Occurrence, distribution and seasonal variation of chlorinated paraffins in coral communities from South China Sea.
Our previous study revealed bioaccumulation and trophic magnification of chlorinated paraffins (CPs) in marine organisms. However, little is known about the occurrence and distribution of CPs in coral reef ecosystems. In this study, the levels of short-chain chlorinated paraffins (SCCPs) and medium-chain chlorinated paraffins (MCCPs) were determined in ten common coral species from the coastal regions of Hainan Island, South China Sea. SCCPs and MCCPs were detected in all coral species in concentrations ranging from 184 to 7,410 and 305 to 14,800 ng g-1 lw, respectively. In most of the coral species, congener group patterns of the SCCPs and MCCPs were dominated by C10Cl6-8 and C14Cl7-8, respectively. The CP levels and congener group patterns changed slightly between the dry and wet seasons. Redundancy analyses indicated that the accumulation patterns of CPs in different corals were partly influenced by Symbiodinium densities and coral species. Significant negative correlations were found between Symbiodinium densities and CP levels. This is the first report of CP exposure in reef corals and highlights the need for CP toxicity data to evaluate the health of coral reef ecosystems.


Indices for the age of the creatine kinase M-chain in the blood.
The apparent activation energy of the CK reaction as well as the Michaelis-Menten constants and the isoelectric point of CK MM can be used as indices for the mean age of the CK M-chain in the blood in vivo and in vitro. Modifications in the CK M-chain take place in vivo in the blood and in vitro in a serum matrix. Gradual increases in the apparent activation energy are also observed both in vivo and in vitro. It is confirmed that the modification in the CK M-chain causes a rise in the apparent activation energy, mu. A gradual increase in apparent activation energy, due to the ageing process of the CK M-chain, was observed after myocardial infarction. A significantly increased value for u was observed at the time that total CK activity already had returned to reference values. In spite of the normal CK value, the apparent activation energy still indicated that there had been myocardial damage. The Michaelis-Menten constants for creatine phosphate and ADP are also influenced significantly by the modification in the M-chain. While the apparent activation energy increases, the Michaelis constants decrease in the order MM3, MM2, MM1. The Michaelis-Menten constants for both ADP and CrP can be used as an index for the mean age of the enzyme in the blood. The Michaelis-Menten constants for CrP and ADP show significant variations with the measuring temperature for virtually all CK MM forms.


Effect of alkalinization and/or hyaluronidase adjuvancy on a local anesthetic mixture for sub-Tenon's ophthalmic block.
pH adjustment and/or addition of hyaluronidase to local anesthetic drugs decrease the time to onset and prolong the duration of regional anesthetic techniques for ocular surgery. The objective of this study was to investigate whether these factors are effective also in sub-Tenon's block. Sixty patients were randomly assigned to four groups in a double blind, prospective fashion, and received 5.125 ml mixtures as follows: 2.5 ml lignocaine 2%, 2.5 ml bupivacaine 0.5% and 0.125 ml isotonic saline (group LB); 2.5 ml lignocaine 2%, 2.5 ml bupivacaine 0.5%, 15 IU hyaluronidase/ml and 0.125 ml isotonic saline (group LBH); 2.5 ml lignocaine 2%, 2.5 ml bupivacaine 0.5% and 0.125 ml sodium bicarbonate 8.4% (group LBpH); and 2.5 ml lignocaine 2%, 2.5 ml bupivacaine 0.5%, 15 IU hyaluronidase/ml and 0.125 ml sodium bicarbonate 8.4% (group LBHpH). This measurement was based on one quadrant sub-Tenon's block. Akinesia was assessed every 30 s. No statistically significant differences were found between the groups regarding mean times to onset and to complete akinesia. Group LBH displayed a significantly lower frequency of patients experiencing pain and a lower need for rescue medication during surgery than the other groups. pH adjustment and/or addition of hyaluronidase to a mixture of lignocaine and bupivacaine did not shorten the time to onset of akinesia following sub-Tenon's technique. However, the addition of hyaluronidase was associated with a lower fraction of patients experiencing pain during surgery.


Promoted spatial charge separation of plasmon Ag and co-catalyst Co x P decorated mesoporous g-C3N4 nanosheet assembly for unexpected solar-driven photocatalytic performance.
Plasmon Ag and co-catalyst Co x P decorated mesoporous graphite carbon nitride nanosheet assemblies have been synthesized via a template-calcination and ball milling strategy combined with photoreduction. The obtained composites are characterized by x-ray diffraction, Fourier transmission infrared spectroscopy, x-ray photoelectron spectroscopy, transmission electron microscopy, and UV-vis diffuse reflectance spectroscopy. The results show that the sample assembly with mesoporous structure has specific surface area of 50.4 m2 g-1, pore size of 11.3 nm and pore volume of 0.21 cm3 g-1. The Ag and Co x P nanoparticles are decorated on the surface of graphite carbon nitride uniformly. Under solar light irradiation, the photocatalytic degradation rate of ceftazidime for the prepared sample assembly is up to ∼92%, and the photocatalytic reaction rate constant is about 10 times higher than that of bare graphite carbon nitride. Moreover, the sample assembly also exhibits a solar-driven photocatalytic hydrogen production rate of 96.66 μmol g-1 h-1. It can attributed to the surface plasmon resonance effect of Ag nanoparticles and Co x P co-catalyst promoting the spatial charge separation and the mesoporous structure providing more surface active sites and favoring mass transfer. This special structure offers new insights for fabricating other high-performance photocatalysts with high spatial charge separation.


