially presented as triggering on wrist movements but rapidly caused a flexor tenosynovitis limiting both finger and wrist movements. Surgical excision was curative.


Ceftazidime in acute myeloid leukemia patients with febrile neutropenia: helpfulness of continuous intravenous infusion in maximizing pharmacodynamic exposure.
The pharmacokinetic-pharmacodynamic profile of a fixed 6-g daily continuous intravenous infusion of ceftazidime was assessed in 20 febrile neutropenic patients with acute myeloid leukemia. Mean steady-state ceftazidime concentrations averaging 40 mg/liter from day 2 on ensured maximized pharmacodynamic exposure (values close to four to five times the MIC breakpoint against Pseudomonas aeruginosa). However, large intra- and interindividual pharmacokinetic variability was documented throughout the study period.


Causal relationships between blood calcium, iron, magnesium, zinc, selenium, phosphorus, copper, and lead levels and multisystem disease outcomes in over 400,000 Caucasian participants.
Metal elements have been associated with a wide range of clinical outcomes. The available epidemiological evidence for these associations is often inconsistent and suffers from confounding and reverse causation. We aimed to explore the broad clinical effects of varying blood metal element levels and possible underlying mechanisms. We performed a two-sample Mendelian randomization (MR) analysis by using metal element-associated genetic loci as instrumental variable to evaluate the causal associations between blood metal element levels and 1050 disease outcomes in a UK Biobank cohort. A total of 408,910 White British participants were enrolled in the analysis. We further used the metal element-related genes and disease-related genes to construct a protein-protein interaction (PPI) network. Eight metal elements were associated with 63 diseases in total. Notably, we found nine pairs of suggestive evidence between two different metal elements for the same disease. Selenium and lead share some of the associated clinical outcomes, including diabetes mellitus, type 2 diabetes, lymphoid leukemia, and acute pharyngitis. Lead and zinc share the associated disease of acquired hypothyroidism. Iron and copper share the associated disease of arthropathies. Copper and zinc share the associated disease of occlusion of cerebral arteries. Calcium and zinc share the associated disease of arthropathies. In addition, the PPI network provided potential links between metal elements and disease outcomes at the genetic level. Our MR study of eight metal elements comprehensively characterized their shared and unique clinical effects, highlighting their potential causal roles in multiple diseases. Given the modifiable nature of blood metal elements and the potential for clinical interventions, these findings warrant further investigation.


Sensory processing in schizophrenia: missing and avoiding information.
The possible coexistence of supersensitivity and overinhibition (Schizophrenia: Origins, Processes, Treatment and Outcome (1993) 335-350) in schizophrenia was studied using the Adult Sensory Profile as a measure of Dunn's (Infants Young Children 9 (1997) 23-25) model of sensory processing. The quadrant model describes sensory sensitivity, sensation avoiding, low registration and sensation seeking as behavioral responses to sensation. Individuals with schizophrenia (N = 27), bipolar disorder (N = 30) and mentally healthy controls (N = 29) were compared using the Adult Sensory Profile. When compared to the mentally healthy group, the results indicated that both the schizophrenia group and the bipolar disorder group had higher scores on sensation avoiding. The schizophrenia group also had higher scores on low registration and lower scores on sensation seeking than the mentally health group. There were no differences between the schizophrenia and bipolar disorder group. According to the findings of this study, individuals with schizophrenia tend to miss available sensory stimuli. When stimuli are indeed detected, they are often avoided.


Effects of glucose, chloromercuribenzene-p-sulphonic acid and 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid on phosphate efflux from pancreatic islets.
Collagenase-isolated pancreatic islets of non-inbred ob/ob mice, containing more than 90% beta-cells, were labelled with radioactive orthophosphate (32P or 33P) and then subjected to non-recirculating perifusion. The basal D-glucose concentration in the perifusion medium was 2.8 mM. When the concentration was suddenly raised to 5.6, 8.3 or 16.7 mM, D-glucose promptly elicited a transient and dose-dependent release of radiophosphate. In the presence of 2.8 mM D-glucose, 0.1 mM of the poorly permeating sulphydryl blocker, chloromercuribenzene-p-sulphonic acid, also evoked a phosphate flush resembling the one induced by D-glucose. The basal radiophosphate release was partially inhibited by 1 mM 4-acetamido-4-'-isothiocyanostilbene-2,2'-disulphonic acid. However, the phosphate flush induced by 16.7 mM D-glucose was not noticeably inhibited by 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid. It is concluded that the phosphate flush emanates from beta-cells and that membrane sulphydryl groups may participate in its regulation. Although at least the basal phosphate release may in part represent transmembrane transport through 4-acetamido-4'-isothiocyanostilbene-2,2'-disulphonic acid-sensitive anion channels, other mechanisms are also likely to participate in the glucose-induced phosphate flush.


Risk of venous occlusion after lead laser extraction preventing future lead implantation.
Lead laser extraction is a well-established method for removing unwanted leads with low morbidity and mortality. In this observational study, we documented our experience with venous occlusion after lead laser extraction. Retrospective data of patients who underwent lead laser extraction between May 2010 and August 2018 was analyzed. Two subgroups of patients were identified. First group represented patients after lead laser extraction who suffered postoperative venous occlusion. Second group represents patients after lead laser extraction, who has documented patent venous access after lead laser extraction. 219 patients underwent percutaneous laser lead extraction. The mean age of patients was 65 ± 14 years. Of these patients, 74% were male. The Most common indication for extraction was Nonfunctional lead (45.2%, n = 99) followed by pocket infection with 33.8% and endocarditis (17.3%). A total number of 447 leads underwent laser extraction. In 7.8% of the patients, lead extraction was partially successful and lead extraction was not successful in only 2.3% of the patients. Only 13 patients developed a documented venous occlusion postoperatively and 26 patients has documented absence of venous occlusion, of whom 17 were under oral anticoagulation. Lead laser extraction may lead to venous occlusion, which is mostly asymptomatic but it prevents future lead implantation. The use of oral anticoagulant may prevent postoperative venous occlusion.


Measles antibodies in the saliva of children with subacute sclerosing panencephalitis.
Using the method of haemagglutination inhibition, the authors determined the levels of measles antibodies in the saliva of 14 children with subacute sclerosing panencephalitis. In 13 of them these antibodies were found in titres from 1:8 to 1:128. In the control groups, comprising 29 children, these antibodies were found in the saliva in only two cases and in low titres. There appears to be a correlation between the levels of these antibodies in the saliva and cerebrospinal fluid in patients with subacute sclerosing panencephalitis.


The design of a multiple inversion recovery sequence for T1 measurement.
Inversion recovery has the potential to be a powerful method of determining the values of T1 in in vivo studies. However, because of its relative slowness it is not practical to undertake several experiments with different values of the interval between the magnetization inverting 180 degree pulse and the interrogating 90 degree one. The multiple inversion recovery method described here uses a series of sampling pulses, most much less than 90 degrees, to produce a series of images. It is shown that slice shape is relatively reproducible from one sample to another and that, largely as a result, the accuracy of the sequence in measuring T1 is encouraging.