Involvement of p38 mitogen-activated protein kinase in the induction of interleukin-12 p40 production in mouse macrophages by berberine, a benzodioxoloquinolizine alkaloid.
Interleukin (IL)-12 plays a pivotal role in the development of T helper type 1 (Th1)-immune response, which may have therapeutic effects on diseases associated with pathologic Th2 responses such as allergic disorders and asthma. In this study, we investigated the effects of berberine, a benzodioxoloquinolizine alkaloid with anti-microbial and anti-tumor activities, on the production of IL-12 p40, an inducible subunit of IL-12, in mouse macrophages. Berberine-induced IL-12 p40 production and activation of p38 mitogen-activated protein kinase (MAPK) in dose-dependent manners, which were significantly inhibited by p38 MAPK inhibitors and yohimbine, indicating that p38 MAPK and alpha(2)-adrenergic receptor were involved in the induction of IL-12 p40 production in mouse macrophages by berberine. Furthermore, berberine significantly enhanced IL-12 p40 production in mouse macrophages when combined with lipopolysaccharide, a well-known inducer of IL-12 production. These findings may explain some of the known biological effects of berberine and suggests berberine as an immunotherapeutic compound for induction of IL-12, which is potentially applicable for tumors, infectious disease, and airway inflammation.


The kinetic mechanism for cytochrome P450 metabolism of type II binding compounds: evidence supporting direct reduction.
The metabolic stability of a drug is an important property that should be optimized during drug design and development. Nitrogen incorporation is hypothesized to increase the stability by coordination of nitrogen to the heme iron of cytochrome P450, a binding mode that is referred to as type II binding. However, we noticed that the type II binding compound 1 has less metabolic stability at sub-saturating conditions than a closely related type I binding compound 3. Three kinetic models will be presented for type II binder metabolism; (1) Dead-end type II binding, (2) a rapid equilibrium between type I and II binding modes before reduction, and (3) a direct reduction of the type II coordinated heme. Data will be presented on reduction rates of iron, the off rates of substrate (using surface plasmon resonance) and the catalytic rate constants. These data argue against the dead-end, and rapid equilibrium models, leaving the direct reduction kinetic mechanism for metabolism of the type II binding compound 1.


High density lipoproteins in ischaemic heart disease.
High density lipoprotein cholesterol concentrations were significantly lower in ischaemic heart disease patients than in healthy subjects when age and sex-matched. This difference was, however, not observed in the older age group (greater than 60 years).


Performance of the Italian version of the subjective well-being under neuroleptic (SWN) scale in schizophrenic outpatients.
Several studies indicate that subjective experience toward antipsychotic drugs (APs) in schizophrenic patients is a key factor in ensuring a smooth recovery from the illness. The principal aim of this study was to establish the psychometric performance of the Subjective Well-being Under Neuroleptic (SWN) scale in its Italian version and to assess, through the SWN scale, the subjective experience of stabilized psychotic outpatients in maintenance with APs. The original short version of SWN, consisting of 20 items, was back translated, and a focus group was also conducted to better improve the comprehension of the scale. The results showed a good performance of the Italian version of the SWN as documented by the internal consistency (Cronbach's alpha; 0.85). A satisfactory subjective experience was reported in the sample of schizophrenic outpatients interviewed (SWN mean total score: 84.95, SD: 17.5). The performance of the SWN scale in the present study was very similar to that reported by Naber et al. in the original validation study. Large multi-center studies are needed to better establish differences in the subjective experience of schizophrenic patients treated with first- and second-generation APs.


Overexpression of folate biosynthesis genes in rice (Oryza sativa L.) and evaluation of their impact on seed folate content.
Folate (vitamin B9) deficiency is a global health problem especially in developing countries where the major staple foods such as rice contain extremely low folates. Biofortification of rice could be an alternative complement way to fight folate deficiency. In this study, we evaluated the availability of the genes in each step of folate biosynthesis pathway for rice folate enhancement in the japonica variety kitaake genetic background. The first enzymes GTP cyclohydrolase I (GTPCHI) and aminodeoxychorismate synthase (ADCS) in the pterin and para-aminobenzoate branches resulted in significant increase in seed folate content, respectively (P < 0.01). Overexpression of two closely related enzymes dihydrofolate synthase (DHFS) and folypolyglutamate synthase (FPGS), which perform the first and further additions of glutamates, produced slightly increase in seed folate content separately. The GTPCHI transgene was combined with each of the other transgenes except ADCS to investigate the effects of gene stacking on seed folate accumulation. Seed folate contents in the gene-stacked plants were higher than the individual low-folate transgenic parents, but lower than the high-folate GTPCHI transgenic lines, pointing to an inadequate supply of para-aminobenzoic acid (PABA) precursor initiated by ADCS in constraining folate overproduction in gene-stacked plants.


Risk Factors Associated with Inadequate Bowel Preparation in Patients with Functional Constipation.
Constipation is a common reason of poor bowel preparation, which negatively influences the quality of colonoscopy. Risk factors for inadequate bowel preparation in constipated patients remain unclear. This study aimed to investigate the high-risk factors that might influence the quality of bowel preparation in patients with functional constipation. Consecutive patients with functional constipation who underwent colonoscopy between June 2016 and April 2017 were enrolled. A standard split dose of 4 l polyethylene glycol was used for bowel preparation. Patient- and procedure-related parameters were recorded. The primary outcome was an adequate rate of bowel preparation. Risk factors for inadequate bowel preparation were screened by multivariate logistic regression analysis. A total of 199 patients were included. Adequate bowel preparation was found in 62.8% (125/199) of patients. At multivariate analysis, Bristol stool form scale (BSFS) 1 [odds ratio (OR) 2.73, 95% confidence interval (CI) 1.26-5.90; P = 0.011], rectal pain score during defecation < 2 (OR 4.14, 95% CI 1.22-13.97; P = 0.022), and starting-to-defecation interval ≥ 4 h (OR 3.83, 95% CI 1.34-10.91; P = 0.012) were risk factors for inadequate bowel preparation in patients with constipation. For patients with no, 1, 2, or 3 risk factors, the rates of inadequate bowel preparation were 11%, 23%, 49%, and 65%, respectively. With the standard preparation regime, > 1/3 of patients with functional constipation had inadequate bowel cleansing. BSFS 1, rectal pain score during defecation < 2, and starting-to-defecation interval ≥ 4 h were identified as independent risk factors for inadequate bowel preparation in constipated patients. ClinicalTrials.gov number NCT02842411.


Mediated semantic priming interference in toddlers as seen through pupil dynamics.
Mediated priming refers to the activation of a target word by a prime word through an intermediate word. This type of priming provides behavioral evidence of between- and within-level spreading activation in the lexical system. Studies of toddlers show phonosemantic between-level mediated priming that supports a cascade of activation between different levels of processing. However, it is not clear whether the activation can spread freely within the same level. This study explored whether 24-month-old toddlers show mediated priming effects at the semantic level (e.g., cat [prime] - mouse [mediator] - cheese [target]) with a preferential looking task using an eye tracker. The results show a smaller proportion of target looking and greater pupil size in the related condition than in the unrelated condition; these effects were greater in the second half of the analysis window. We interpret these data as a spreading activation that is partially free but modulated during infancy. We also provide evidence of pupil dilation as a neurophysiological marker in a preferential looking task with priming. We discuss the results in light of the cognitive control, inhibition, and general cognitive skills of toddlers.


The effect of roasting, storage temperature, and ethanoic basil (Ocimum basilicum L.) extract on the oxidative stability of crude sesame (Sesamum indicum L.) oil.
Sesame (Sesamum indicum L.) is an annual oilseed crop that is widely used for crude sesame oil (CSO) extraction. CSO is unrefined, thus, may impact the storage stability due to the uncontrolled processing and handling conditions, and absence of preservatives. The purpose of this study intends to analyze the fatty acid profile and oxidative stability of CSO. In a complete randomized (2*2*2) factorial design, clean sesame seeds (3.92% moisture content) were used for oil extraction with/without roasting treatment (200°C). The fatty acid profile and oxidative value of the CSO were analyzed. The roasted sesame seed oil extraction yield was higher (50.9%) and composed of 83.15% unsaturated fatty acids with an omega-6 to omega-3 ratio of 95.3. The ratio of polyunsaturated fatty acids (PUFAs) to saturated fatty acids (SFAs) was 2.9, while the moisture content of the CSO was 0.37%, exceeding the tolerable limit. The predominant fatty acids of CSO include palmitic, stearic, oleic, and linoleic acids. Elevated thermal condition during processing and handling speeding up oxidation exceeded the tolerable limit after 25 days of storage, while the ethanoic basil extract was found to inhibit oxidation in the range of 16.38%-90% (p-value < .05). The peroxide value (PV), para-anisidine value (p-AV), and total oxidation (TOTOX) value of CSO with 50 ppm (parts per million) basil extract were detected within the range of 0.29-3.92, 0.75-2.59, and 1.57-8.6 milliequivalents (meq) O2/kg oil, respectively, below the tolerable limit. Nevertheless, basil extract's antioxidant property was declined during prolonged storage, in particular, at elevated temperature. The use of organic extracts of locally available sweet basil herb is capable of mitigating oxidation and substituting inorganic antioxidant for a healthier diet.


Manipulating low-dimensional materials down to the level of single atoms with electron irradiation.
Recent advances in scanning transmission electron microscopy (STEM) instrumentation have made it possible to focus electron beams with sub-atomic precision and to identify the chemical structure of materials at the level of individual atoms. Here we discuss the dynamics that are observed in the structure of low-dimensional materials under electron irradiation, and the potential use of electron beams for single-atom manipulation. As a demonstration of the latter capability, we show how momentum transfer from the electrons of a 60-keV Ångström-sized STEM probe can be used to move silicon atoms embedded in the graphene lattice with atomic precision.