Antispermatogenic effect of aspirin and its prevention by prostaglandin E2.
Aspirin treatment causes a decrease in Leydig cell function, change in Sertoli cell morphology and a subsequent decrease in Spermatid count. Administration of Prostaglandin E2 prevents the effect of Aspirin on the Sertoli cell morphology and Spermatid degeneration without significant improvement of the Leydig cell function. On the basis of these findings, a possible relationship between Prostaglandin and testicular spermatogenesis has been discussed.


Influences of the steam sterilization on the properties of calcium phosphate porous bioceramics.
The influences of steam sterilization on the physicochemical properties of calcium phosphate (Ca-P) porous bioceramics, including β-tricalcium phosphate (β-TCP), biphasic calcium phosphate (BCP) and hydroxyapatite (HA) are investigated. After being steam sterilized in an autoclave (121 °C for 40 min), the porous bioceramics are dried and characterized. The steam sterilization has no obvious effects on the phase composition, thermal stability, pH value and dissolubility of β-TCP porous bioceramic, but changes its morphology and mechanical strength. Meanwhile, the steam sterilization leads to the significant changes of the morphology, phase composition, pH value and dissolubility of BCP porous bioceramic. The increase of dissolubility and mechanical strength, the decrease of pH value of the immersed solution and partial oriented growth of crystals are also observed in HA porous bioceramic after steam sterilization. These results indicate that the steam sterilization can result in different influences on the physicochemical properties of β-TCP, BCP and HA porous bioceramics, thus the application of the steam sterilization on the three kinds of Ca-P porous bioceramics should be considered carefully based on the above changed properties.


Prognostic factors in head and neck mucoepidermoid carcinoma: experience at a single institution based on 64 consecutive patients over a 28-year period.
Mucoepidermoid carcinoma (MEC) is the most common malignancy of the salivary glands. The clinical behaviour of MEC is largely unpredictable, ranging from indolent tumour growth to highly aggressive metastatic spread. The objective of this study was to determine the clinicopathological predictors of recurrence and survival in patients with head and neck MEC. The medical records of 64 patients who underwent surgical treatment for head and neck MEC between 1982 and 2010 were reviewed. The main outcome measures were disease-free survival (DFS) and overall survival (OS). Clinicopathological parameters evaluated were age, sex, anatomical subsite, histological grade, tumour stage, tumour size, adjuvant therapy, and nodal and margin status. For the entire cohort, the 5-year DFS was 82.8% and the 5-year OS was 67.2%. Histological grade and tumour subsite were statistically significant predictors of OS. Furthermore, tumour stage and nodal status were statistically significant predictors with respect to OS. Advanced tumour stage, high histological grade, submandibular/sublingual localization, and positive nodal status were independent predictors of the prognosis in patients with head and neck MEC. Further studies into the molecular biology of MEC are needed in order to provide new therapeutic strategies for patients with locally aggressive and highly metastatic carcinomas.


The expression of aluminum stress induced polypeptides in a population segregating for aluminum tolerance in wheat (Triticum aestivum L.).
This study examined the changes in gene expression induced by aluminum (Al) stress in wheat root tips. Seedlings of Triticum aestivum L. cvs. Katepwa (Al sensitive), Maringa (Al tolerant), and Alikat (Al tolerant near isoline; 'Katepwa'*3/'Maringa') and a F2 population derived from 'Katepwa' x 'Alikat', were grown for 3 days in either 0 or 1 μg∙mL−1 Al. Polypeptides were labeled with 35S-methionine prior to separation by gel electrophoresis. There were a few polypeptides from whole cell lysates that showed enhanced expression in all of the genotypes in 1 μg∙mL−1 Al, however, the whole cell lysate and microsomal polypeptide profiles also revealed numerous unique changes in gene expression in Al-sensitive 'Katepwa' at 1 μg∙mL−1 Al; the latter cosegregated with only the Al-sensitive F2 bulks. The microsomal polypeptide profiles of the Al-tolerant lines 'Maringa' and 'Alikat' changed marginally in the presence of Al and these changes were also reflected in the Al-tolerant F2 bulks. The data showed that there were many changes in gene expression which cosegregated with Al sensitivity and suggest that Al tolerance in wheat may rely on constitutively expressed polypeptides.


Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.
Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.


Some physical parameters controlling cell size during the evolution of the procaryons.
Possible factors controlling cell size during the evolution of unicellular organisms have been examined. It has been shown that considerations of osmotic and membrane pressure eqilibria will predict minimal cell sizes which are in good agreement with those found in present day microorganisms. It has also been shown that the possibility of random proton 'noise' would not be a limiting factor for even the smallest organisms or structures. Maximum cell size would be governed by the requirements of diffusion and transport within the cell.


Effects of pancreatic polypeptide and vasoactive intestinal polypeptide on rat ileal and colonic water and electrolyte transport in vivo.
Two gastrointestinal peptides, vasoactive intestinal polypeptide (VIP) and pancreatic polypeptide, suspected of being associated with symptoms of WDHA syndrome (pancreatic cholera) were tested on the rat small and large intestine for their effects on water and electrolyte transport. Intravenous infusion of VIP (14.3 microgram/kg/hr) inhibited net absorption of water and electrolytes in the ileum and reversed net absorption to net secretion in the colon. In contrast, bovine pancreatic polypeptide (52 microgram/kg/hr) did not inhibit absorption or stimulate secretion. These data indicate VIP causes colonic secretion in vivo, an effect previously shown only in vitro, and that bovine pancreatic polypeptide (at this dose) is not a secretagogue in the small or large intestine of the rat. Thus, while consistent with VIP being a contributory agent to the secretion of pancreatic cholera, the data do not support the notion that pancreatic polypeptide might be a causative agent in this syndrome.


The impact of phonon-assisted tunneling on optical and quantum characteristics of a coupled two-quantum dot system.
This work investigates the impact of decoherence induced by pure dephasing and phonon-assisted tunneling mechanisms on the optical and quantum properties of two quantum dots. Special attention is given to the density matrix at steady state, and a detailed analysis of populations, coherences, optical transitions and the emission spectrum is performed. Additionally, we study the influence of both phonon-decoherence mechanisms on bipartite entanglement and the degree of mixedness of the system. In particular, our findings indicate that the phonon-assisted tunneling mechanism partially affects the coherences of the system and quantum properties when the imbalance of phonon absorption and emission is significant. Conversely, the pure dephasing mechanism does not affect the populations but strongly entangles the quantum dots and the reservoir, inducing maximally mixed states and significantly reducing the spectral splitting in the emission spectrum of the system.


Rejuvenating activity of salidroside (SDS): dietary intake of SDS enhances the immune response of aged rats.
It is well known that immune response decreases with aging. Salidroside (SDS), an antioxidant component isolated from the traditional Chinese medicine roseroot Rhodiola rosea, has been demonstrated to possess potent anti-aging and health-promoting activities. However, the mechanism underlying these activities is poorly understood. In this study, we clearly demonstrated that (1) dietary intake of SDS induced a considerable increase in total T cells (CD3(+)) and T helper cells (CD4(+)) in aged (21 months old) Wistar male rats; (2) SDS supplementation significantly increased the DTH response, a T cell-mediated immune response, in aged rats; and (3) SDS supplementation remarkably promoted the production of total anti-KLH IgG, anti-KLH IgG1, and anti-KLH IgG2α in aged rats without disturbing immune homeostasis. These indicate that SDS is able to counteract immunosenescence, thereby resulting in rejuvenation. Practically, SDS may be used to help the elderly to generate an improved response to vaccine with stronger humoral and cell-mediated immune responses.


Cardiac stem and progenitor cell biology for regenerative medicine.
Stem cell therapy is a new and promising treatment of heart disease. However, the race is still on to find the "best" cell to reconstitute the myocardium and improve function after myocardial damage. The recent discovery in the adult mammalian myocardium of a small cell population with the phenotype, behavior, and regenerative potential of cardiac stem and progenitor cells has proposed these cells as the most appropriate for cell therapy. The existence of these cells has provided an explanation for the hitherto unexplained existence of a subpopulation of immature cycling myocytes in the adult myocardium. These findings have placed the heart squarely among other organs with regenerative potential despite the fact that the working myocardium is mainly constituted of terminally differentiated cells. Although CSCs (cardiac cells proven to have stem and/or progenitor characteristics) can be isolated and amplified in vitro or stimulated to differentiate in situ, it has become reasonable to exploit this endogenous regenerative potential to replace the lost muscle with autologous functional myocardium. Therefore, it is imperative to obtain a better understanding of the biology and regenerative potential of the endogenous CSCs. This will enable us to design better protocols for the regeneration of functional contractile mass after myocardial injury.


Unequal impairment in the recognition of positive and negative emotions after right hemisphere lesions: a left hemisphere bias for happy faces.
The processing of several important aspects of a human face was investigated in a single patient (LZ), who had a large infarct of the right hemisphere involving the parietal, and temporal lobes with extensions into the frontal region. LZ showed selective problems with recognizing emotional expressions, whereas she was flawless in recognizing gender, familiarity, and identity. She was very poor in recognizing negative facial expressions (fear, disgust, anger, sadness), but scored as well as the controls on the positive facial expression of happiness. However, in two experiments using both static and dynamic face stimuli, we showed that LZ also did not have a proper notion of what a facial expression of happiness looks like, and could not adequately apply this label. We conclude that the proper recognition of both negative and positive facial expressions relies on the right hemisphere, and that the left hemisphere produces a default state resulting in a bias towards evaluating expressions as happy. We discuss the implications of the current findings for the main models that aim to explain hemispheric specializations for processing of positive and negative emotions.


Anti-inflammatory effects of aloe vera gel in human colorectal mucosa in vitro.
Oral aloe vera gel is widely used by patients with inflammatory bowel disease and is under therapeutic evaluation for this condition. To assess the effects of aloe vera in vitro on the production of reactive oxygen metabolites, eicosanoids and interleukin-8, all of which may be pathogenic in inflammatory bowel disease. The anti-oxidant activity of aloe vera was assessed in two cell-free, radical-generating systems and by the chemiluminescence of incubated colorectal mucosal biopsies. Eicosanoid production by biopsies and interleukin-8 release by CaCo2 epithelial cells in the presence of aloe vera were measured by enzyme-linked immunosorbent assay. Aloe vera gel had a dose-dependent inhibitory effect on reactive oxygen metabolite production; 50% inhibition occurred at 1 in 1000 dilution in the phycoerythrin assay and at 1 in 10-50 dilution with biopsies. Aloe vera inhibited the production of prostaglandin E2 by 30% at 1 in 50 dilution (P = 0.03), but had no effect on thromboxane B2 production. The release of interleukin-8 by CaCo2 cells fell by 20% (P < 0.05) with aloe vera diluted at 1 in 100, but not at 1 in 10 or 1 in 1000 dilutions. The anti-inflammatory actions of aloe vera gel in vitro provide support for the proposal that it may have a therapeutic effect in inflammatory bowel disease.


Once-daily ethosuximide in the treatment of absence epilepsy.
Once-daily ethosuximide was used to treat 10 consecutive children with typical absence seizures. Three patients had gastrointestinal side effects which resolved when the same total daily dose was divided into 2 doses. Two other patients continued to have seizures on ethosuximide, whether given once or twice daily. Five patients had complete seizure control without adverse effects on once-daily ethosuximide.


Induction of epidermal cell proliferation by a tumour promoter in vitamin B6-deficient mice.
Topical application of the tumour promoter 12-0-tetradecanoyl-phorbol-13-acetate to skin caused a marked enhancement of mitotic activity both in mice maintained on a complete diet or on a vitamin B6-deficient diet.


Analyzing Angiotensin II Receptor Type 1 Clustering in PC12 Cells in Response to Hypoxia Using Direct Stochastic Optical Reconstruction Microscopy (dSTORM).
Angiotensin II (Ang II) is a hormone that plays a major role in maintaining homeostasis. The Ang II receptor type 1 (AT1R) is expressed in acute O2 sensitive cells, including carotid body (CB) type I cells and pheochromocytoma 12 (PC12) cells, and Ang II increases cell activity. While a functional role for Ang II and AT1Rs in increasing the activity of O2 sensitive cells has been established, the nanoscale distribution of AT1Rs has not. Furthermore, it is not known how exposure to hypoxia may alter the single-molecule arrangement and clustering of AT1Rs. In this study, the AT1R nanoscale distribution under control normoxic conditions in PC12 cells was determined using direct stochastic optical reconstruction microscopy (dSTORM). AT1Rs were arranged in distinct clusters with measurable parameters. Across the entire cell surface there averaged approximately 3 AT1R clusters/μm2 of cell membrane. Cluster area varied in size ranging from 1.1 × 10-4 to 3.9 × 10-2 μm2. Twenty-four hours of exposure to hypoxia (1% O2) altered clustering of AT1Rs, with notable increases in the maximum cluster area, suggestive of an increase in supercluster formation. These observations could aid in understanding mechanisms underlying augmented Ang II sensitivity in O2 sensitive cells in response to sustained hypoxia.


Interspecific competition can drive plasmid loss from a focal species in a microbial community.
Plasmids are key disseminators of antimicrobial resistance genes and virulence factors, and it is therefore critical to predict and reduce plasmid spread within microbial communities. The cost of plasmid carriage is a key metric that can be used to predict plasmids' ecological fate, and it is unclear whether plasmid costs are affected by growth partners in a microbial community. We carried out competition experiments and tracked plasmid maintenance using a model system consisting of a synthetic and stable five-species community and a broad host-range plasmid, engineered to carry different payloads. We report that both the cost of plasmid carriage and its long-term maintenance in a focal strain depended on the presence of competitors, and that these interactions were species specific. Addition of growth partners increased the cost of a high-payload plasmid to a focal strain, and accordingly, plasmid loss from the focal species occurred over a shorter time frame. We propose that the destabilising effect of interspecific competition on plasmid maintenance may be leveraged in clinical and natural environments to cure plasmids from focal strains.