The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy.
The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin-angiotensin-aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. We identified a SNP within the EGFR promoter that modulates MR-induced EGFR expression. In RNA-sequencing and qPCR experiments in heart tissue of EGFR KO and WT mice, changes in EGFR abundance led to differential expression of cardiac ion channels, especially of the T-type calcium channel CACNA1H. Accordingly, CACNA1H expression was increased in WT mice after in vivo MR activation by aldosterone but not in respective EGFR KO mice. Aldosterone- and EGF-responsiveness of CACNA1H expression was confirmed in HL-1 cells by Western blot and by measuring peak current density of T-type calcium channels. Aldosterone-induced CACNA1H protein expression could be abrogated by the EGFR inhibitor AG1478. Furthermore, inhibition of T-type calcium channels with mibefradil or ML218 reduced diameter, volume and BNP levels in HL-1 cells. In conclusion the MR regulates EGFR and CACNA1H expression, which has an effect on HL-1 cell diameter, and the extent of this regulation seems to depend on the SNP-216 (G/T) genotype. This suggests that the EGFR may be an intermediate for MR-mediated cardiovascular changes and that SNP analysis can help identify subgroups of patients that will benefit most from MR antagonists.


Effects of orthognathic surgery on oropharyngeal airway: a meta-analysis.
Oropharyngeal changes caused by orthognathic surgery have been a concern because the sleep quality of patients may be enhanced or worsened by these changes. The purpose of this meta-analysis was to identify, review and compare scientific literature about changes in airway in adult patients undergoing orthognathic surgery to correct anteroposterior osseous discrepancies. An electronic search of four databases was carried out up to July 2010, with supplemental hand searching of the references of the retrieved articles. Quality assessment of the included articles was carried out. Data were extracted and a meta-analysis was performed. Heterogeneity was assessed amongst the studies and results were presented in forest plots. 49 studies met the inclusion criteria. Only studies with moderate or high methodological soundness were included in the review. Moderate evidence was found to support a significant decrease in the oropharyngeal airway in mandibular setback surgery, a milder decrease in bimaxillary surgery to correct Class III and an increase in maxillomandibular advancement surgery. Evidence is lacking on airway volume changes after orthognathic surgery.


Long-term urine biobanking: storage stability of clinical chemical parameters under moderate freezing conditions without use of preservatives.
To examine the long-term stability and validity of analyte concentrations of 21 clinical biochemistry parameters in 24-h urine samples stored for 12 or 15 yr at -22°C and preservative free. Healthy children's 24-h urine samples in which the respective analytes had been measured shortly after sample collection (baseline) were reanalyzed. Second measurement was performed after 12 yr (organic acids) and 15 yr (creatinine, urea, osmolality, iodine, nitrogen, anions, cations, acid-base parameters) with the same analytical methodology. Paired comparisons and correlations between the baseline and repeated measurements were done. Recovery rates were calculated. More than half of the analytes (creatinine, urea, iodine, nitrogen, sodium, potassium, magnesium, calcium, ammonium, bicarbonate, citric & uric acid) showed measurement values after >10 yr of storage not significantly different from baseline. 15 of the 21 parameters were highly correlated (r=0.99) between baseline and second measurement. Poorest correlation was r=0.77 for oxalate. Recovery ranged from 73% (oxalate) to 105% (phosphate). Our results suggest high long-term stability and measurement validity for numerous clinical chemistry parameters stored at -22°C without addition of any urine preservative. Prospective storage of urine aliquots at -22°C for periods even exceeding 10 yr, appears to be an acceptable and valid tool in epidemiological settings for later quantification of several urine analytes.


Trends in sedation practices in Danish intensive care units in 2003: a national survey.
The aim of the study was to explore trends and changes in sedation practices for mechanically ventilated patients in Danish intensive care units (ICUs) and to compare sedation practices in 1997 and 2003. The study was a follow-up survey with a descriptive and comparative cross-sectional multicenter design. Questionnaires were mailed in January 2003 to all Danish ICUs providing mechanical ventilation (n=48). One head physician at each ICU in Denmark. INTERVENTIONS, MEASUREMENTS, AND RESULTS: Thirty-nine questionnaires were returned, yielding a response rate of 81%, representing 82% of Danish ICU beds. The main findings were a significant increase in the use of sedation scoring systems and a significant reduction of sedation and analgesia in relation to various modalities of mechanical ventilation and disease groups. Other important findings were a significant reduction in the use of benzodiazepines and opioids and a significant increase in the use of propofol in relation to all ventilator modes. The administration routes of sedative agents remained unchanged. Sedatives and analgesics are still widely used in Danish ICUs. The trend is toward lighter sedation along with a shift from benzodiazepines toward propofol and from morphine toward fentanyl given by continuous infusion. More attention needs to be directed toward sedation standards and scoring systems in order to reduce the risk associated with sedation in mechanically ventilated patients.