Correlation between a patient-derived functional questionnaire and abnormal neuromuscular transmission in Myasthenia Gravis patients.
To correlate the patient-derived physical function score, as measured by the disease specific Myasthenia Gravis Questionnaire (MGQ), and the score obtained with commonly used generic 36-item questionnaire, the Short-Form health survey (SF-36), with the degree of abnormal neuromuscular transmission measured by Single-Fibre EMG (SFEMG) and repetitive nerve stimulation (RNS) in Myasthenia Gravis (MG) patients. SFEMG and RNS were performed in the deltoid muscle and SFEMG was also performed in the orbicularis oculi muscle in 45 MG patients. The patients were asked to fill out the MGQ, which has been translated and validated into Swedish, and the SF-36. The sum of MGQ items generates a global MGQ score. Items are also divided into 3 muscle specific domains: generalized, bulbar and ocular. The global MGQ score and generalized domain score of MGQ were strongly correlated with the degree of abnormal neuromuscular transmission, as measured by SFEMG in the deltoid muscle. Scores from ocular and bulbar domains of MGQ were not related to neurophysiological findings. Physical composite scores of SF-36 correlated significantly with the abnormal SFEMG findings in the deltoid. The degree of disturbed neuromuscular transmission in a proximal limb muscle correlates with a patient's subjective experience of generalized myasthenic dysfunction. The observed correlation adds a new dimension to neurophysiological examinations in patients with MG.


MEF2: a central regulator of diverse developmental programs.
The myocyte enhancer factor 2 (MEF2) transcription factor acts as a lynchpin in the transcriptional circuits that control cell differentiation and organogenesis. The spectrum of genes activated by MEF2 in different cell types depends on extracellular signaling and on co-factor interactions that modulate MEF2 activity. Recent studies have revealed MEF2 to form an intimate partnership with class IIa histone deacetylases, which together function as a point of convergence of multiple epigenetic regulatory mechanisms. We review the myriad roles of MEF2 in development and the mechanisms through which it couples developmental, physiological and pathological signals with programs of cell-specific transcription.


Raised uterine artery impedance is associated with increased maternal arterial stiffness in the late second trimester.
To assess the relationship between uterine artery Doppler pulsatility index (PI) and maternal global arterial stiffness and aortic stiffness in women at high a priori risk of preeclampsia in the late second trimester of pregnancy. A prospective cohort study was performed. 99 women were recruited from the high-risk obstetric ultrasound clinic in the second trimester; median (±IQR) age and gestation were 33 (29-37) years and 23(+6) (23(+3)-24(+4)) weeks respectively. Transabdominal uterine artery Doppler was performed and mean values recorded. Women returned at a later date, median gestation (±IQR) 26(+5) (25(+6)-28(+0)) weeks, for measurement of blood pressure, augmentation index (AIx) and aortic pulse wave velocity (aPWV). Uterine artery PI is positively associated with both AIx (r = 0.4, P <0.0001, 95% CI: 0.22-0.55) and aPWV (r = 0.22, P = 0.03, 95% CI: 0.02-0.40). No relationship was found between uterine artery PI and mean arterial pressure or pulse pressure. AIx was significantly higher in women with uterine artery PI > 1.45 (P = 0.003, 95% CI: 3.1-14.9) but not aPWV (P = 0.45). AIx, but not aPWV, was significantly higher in women who developed preeclampsia (14% vs 9%, 95% CI: 2.0-8.6, P = 0.0018) or IUGR (11% vs 9%, 95% CI: 0.3-4.2, P = 0.027). AIx showed a negative correlation with birth weight z-score (r = -0.25, 95% CI: -0.43 to -0.06, P = 0.013). Increasing uterine artery Doppler PI reflects impaired placentation and increasing risk of preeclampsia. We show a positive association between uterine artery Doppler PI and both global arterial and aortic stiffness. We also show that increased maternal arterial stiffness is associated with a lower birth weight. These findings may represent evidence of an early effect of impaired placentation on the maternal vasculature. Alternatively, given the association between preeclampsia and later cardiovascular disease, ineffective placentation may result from impaired arterial function.


Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial.
The cause of pruritus of cholestasis is unknown. We have hypothesized that pruritus may be caused by an indirect effect of high hepatic concentrations of toxic bile acids. To test this hypothesis, we have conducted a double-blind, controlled, crossover clinical trial of rifampin, an agent that inhibits hepatic bile acid uptake and may detoxify hepatic bile acids by stimulation of mixed-function oxidases. Nine patients with primary biliary cirrhosis received 300-450 mg/day of rifampin and placebo sequentially, in random order. Each treatment was administered for 14 days, with a 14-day washout between treatments. Endpoints included patient preference, changes in a daily visual analogue scale pruritus score, and amount of cholestyramine ingested. Antipyrine elimination rates and serum bile acids were tested at the end of each treatment period. All 9 patients completed the trial and 8 of them preferred rifampin to placebo (p = 0.03). There were no adverse reactions. Visual analogue scale pruritus scores showed no significant placebo response or any effect from the order of treatment, but did show a highly significant reduction in pruritus in response to rifampin (p less than 0.002). This effect was evident within the first week of rifampin treatment. Rifampin produced a 33% reduction in antipyrine plasma half-life, but no change in fasting total serum bile acids. Cholestyramine usage did not change significantly. We conclude that rifampin is useful for short-term relief of pruritus in primary biliary cirrhosis; however, the mechanism of this effect is unknown. Longer trials are needed, as are trials in other cholestatic disorders.


Smoking and Long-Term Sick Leave in a Japanese Working Population: Findings of the Japan Epidemiology Collaboration on Occupational Health Study.
Few studies have investigated the association between tobacco smoking and sick leave (SL) in Japan. We followed 70 896 workers aged 20-59 years (60 133 males, 10 763 females) between April 2012 and March 2017. A Cox proportional hazards model was used to investigate the associations between smoking (smoking status and intensity) and long-term SL (ie, SL lasting ≥30 consecutive days). Cause-specific analyses were also conducted. A total of 1777 people took long-term SL during a follow-up of 307 749 person years. Compared with never-smokers, current smokers were at a higher risk of long-term SL (hazard ratio [HR] = 1.32; 95% confidence interval [CI] = 1.19 to 1.48). Cause-specific analyses revealed that current smoking was associated with a higher risk of SL due to all physical disorders (HR = 1.44, 95% CI = 1.22 to 1.69), cancer (HR = 1.49, 95% CI = 1.10 to 2.01), cardiovascular disease (CVD; HR = 2.16, 95% CI = 1.31 to 3.55), and injuries/external causes (HR = 1.83, 95% CI = 1.31 to 2.58). Former smokers were at a higher risk of SL due to cancer at a borderline significance level (HR = 1.38, 95% CI = 0.99 to 1.92). Low-intensity smoking (ie, 1-10 cigarettes smoked per day) was associated with all-cause SL, SL due to CVD, and SL due to injuries/external causes compared with never-smokers. In a large cohort of working-age Japanese, smoking was associated with a greater risk of long-term SL. Greater effort is needed to mitigate disease burden associated with smoking at workplace in Japan. Our study contributes to the literature on the association between smoking and SL in several ways. First, the study was conducted among a Japanese working population. While the association has been extensively studied in Western setting, few attempts have been made elsewhere. Second, cause-specific analyses were undertaken in our study. Third, we paid attention to the effect of low-intensity smoking on SL given that there is growing evidence of an elevated health risk associated with low-intensity smoking.


Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2.
To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.


Participation and Life Satisfaction in Aged People with Spinal Cord Injury: Does Age at Onset Make a Difference?
Few studies have reported on outcomes in samples of elderly people with SCI and the impact of the age at onset of SCI is unclear. To study levels of participation and life satisfaction in individuals with SCI aged 65 years or older and to analyze differences in participation and life satisfaction scores between individuals injured before or after 50 years of age. This cross-sectional survey included 128 individuals with SCI who were at least 65 years old. Age at onset was dichotomized as <50 or ≥ 50 years of age. Participation was measured with the Frequency scale of the Utrecht Scale for Evaluation-Participation, and life satisfaction was measured with 5 items of the World Health Organization Quality of Life abbreviated form. Participants who were injured before 50 years of age showed similar levels of functional status and numbers of secondary health conditions but higher participation and life satisfaction scores compared to participants injured at older age. In the multiple regression analysis of participation, lower current age, higher education, and having paraplegia were significant independent determinants of increased participation (explained variance, 25.7%). In the regression analysis of life satisfaction, lower age at onset and higher education were significant independent determinants of higher life satisfaction (explained variance, 15.3%). Lower age at onset was associated with better participation and life satisfaction. This study did not reveal indications for worsening participation or life satisfaction due to an accelerated aging effect in this sample of persons with SCI.


Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways.
Facing the threat of highly variable virus infection, versatile vaccination systems are urgently needed. Intranasal mRNA vaccination provides a flexible and convenient approach. However, the nasal epithelium remains a major biological barrier to deliver antigens to nasal associated lymphoid tissue (NALT). To address this issue, a potent polymer-based intranasal mRNA vaccination system for HIV-1 treatment was synthesized using cationic cyclodextrin-polyethylenimine 2k conjugate (CP 2k) complexed with anionic mRNA encoding HIV gp120. The delivery vehicle containing CP 2k and mRNA overcame the epithelial barrier by reversibly opening the tight junctions, enhanced the paracellular delivery of mRNA and consequently minimized absorption of toxins in the nasal cavity. Together with the excellent intracellular delivery and prolonged nasal residence time, strong system and mucosal anti-HIV immune responses as well as cytokine productions were achieved with a balanced Th1/Th2/Th17 type. Our study provided the first proof of evidence that cationic polymers can be used as safe and potent intranasal mRNA vaccine carriers to overcome the nasal epithelial barrier. The safe and versatile polymeric delivery system represents a promising vaccination platform for infectious diseases.


The effects of word orientation and imageability on visual half-field presentations with a lexical decision task.
Two studies examined the effects of word orientation and word imageability in a visual half-field procedure. The studies involved a lexical decision task in which items were presented in either a horizontal or vertical orientation randomly intermixed in Experiment 1 and blocked in Experiment 2. Overall, a RVF advantage resulted with horizontal items, yet no visual-field asymmetries were found with the vertical items. These results indicate that altering the orientation can affect visual-field superiority. It is proposed that the novelty of vertical displays leads to greater involvement of the right hemisphere. Imageability was related to performance only for horizontal displays; but there were no significant differences in imageability effects between the two visual fields. It is concluded that word imageability has little effect on visual-field differences, at least not for lexical decisions.


Factors associated with intraocular pressure before and during 9 years of treatment in the Collaborative Initial Glaucoma Treatment Study.
To evaluate, both at initial glaucoma diagnosis and during treatment, the role of demographic and clinical factors on intraocular pressure (IOP). Cohort study of patients enrolled in a randomized clinical trial. Six hundred seven patients with newly diagnosed open-angle glaucoma (OAG) were enrolled at 14 centers in the United States. After randomization to initial surgery or medications, patients were followed at 6-month intervals. Intraocular pressure was measured by Goldmann applanation tonometry. Predictive factors for IOP at baseline and during follow-up were analyzed using linear mixed models. Intraocular pressure at baseline and during follow-up. The mean baseline IOP was 27.5 mmHg (standard deviation, 5.6 mmHg). Predictive factors for higher baseline IOP included younger age (0.7 mmHg per 10 years), male gender (2.4 mmHg higher than females), pseudoexfoliative glaucoma (5.4 mmHg higher than primary OAG), and pupillary defect (2.2 mmHg higher than those without a defect). During 9 years of follow-up, both surgery and medications dramatically reduced IOP from baseline levels, but the extent of IOP reduction was consistently greater in the surgery group. Over follow-up years 2 through 9, mean IOP was 15.0 versus 17.2 mmHg for surgery versus medicine, respectively. Predictive associations with higher IOP during follow-up included higher baseline IOP (P<0.0001), worse baseline visual field (mean deviation; P<0.0001), and lower level of education (P = 0.0019). Treatment effect was modified by smoking status: nonsmokers treated surgically had lower IOP than smokers treated surgically (14.6 vs. 16.7 mmHg, respectively; P = 0.0013). Clinical center effects were significant (P<0.0001) in both the baseline and follow-up models. In this large cohort of newly diagnosed glaucoma patients, predictors of pretreatment IOP and IOP measurements over 9 years of follow-up were identified. Our findings lend credence to the postulate that sociodemographic, economic, compliance, or other environmental influences play a role in IOP control during treatment.


Reducing unnecessary testing on sputum specimens from patients with cystic fibrosis: pathology stewardship in microbiology.
Chronic respiratory tract infection by Pseudomonas aeruginosa is the hallmark of established lung disease in patients with cystic fibrosis (CF). Antibiotic therapy can usually only suppress but not eradicate infection. In recent years, pulmonary infection with non-tuberculous Mycobacteria (NTM) species has also been increasing. These patients are often colonised with multiple isolates and determination of clinical significance of each isolate is difficult. The clinical value of frequent routine susceptibility testing of individual isolates is unproven, particularly since a delay in susceptibility testing is inevitable when purification of multiple cultured isolates is required to test each isolate separately. From August 2019 until December 2020 we ceased routine susceptibility testing on P. aeruginosa respiratory tract isolates from patients with CF if a previous isolate from the patient had susceptibility testing performed. We found that the proportion of P. aeruginosa isolates that had susceptibility testing performed dropped from 97% to 11% as a result of this change in laboratory process. During this time, we also ceased routine culture for acid-fast bacilli if this had been performed within the previous 6 months. We present the cost and resource savings for these changes in laboratory process and assess for clinical impact measured as hospital admissions, length of stay in hospital and mortality.