Dependency of energy and spatial distributions of photons on edge of object in brain SPECT.
Accurate mu maps are important for quantitative image reconstruction in SPECT. The Compton scatter energy window (CSW) technique has been proposed to define the outline of objects. In this technique, a lower energy window image is acquired in addition to the main photo-peak energy window. The image of the lower energy window is used to estimate the edge of the scanned object to produce a constant attenuation map. The aim of this study was to investigate the dependency of CSW on the spatial and energy distribution of radioisotope to predict the edges of objects. Two particular cases of brain study were considered, namely uniform distribution and non-uniform distribution using Monte Carlo simulation and experiments with uniform cylindrical phantom and hotspot phantom. The phantoms were filled with water and a radioactive solution of 99mTc. For each phantom, 20%, 30%, 40% and 50% thresholds of the mean profile were applied to estimate Ewt, the energy window for minimum difference between the estimated and true edge of objects. The Ewt's were 100-120 keV with a 40% threshold and 92-114 keV with a 30% threshold for uniform and hotspot phantoms, respectively. Edge of the objects with CSW technique varies with energy window and thresholds. Careful setting of the energy window is required to use the CSW technique.


Chronic Kidney Disease-State of Either "Too Much" or "Too Little".
Chronic kidney disease (CKD) is a world-wide phenomenon with an increasing incidence and prevalence [...].


Functional effects of disease-associated variants reveal that the S1-M1 linker of the NMDA receptor critically controls channel opening.
The short pre-M1 helix within the S1-M1 linker (also referred to as the pre-M1 linker) between the agonist-binding domain (ABD, S1) and the M1 transmembrane helix of the NMDA receptor (NMDAR) is devoid of missense variants within the healthy population but is a locus for de novo pathogenic variants associated with neurological disorders. Several de novo variants within this helix have been identified in patients presenting early in life with intellectual disability, developmental delay, and/or epilepsy. In this study, we evaluated functional properties for twenty variants within the pre-M1 linker in GRIN1, GRIN2A, and GRIN2B genes, including six novel missense variants. The effects of pre-M1 variants on agonist potency, sensitivity to endogenous allosteric modulators, response time course, channel open probability, and surface expression were assessed. Our data indicated that virtually all of the variants evaluated altered channel function, and multiple variants had profound functional consequences, which may contribute to the neurological conditions in the patients harboring the variants in this region. These data strongly suggest that the residues within the pre-M1 helix play a key role in channel gating and are highly intolerant to genetic variation.


Elevated resting heart rate is an independent risk factor for cardiovascular disease in healthy men and women.
Elevated resting heart rate (RHR) is known to be associated with reduced survival but inconsistencies remain, including lack of significance in most studies of healthy women, lack of independence from systolic blood pressure (SBP) in some, and the suggestion that RHR is merely functioning as a marker of physical inactivity or other comorbidities. We aimed to clarify these inconsistencies. We analyzed the effect of RHR on end points in the National FINRISK Study; a representative, prospective study using Cox proportional hazards model. Ten-thousand five-hundred nineteen men and 11,334 women were included, excluding those with preexisting coronary heart disease, angina, heart failure, or on antihypertensive therapy. The hazard ratios for cardiovascular disease (CVD) mortality for each 15 beats/min increase in RHR were 1.24 (1.11-1.40) in men and 1.32 (1.08-1.60) in women, adjusted for age, gender, total cholesterol, physical activity (categorical), SBP, body mass index, and high-density lipoprotein cholesterol. This relationship remained significant after exclusion of those with comorbidities and events occurring within first 2 years of observation. Relationship with coronary mortality was stronger and with total mortality was slightly weaker. Inclusion of nonfatal end points weakened the relationship. A strong, graded, independent relationship between RHR and incident CVD was demonstrated. This was consistent in healthy men and women. We have clarified that the relationship is independent of SBP and that the temporal sequence would be compatible with a causal relationship. New findings include independence from both a validated measure of physical activity and comorbidities and the demonstration of a stronger effect for fatal than nonfatal events, supporting increased arrhythmogenicity of one of the mechanisms.


A single center survey study of systemic vasculitis and COVID-19 during the first months of pandemic
COVID-19 pandemic created concerns among patients receiving immunosuppressive therapy. Frequency of COVID-19 and impact of lockdown on treatment compliance in patients with vasculitis are largely unknown. Patients with ANCA-associated and large vessel vasculitis that have been followed-up in our clinic were contacted by phone and a questionnaire containing home isolation status, treatment adherence and history of COVID -19 between March 1st and June 30th, 2020 was applied. The survey was applied to 103 patients (F/M: 59/44, mean age: 53.2±12.5). Thirty-three (32%) patients didn?t attend at least one appointment; 98(95.1%) noted that they spent 3 months in home isolation. Five patients (4.8%) received immunosuppressives irregularly and 3(2.9%) developed symptoms due to undertreatment. Four (3.9%) patients admitted to hospital with a suspicion of COVID-19, but none of them had positive PCR or suggestive findings by imaging. COVID-19 diagnosed in a patient with granulomatosis with polyangiitis during hospitalization for disease flare and she died despite treatment. Frequency of COVID-19 was low in patients with vasculitis in our single center cohort. Although outpatient appointments were postponed in one-third of our patients, high compliance with treatment and isolation rules ensured patients with vasculitis overcome this period with minimal morbidity and mortality.