Continuous glucose monitoring in patients with type 2 diabetes treated with glucagon-like peptide-1 receptor agonist dulaglutide in combination with prandial insulin lispro: an AWARD-4 substudy.
To conduct a substudy, using 24-hour continuous glucose monitoring (CGM), of the AWARD-4 trial, which was designed to compare insulin + glucagon-like peptide-1 receptor agonist treatment with an insulin-only regimen. The AWARD-4 trial randomized 884 conventional insulin regimen-treated patients to dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, all in combination with prandial insulin lispro. The CGM substudy included 144 patients inserted with a Medtronic CGMS iPro CGM device to enable 3-day glucose monitoring. CGM sessions were completed at weeks 0, 13, 26 and 52. CGM measures included mean 24-hour glucose, percentage time in target glucose ranges, hyper- and hypoglycaemia and glucose variability. The primary objective was treatment comparison for percentage time spent with CGM glucose values in the 3.9-7.8 mmol/L range after 26 weeks. At week 26, mean CGM values decreased in all treatment groups (change from baseline -2.8 ± 0.3, -2.4 ± 0.3 and -2.5 ± 0.3 mmol/L for dulaglutide 1.5 mg, dulaglutide 0.75 mg and glargine, respectively); between-group differences were not statistically significant. Treatment groups were similar for percentage time in the 3.9-7.8 mmol/L range. Percentage time in the 3.9-10.0 mmol/L range was greater for dulaglutide 1.5 mg than for glargine (p < 0.05). Dulaglutide and glargine were associated with decreased glucose variability for all CGM variability indices. The overall within-patient standard deviation (s.d.) was significantly reduced with dulaglutide 1.5 mg versus glargine (p < 0.05). At week 52, there were no significant differences among the groups with regard to measures of normoglycaemia or near-normoglycaemia and for the overall within-patient s.d. Treatment with glargine was associated with greater increases in percentage time spent with glucose values ≤3.9 mmol/L, with statistically significant differences between the groups at 52 weeks (p < 0.05). In combination with prandial lispro, treatment with dulaglutide and glargine resulted in similar proportions of glucose values in the normoglycaemic range, but dulaglutide provided an improved balance between the proportion of values within the near-normoglycaemia range and values within the hypoglycaemic range.


Dendritic right/left asymmetries in the neurons of the human hippocampal formation: a quantitative Golgi study.
To search for right/left asymmetries in the dendritic trees of the neuronal populations and in the cell-free layer volumes of the human hipoccampal formation. In necropsic material obtained from six male individuals we performed a quantitative Golgi study of the dendritic trees of dentate granules, CA3 and CA1 pyramidal neurons and a volumetric analysis of dentate gyrus molecular layer, strata oriens plus alveus and strata lacunosum-moleculare plus radiatum of CA3 and CA1 fields. We found inter-hemispheric asymmetries in the dendrites trees of all neurons, reaching the significant level in the number of granule cells dendritic segments (higher in the left than in the right hemisphere), dendritic branching density of CA3 pyramidal cells and mean dendritic length of CA1 apical terminal segments (higher in the right than in the opposite side). No volumetric differences were observed. This study points to different anatomical patterns of connectivity in the hippocampal formations of both hemispheres which may underlie functional asymmetries.


Cerebellar atrophy in schizophrenia and affective disorder.
The authors evaluated 108 patients with schizophrenia, 50 patients with affective disorder, and 74 age- and sex-matched control subjects by CAT scan for evidence of global cerebellar atrophy. No difference was found between control subjects and schizophrenic patients or between control subjects and patients with affective disorder. This study does not confirm previous reports linking cerebellar atrophy to schizophrenia.


Dogger Bank itch in the eastern English Channel: a newly described geographical distribution of an old problem.
Dogger Bank itch is an allergic contact dermatitis to the (2-hydroxyethyl) dimethylsulphoxonium ion, a metabolite produced by the marine Bryozoan Alcyonidium diaphanum. The condition may become disabling in affected individuals, who are chiefly fishermen and dock labourers. It involves regions of skin directly exposed to sea water and areas where water may course. As A. diaphanum is common in the coastal waters of Britain, Ireland and neighbouring mainland Europe, it is important for dermatologists to be aware of Dogger Bank itch. Data published in 1966 suggested that 7% of trawler-men at the UK port of Lowestoft had the condition. The current epidemiology is unknown, but the disease still occurs despite shrinkage of the fishing industry, and the condition is not confined to North Sea trawler-men as had been thought previously. It has been reported in trawler-men from Le Havre and shell fishermen from Cornwall, and we report it here in a fisherman using fixed nets in the eastern English Channel.


Finger tapping impairments are highly sensitive for evaluating upper motor neuron lesions.
Identifying highly sensitive and reliable neurological exam components are crucial in recognizing clinical deficiencies. This study aimed to investigate finger tapping performance differences between patients with CNS demyelinating lesions and healthy control subjects. Twenty-three patients with multiple sclerosis or clinically isolated syndrome with infratentorial and/or cervical cord lesions on MRI, and 12 healthy controls were videotaped while tapping the tip of the index finger against the tip and distal crease of the thumb using both the dominant and non-dominant hand. Videos were assessed independently by 10 evaluators (three MS neurologists, four neurology residents, three advanced practice providers). Sensitivity and inter-evaluator reliability of finger tapping interpretations were calculated. A total of 1400 evaluations (four videos per each of the 35 subjects evaluated by 10 independent providers) were obtained. Impairments in finger tapping against the distal thumb crease of the non-dominant hand, identified by neurologists, had the greatest sensitivity (84%, p < 0.001) for detecting impairment. Finger tapping against the thumb crease was more sensitive than the thumb tip across all categories of providers. The best inter-evaluator reliability was associated with neurologists' evaluations for the thumb crease of the non-dominant hand (kappa = 0.83, p < 0.001). Impaired finger tapping against the distal thumb crease of the non-dominant hand was a more sensitive technique for detecting impairments related to CNS demyelinating lesions. Our findings highlight the importance of precise examinations of the non-dominant side where impaired fine motor control secondary to an upper motor injury might be detectable earlier than the dominant side.


Unpredicted bilateral device breakage during active phase of mandibular distraction: A case report and literature review.
Distraction osteogenesis is a popular treatment modality to lengthen the mandible. It is commonly performed in wide varieties of craniofacial syndromes, temporomandibular joint (TMJ) ankylosis, and obstructive sleep apnea cases requiring a significant amount of mandibular lengthening. There are many complications associated with mandibular distraction osteogenesis procedure and the breakage of the distractor is very rare. There are few reports in the literature mentioning the breakage of a distractor. This article highlights an up-to-date knowledge of the etiology and prevention of mandibular distractor breakage and a case report which was managed well after bilateral internal mandibular distractor breakage. This is the first case report describing the spontaneous bilateral mandibular distractor breakage during the active phase of distraction osteogenesis.


Event-related EEG field changes in aroused subjects and schizophrenic patients.
The average auditory event-related potential (AAEP) to nonmeaningful stimuli has maximum vertex negative and positive amplitudes at about 100 and 200 msec, respectively. This "vertex potential" was studied under different arousal conditions in 15 normal men and 30 chronic schizophrenic subjects using the average event-related vector electro-encephalogram (AEVE) and the AAEP. The AEVE shows the path, in time, of the event-related electric field vector. To produce intramodal arousal, normal subjects also had EEG recordings made during the random sounding of a loud bell. AAEPs and AEVEs were calculated for spontaneous changes in arousal, as indicated by EEG delta band power. Bell arousal of the normal subjects increased the AAEP and AEVE measures of vertex potential maxima, thus increasing the existing differences between normals and schizophrenics. Analysis of the AEVE path indicates that arousal increased the electric field intensity, but probably did not alter, within the first 250 msec, the spatial distribution of the cortical EEG generators. After 250 msec, a reorganization of generators was indicated for the three groups. Schizophrenics differed from normals in the decreased maximum intensity of the vertex negative electric field, which was indicated by both the AEVE and AAEP.