Study the lipidoid nanoparticle mediated genome editing protein delivery using 3D intestinal tissue model.
Lipid nanoparticles are promising carriers for oral drug delivery. For bioactive cargos with intracellular targets, e.g. gene-editing proteins, it is essential for the cargo and carrier to remain complexed after crossing the epithelial layer of intestine in order for the delivery system to transport the cargos inside targeted cells. However, limited studies have been conducted to verify the integrity of cargo/carrier nanocomplexes and their capability in facilitating cargo delivery intracellularly after the nanocomplex crossing the epithelial barrier. Herein, we used a traditional 2D transwell system and a recently developed 3D tissue engineered intestine model and demonstrated the synthetic lipid nanoparticle (carrier) and protein (cargo) nanocomplexes are able to cross the epithelial layer and deliver the protein cargo inside the underneath cells. We found that the EC16-63 LNP efficiently encapsulated the GFP-Cre recombinase, penetrated the intestinal monolayer cells in both the 2D cell culture and 3D tissue models through temporarily interrupting the tight junctions between epithelial layer. After transporting across the intestinal epithelia, the EC16-63 and GFP-Cre recombinase nanocomplexes can enter the underneath cells to induce gene recombination. These results suggest that the in vitro 3D intestinal tissue model is useful for identifying effective lipid nanoparticles for potential oral drug delivery.


Chordoma arising from the coccygeal disc and mimicking a pilonidal cyst.
Chordomas are rare, low-grade malignant tumors often found in the sacrococcygeal region and prone to local recurrence. We report an atypical presentation of a 40-year-old patient with a symptomatic midline retrococcygeal lesion that was presumptively treated as a pilonidal cyst due to its clinical and imaging features. After surgical pathology rendered the diagnosis of chordoma, the patient required salvage surgery in the form of partial sacrectomy with soft tissue flap coverage. In addition to the unusually predominant retrococcygeal location, surgical pathology identified an intervertebral disc origin rather than the typical osseous origin. To our knowledge, this presentation of chordoma with coccygeal intervertebral origin and a large subcutaneous mass at imaging has rarely been reported in the literature. We describe this case to raise awareness of atypical presentations of sacrococcygeal chordoma that may lead to erroneous presumptive diagnosis and treatment.


Heterogeneous expression of voltage-gated potassium channels in the heart: roles in normal excitation and arrhythmias.
In the mammalian myocardium, there are marked regional differences in action potential waveforms and frequency dependences. This heterogeneity impacts the normal dispersion of ventricular repolarization and appears to reflect the differential expression of voltage-gated K+ channels. Multiple types of voltage-gated K+ currents have been distinguished in mammalian ventricles and, in many cases, the K+ (Kv) channel pore-forming (alpha) and accessory (beta) subunits encoding these channels have been identified. In the diseased myocardium, remodeling of voltage-gated K+ currents occurs, influencing propagation and rhythmicity, effects that can lead to increased dispersion of ventricular repolarization and create substrates for reentrant arrhythmias. Targeting the K+ channels that function to maintain the normal dispersion of ventricular repolarization could be effective in treating cardiac arrhythmias.


Expansion of the QARS deficiency phenotype with report of a family with isolated supratentorial brain abnormalities.
We describe a family with QARS deficiency due to compound heterozygous QARS mutations, including c.1387G > A (p.R463*) in the catalytic core domain and c.2226C > G (p.Q742H) in the anticodon domain, both previously unreported and predicted damaging. The phenotype of the male index further confirms this specific aminoacyl-transfer RNA (tRNA) synthetase disorder as a novel genetic cause of progressive microcephaly with diffuse cerebral atrophy, severely deficient myelination, intractable seizures, and developmental arrest. However, in contrast to the two hitherto published families, the cerebellum and its myelination are not affected. An awareness that QARS mutations may cause isolated supratentorial changes is crucial for properly directing genetic analysis.


Estimating the force of measles virus infection from hospitalised cases in Lusaka, Zambia.
Estimates of the force of infection (the rate at which susceptible individuals acquire infection) are essential for modelling the transmission dynamics of infectious diseases and can be a useful tool in evaluating mass vaccination strategies. Few estimates exist of the force of infection of measles virus in sub-Saharan Africa. A mathematical model was applied to age-specific recorded hospital admissions between September 1996 and September 1999 to estimate the force of measles virus infection in Lusaka, Zambia. The average force of infection was estimated to be 20% per year (95% confidence intervals (CI) 16.5, 23.5) which was insensitive to varying assumptions about vaccine coverage. The force of infection varied from year to year (P < 0.001) reflecting the cyclic pattern of measles incidence. The estimated probability of a case being hospitalised decreased with age, consistent with less severe disease in older children. Estimates of the force of infection using routinely available data were consistent with those based upon serological surveys in other sub-Saharan African countries.