Simultaneous hydrodynamic cavitation and nanosecond pulse discharge plasma enhanced by oxygen injection.
A novel Hydrodynamic Cavitation-Assisted Oxygen Plasma (HCAOP) process, which employs a venturi tube and oxygen injection, has been developed for enhancing the production and utilization of hydroxyl radicals (·OH) in the degradation of organic pollutants. This study has systematically investigated the fluid characteristics and discharge properties of the gas-liquid two-phase body in the venturi tube. The hydraulic cavitation two-phase body discharge is initiated by the bridging of the cavitation cloud between the electrodes. The discharge mode transitions from diffuse to spark to corona as the oxygen flow rate increases. The spark discharge has the highest current and discharge energy. Excessive oxygen results in the change of the flow from bubbly to annular and a subsequent decrease in discharge energy. The effects of cavitation intensity, oxygen flow rate, and power polarity on discharge characteristics and ·OH production were evaluated using terephthalic acid as a fluorescent probe. It was found that injecting 3 standard liter per minute (SLPM) of oxygen increased the ·OH yield by 6 times with only 1.2 times increase in power, whereas<0.5 SLPM of oxygen did not improve the ·OH yield due to lower breakdown voltage. Negative polarity voltage increased the breakdown voltage and ·OH yield due to asymmetric density and pressure distribution in the throat tube. This polarity effect was explained by numerical simulation. Using indigo carmine (E132) as a model pollutant, the HCAOP process degraded 20 mg/L of dye in 5 L water within 2 min following a first-order reaction. The lowest electric energy per order (EEO) was 0.26 (kWh/m3/order). The HCAOP process is a highly efficient flow-type advanced oxidation process with potential industrial applications.


Quantitation of epinephrine- and glucagon-sensitive adenylate cyclases of rat liver. Implications of alterations of enzymatic activities during preparation of particulate fractions and membranes.
Stimulated and basal adenylate cyclase activities from livers of young and old rats were lower in particulates than in homogenates. Particulates were compared to homogenates by reconstituting the suspensions to the volume of the homogenates from which they were derived; enzyme activities in paired homogenates and particulates therefore reflected the same amounts of membrane-bound enzyme. The magnitude of the losses of hormone-sensitive activities in particulates was dependent on the age and sex of the animals and the concentrations of hormone. Particulates from 3-month-old animals showed glucagon-(1 . 10(-5) M) and epinephrine-sensitive (1 . 10(-4) M) activities which were 67 and 78% of homogenate activities, respectively; particulates from 24-month-old animals had activities relative to homogenates of 55% for glucagon and as low as 32% for epinephrine. The glucagon dose vs. response curve in particulates and membranes showed maximal activity at 1 . 10(-7) M glucagon while in homogenates activity increased linearly with increasing glucagon concentrations up to 1 . 10(-5) M. Losses of basal and anion-stimulated activities were similar at both ages. Fluoride and azide stimulations relative to basal activities were greater in particulates than in homogenates, while relative epinephrine activity was lower in particulates, suggesting qualitative alteration of adenylate cyclase during preparation of particulates. These studies show that adenylate cyclase activity in rat liver is presently best quantitated in homogenates and suggest caution in comparisons of enzyme activities based on particulates or membranes prepared from animals of differing physiologic states.


The Role of Dialysis Membranes on Intradialytic Selenium Removal and on Selenium Status in Patients Receiving Renal Replacement Therapy.
Dialysis membrane has been implicated in selenium (Se) deficiency in hemodialysis (HD). Intradialytic Se removal into dialysate through different membranes was investigated. We studied 19 patients on standard HD with low-flux polysulfone membrane (group A), 10 patients on standard HD with ethylene vinyl alcohol membrane (group B), 12 patients on hemodiafiltration (HDF; group C) and 16 healthy subjects (control group D). Se was measured in blood before and after dialysis session and in effluent dialysate every hour during session. In all patients together, pre-dialysis serum Se levels were lower than those in control group, but, in a separate analysis, only in standard HD. In all patient groups, there was a net Se removal into dialysate but it was greater in HDF patients who, however, had similar pre-dialysis serum Se levels to those in healthy controls. An intradialytic Se loss was found with all 3 membrane types, but it is not the principal factor for Se depletion in HD.


Evaluation of six regions for their potential as DNA barcodes in epiphyllous liverworts from Thailand.
Studies on the diversity of epiphyllous bryophytes have been limited because of minute and incomplete specimens and a lack of taxonomic expertise. The recent development of the DNA barcoding approach has allowed taxon identification and species discovery of many obscure groups of organisms. With DNA extractions from 99 samples of 16 species, we compared the efficiencies of six DNA markers (rbcL, matK, trnL-F, psbA, ITS1, and ITS2) in their ability to amplify, using a standard set of primers, as well as their discriminatory power, using distance-based and tree-based approaches with nucleotide data. The amplification success was relatively high (70-90%) with all of the markers, except for matK, which yielded no success. The barcoding gap, as calculated from the difference between inter- and intraspecific genetic distances, was the highest in ITS2, whereas the highest numbers of monophyletic groups were found with ITS2 and rbcL. rbcL should be used as a main barcoding marker with the addition of ITS2 for epiphyllous species. The development of DNA barcoding as a tool for quantifying species diversity will provide a rapid and reliable identification tool for epiphyllous bryophytes.


A novel in vivo approach to assess strains of the human abdominal wall under known intraabdominal pressure.
The study concerns mechanical behaviour of a living human abdominal wall. A better mechanical understanding of a human abdominal wall and recognition of its material properties is required to find mechanically compatible surgical meshes to significantly improve the treatment of ventral hernias. A non-invasive methodology, based on in vivo optical measurements is proposed to determine strains of abdominal wall corresponding to a known intraabdominal pressure. The measurement is performed in the course of a standard procedure of peritoneal dialysis. A dedicated experimental stand is designed for the experiment. The photogrammetric technique is employed to recover the three-dimensional surface geometry of the anterior abdominal wall at the initial and terminal instants of the dialysis. This corresponds to two deformation states, before and after filling the abdominal cavity with dialysis fluid. The study provides information on strain fields of living human abdominal wall. The inquiry is aimed at principal strains and their directions, observed at the level from -10% to 17%. The intraabdominal pressure related to the amount of introduced dialysis fluid measured within the medical procedure covers the range 11-18.5 cmH2O. The methodology leads to the deformation state of the abdominal wall according to the corresponding loading conditions. Therefore, the study is a step towards an identification of mechanical properties of living human abdominal wall.


Spatiotemporal dynamics of innate immune signaling via RIG-I-like receptors.
RIG-I, MDA5, and LGP2 comprise the RIG-I-like receptors (RLRs). RIG-I and MDA5 are essential pathogen recognition receptors sensing viral infections while LGP2 has been described as both RLR cofactor and negative regulator. After sensing and binding to viral RNA, including double-stranded RNA (dsRNA), RIG-I and MDA5 undergo cytosol-to-membrane relocalization to bind and signal through the MAVS adaptor protein on intracellular membranes, thus directing downstream activation of IRF3 and innate immunity. Here, we report examination of the dynamic subcellular localization of all three RLRs within the intracellular response to dsRNA and RNA virus infection. Observations from high resolution biochemical fractionation and electron microscopy, coupled with analysis of protein interactions and IRF3 activation, show that, in resting cells, microsome but not mitochondrial fractions harbor the central components to initiate innate immune signaling. LGP2 interacts with MAVS in microsomes, blocking the RIG-I/MAVS interaction. Remarkably, in response to dsRNA treatment or RNA virus infection, LGP2 is rapidly released from MAVS and redistributed to mitochondria, temporally correlating with IRF3 activation. We reveal that IRF3 activation does not take place on mitochondria but instead occurs at endoplasmic reticulum (ER)-derived membranes. Our observations suggest ER-derived membranes as key RLR signaling platforms controlled through inhibitory actions of LGP2 binding to MAVS wherein LGP2 translocation to mitochondria releases MAVS inhibition to facilitate RLR-mediated signaling of innate immunity.


Sprouty2 Protein Regulates Hypoxia-inducible Factor-α (HIFα) Protein Levels and Transcription of HIFα-responsive Genes.
The α-subunits of hypoxia-inducible factors (HIF1α and HIF2α) promote transcription of genes that regulate glycolysis and cell survival and growth. Sprouty2 (Spry2) is a modulator of receptor tyrosine kinase signaling and inhibits cell proliferation by a number of different mechanisms. Because of the seemingly opposite actions of HIFα subunits and Spry2 on cellular processes, we investigated whether Spry2 regulates the levels of HIF1α and HIF2α proteins. In cell lines from different types of tumors in which the decreased protein levels of Spry2 have been associated with poor prognosis, silencing of Spry2 elevated HIF1α protein levels. Increases in HIF1α and HIF2α protein levels due to silencing of Spry2 also up-regulated HIFα target genes. Using HIF1α as a prototype, we show that Spry2 decreases HIF1α stability and enhances the ubiquitylation of HIF1α by a von Hippel-Lindau protein (pVHL)-dependent mechanism. Spry2 also exists in a complex with HIF1α. Because Spry2 can also associate with pVHL, using a mutant form of Spry2 (3P/3A-Spry2) that binds HIF1α, but not pVHL, we show that WT-Spry2, but not the 3P/3A-Spry2 decreases HIF1α protein levels. In accordance, expression of WT-Spry2, but not 3P/3A-Spry2 results in a decrease in HIF1α-sensitive glucose uptake. Together our data suggest that Spry2 acts as a scaffold to bring more pVHL/associated E3 ligase in proximity of HIF1α and increase its ubiquitylation and degradation. This represents a novel action for Spry2 in modulating biological processes regulated by HIFα subunits.


Oral contrast agents lead to underestimation of dose calculation in volumetric-modulated arc therapy planning for pelvic irradiation.
The effects of oral contrast agents (OCAs) on dosimetry have not been studied in detail. Therefore, this study aimed to examine the influence of OCAs on dose calculation in volumetric-modulated arc therapy plans for rectal cancer. From 2008 to 2016, computed tomography (CT) images were obtained from 33 rectal cancer patients administered OCA with or without intravenous contrast agent (ICA) and 14 patients who received no contrast agent. CT numbers of organs at risk were recorded and converted to electronic densities. Volumetric-modulated arc therapy plans were designed before and after the original densities were replaced with non-enhanced densities. Doses to the planned target volume (PTV) and organs at risk were compared between the plans. OCA significantly increased the mean and maximum densities of the bowels, while the effects of ICA on these parameters depended on the blood supply of the organs. With OCA, the actual doses for PTV were significantly higher than planned and doses to the bowel increased significantly although moderately. However, the increase in the volume receiving a high-range doses was substantial (the absolute change of intestine volume receiving ≥52 Gy: 1.46 [0.05-3.99, cubic centimeter range: -6.74 to 128.12], the absolute change of colon volume receiving ≥50 Gy: 0.34 [0.01-1.53 cc, range: -0.08 to 3.80 cc]. Dose changes due to ICA were insignificant. Pearson correlation showed that dose changes were significantly correlated with a high intestinal volume within or near the PTV (ρ > 0.5, P < 0.05) and with the density of enhanced intestine (ρ > 0.3, P < 0.05). Contrast agents applied in simulation cause underestimation of doses in actual treatment. The overdose due to ICA was slight, while that due to OCA was moderate. The bowel volume receiving ≥50Gy was dramatically increased when OCA within the bowel was absent. Physicians should be aware of these issues if the original plan is barely within clinical tolerance or if a considerable volume of enhanced intestine is within or near the PTV.


Naphthalene- and anthracene-2,3-dialdehyde as precolumn labelling reagents for primary amines using reversed- and normal-phase liquid chromatography with peroxyoxalate chemiluminescence detection.
Naphthalene-2,3-dialdehyde (NDA) and anthracene-2,3-dialdehyde (ADA) were applied as pre-column labelling reagents for the peroxyoxalate chemiluminescence detection of primary amines. The advantages of these labels are the selective derivatization reaction with primary amines and the good chemiluminescence properties. A serious disadvantage is the formation of cyanide-induced side-products which are major interferences in reversed-phase chromatography. For normal-phase chromatography, the excess of reagent was removed by adding a polar amine after derivatization, with subsequent extraction of the labelled analyte with an apolar solvent. The detection limit for NDA-labelled fluvoxamine, an anti-depressant, was in the low femtomole range in standard solutions and in urine samples. For ADA-labelled analytes difficulties were obtained with linearity in peroxyoxalate chemiluminescence detection, probably owing to oxidation of the derivative by hydrogen peroxide.


Assessing outcomes from rhinoplasty using clinical and patient reported measures (FACE-Q™).
To assess the effect of cosmetic rhinoplasty on PROMS using the FACE-Q™ tool. Between July 2020 and February 2022 all patients undergoing rhinoplasty by a single surgeon were approached pre-operatively and 6 months post-operatively to complete the Face-Q™ "Satisfaction with Nose" module. Post-operative patients were asked to complete the FACE-Q™ "Satisfaction with Outcome" module. One hundred and sixty-five patients underwent rhinoplasty (147 primary, 18 revisions). Eighty two percent (n = 135) completed a pre-operative "Satisfaction with Nose" module. Thirty three percent (n = 54) completed the full pre and post- operative dataset. The mean pre-operative "Satisfaction with Nose" score was 32.88 (± 8.40). The mean post-operative "Satisfaction with Nose" score was 77.45 (SD17.26) and "Satisfaction with Outcome" score was 75.27(SD 21.88). The mean change in score 133% (SD 63%). Seventy-seven percent of patients were "very satisfied" or "somewhat satisfied" across all 10 aspects of the nose. The tip had the lowest post-operative satisfaction with 19% of patients somewhat or very dissatisfied. Rhinoplasty generates significant improvements in PROMS and satisfaction is high, an important positive finding for patients considering surgery. Routine collection of PROMS for rhinoplasty can inform practice and guide expectations as to its psychological impact.