Enhancement of Cooperation and Reentrant Phase of Prisoner's Dilemma Game on Signed Networks.
We studied the prisoner's dilemma game as applied to signed networks. In signed networks, there are two types of links: positive and negative. To establish a payoff matrix between players connected with a negative link, we multiplied the payoff matrix between players connected with a positive link by -1. To investigate the effect of negative links on cooperating behavior, we performed simulations for different negative link densities. When the negative link density is low, the density of the cooperator becomes zero because there is an increasing temptation payoff, b. Here, parameter b is the payoff received by the defector from playing the game with a cooperator. Conversely, when the negative link density is high, the cooperator density becomes almost 1 as b increases. This is because players with a negative link will suffer more payoff damage if they do not cooperate with each other. The negative link forces players to cooperate, so cooperating behavior is enhanced.


Early parental loss in childhood and depression in adults: A systematic review and meta-analysis of case-controlled studies.
Many researchers have concluded that early parental loss during childhood is a risk factor for depression in late life of adults; however others didn't find any association. The objective of this systematic review is to assess whether this association exists or not by conducting a meta-analysis of published studies. Nine published case-controlled studies were chosen through literature searches in PUBMED, and LIBRARY GENESIS. Newcastle-Ottawa Scale (NOS) have been used to assess the quality of studies included. Thereafter, data were extracted from each study and analysed using ProMeta. Nine case-controlled studies (representing n = 2784, cases=716 and controls=2068) were included in meta-analysis. The overall random effects model results of parental loss [OR = 2.18, 95% CI, 1.63-2.90, p < 0.00; I2 = 15.79%, df = 8, p = 0.302], parental death [OR = 1.76, 95% CI, 1.13-2.73, p = 0.012; I2 = 0.00%, df = 3, p = 0.600] and parental separation [OR = 3.14, 95% CI, 1.92-5.15, p < 0.001; I2 = 0.00%, df = 2, p = 0.675] showed a strong positive effect on developing depression in adults. Egger's linear regression test [t = 0.14, p = 0.895] and Begg and Mazumdar's rank correlation test [z = 0.63, p = 0.532] confirmed absence of publication bias of studies included in this meta-analysis. This systematic review was limited by a small number of case-controlled studies included in meta-analysis due to the differences in methodological designs of studies. The study concluded that parental loss, parental death, and parental separation before age 18 are risk factors of depression in adulthood.


Immunohistochemical Detection of the Chaperone-Mediated Autophagy Markers LAMP2A and HSPA8 in Formalin-Fixed and Paraffin-Embedded Tissues.
Autophagy is crucial for maintaining cellular homeostasis and its deregulation is involved in disease development, including cancer. The key players of chaperone-mediated autophagy (CMA), a particular selective subtype of autophagy, are HSPA8 and LAMP2A. Both proteins can be immunohistochemically detected in formalin-fixed paraffin-embedded (FFPE) tissue. LAMP2A is frequently overexpressed in a variety of cancers where it likely supports cancer cell survival and resistance to anti-cancer therapies in a context-dependent manner. Here we present the immunohistochemical staining protocol of antibodies against LAMP2A and HSPA8, using an automated staining system, suitable for routine diagnostics. Additionally, we also suggest a staining evaluation method.


Will the real resource theory please stand up! Vigilance is a renewable resource and should be modeled as such.
The vigilance decrement or decline in signal detection performance with time on task is one of the most reliable findings in the cognitive neuroscience and psychology literatures. The majority of theories proposed to explain the decrement are limited cognitive or attention resource based theories; the central nervous system is a limited capacity processor. The decrement in performance is then due to resource reallocation (or misallocation), resource depletion or some combination of both mechanisms. The role of resource depletion, in particular, is hotly debated. However, this may be due to a lack of understanding of the renewable nature of the vigilance resources and how this renewal process impacts performance during vigilance tasks. In the present paper, a simple quantitative model of vigilance resource depletion and renewal is described and shown to generate performance data similar to results seen in both humans and spiders. This model clarifies the role resource depletion and resource renewal may play in vigilance in both people and other animals.


Physicochemical properties of starches from diverse rice cultivars varying in apparent amylose content and gelatinisation temperature combinations.
The physicochemical properties of starches isolated from 14 rice cultivars produced in China were investigated. These rice starches showed a non-random combination of AAC and GT. Rice starches showed a typical A-type diffraction pattern with the degree of crystallinity ranging from 32.3% (a high AAC rice) to 45.5% (a waxy rice). AAC was significantly correlated with the pasting, thermal and textural properties. The positive correlations were found with PV, HPV, CPV, SB and HD (p<0.05), while the negative corrections were found with SP, ADH, COH, T(o), T(p), T(c) and ΔH (p<0.05). However, AAC had no correlations with BD, PTime and percentage of retrogradation (R%). The degree of crystallinity and GT had a positive correlation with the retrogradation properties. It could be concluded that although AAC was the major factor affecting the physicochemical properties of rice starch, the retrogradation property of rice starch was mainly determined by the degree of crystallinity and GT.


Administration of analgesia for acute abdominal pain sufferers in the accident and emergency setting.
Recent trials suggest that the early administration of analgesia in patients with acute abdominal pain facilitates examination and does not delay diagnosis. We investigated current practice regarding analgesia for these patients. All patients admitted via the accident and emergency department with abdominal pain were included. The main outcome measures evaluated were waiting time for analgesia and its relationship to subjective visual analogue pain scores and clinical diagnoses. Data from 107 consecutive patients were investigated; seven patients were excluded. Forty-two per cent were male. The mean age was 40.1 years (6-85). The mean overall waiting time for analgesia was 1.4 h (2 min to 14 h). Sixty-seven per cent received analgesia within one hour, although 22% waited 2-14 h after presentation. Those with mild pain waited significantly longer for analgesia (mean 247 min) than those with severe pain (mean 82 min; P=0.01). Those with moderate pain had intermediate waiting times (mean 111 min), although they were not statistically different from the severe group (P=0.43). Female patients had to wait longer (mean 129 min) than male patients (mean 69 min; P=0.09 analysis of variance). Of 64% who were general practitioner referrals, only 11% (all severe group, P=0.02) received analgesia in the community. Neither clinical diagnosis nor age influenced the timing of analgesia. Seventy-three per cent received analgesia in the casualty department (mean 0.5 h; range 0.02-3.2), whereas those admitted in the ward without receiving analgesia in casualty had to wait significantly longer for their pain relief (mean 5 h; 1.2-14). This study shows the need for standardized protocols for analgesia usage in patients presenting with acute abdominal pain.


Function of Polyamines in Regulating Cell Cycle Progression of Cultured Silkworm Cells.
Putrescine, spermidine, and spermine are polyamines that are ubiquitously distributed in prokaryotic and eukaryotic cells, which play important roles in cell proliferation and differentiation. We investigated the expression profiles of polyamine pathway genes by qRT-PCR in different tissues of the lepidopteran silkworm. The polyamine levels in cultured silkworm cells were measured by HPLC. Spermidine and polyamine biosynthetic inhibitors were used for treating the cultured silkworm cells in order to clarify their effects on cell cycle progression. We identified the anabolic and catabolic enzymes that are involved in the polyamine biosynthetic pathway in silkworm. Transcriptional expression showed at least seven genes that were expressed in different silkworm tissues. Treatments of the cultured silkworm cells with spermidine or inhibitor mixtures of DFMO and MGBG induced or inhibited the expression of cell cycle-related genes, respectively, and thus led to changed progression of the cell cycle. The present study is the first to identify the polyamine pathway genes and to demonstrate the roles of polyamines on cell cycle progression via regulation of the expression of cell cycle genes in silkworm.


Resolution of uncertainty of a four-stage sequential extraction procedure using analysis of variance.
Sequential extraction procedures are mostly applied to soils and sediments. Investigations were made for testing the applicability of a selected extraction scheme on spoil pile material. Therefore, different spoil pile samples from uranium mining were extracted into four steps (exchangeable, reducible, oxidizable, and aqua regia soluble phase) and the contents of the elements Cr, Cu, Fe, K, Ni, and Zn were analyzed. To substitute the sequential extraction by a sequence of single extractions and thus keep uncertainties of extraction on a low level, both procedures were compared regarding conformity of their results. The effects of sample handling as well as those of analysis on the measured metal contents were determined by means of analysis of variance and sources of uncertainties were discussed.


An advanced navigational surgery system for dental implants completed in a single visit: an in vitro study.
In this study, we have developed an advanced navigational implant surgery system to overcome some disadvantages of the conventional method and have evaluated the accuracy of the system under in vitro environment. The patient splint for registration and tracking was improvised using a bite splint without laboratory work and the offset of an exchanged drill was calibrated directly without pivoting during surgery. The mean target registration errors (TRE) were 0.35 ± 0.11 mm using the registration body, 0.34 ± 0.18 mm for the registration method with prerecorded fiducials, and 0.35 ± 0.16 mm for the direct calibration of a drill offset. The mean positional deviations between the planned and placed implants in 110 implant surgeries were 0.41 ± 0.12 mm at the center point of the platform and 0.56 ± 0.14 mm at the center point of the apex. The mean angular deviation was 2.64°± 1.31 for the long axis of the implant. In conclusion, the developed system exhibited high accuracy, and the improved tools and simplified procedures increased the convenience and availability. With this advanced approach, it will be possible to complete dental implant surgery during a single visit at local clinics using a navigational guidance involving cone-beam computed tomographic images.


Natural Arabidopsis brx loss-of-function alleles confer root adaptation to acidic soil.
Soil acidification is a major agricultural problem that negatively affects crop yield. Root systems counteract detrimental passive proton influx from acidic soil through increased proton pumping into the apoplast, which is presumably also required for cell elongation and stimulated by auxin. Here, we found an unexpected impact of extracellular pH on auxin activity and cell proliferation rate in the root meristem of two Arabidopsis mutants with impaired auxin perception, axr3 and brx. Surprisingly, neutral to slightly alkaline media rescued their severely reduced root (meristem) growth by stimulating auxin signaling, independent of auxin uptake. The finding that proton pumps are hyperactive in brx roots could explain this phenomenon and is consistent with more robust growth and increased fitness of brx mutants on overly acidic media or soil. Interestingly, the original brx allele was isolated from a natural stock center accession collected from acidic soil. Our discovery of a novel brx allele in accessions recently collected from another acidic sampling site demonstrates the existence of independently maintained brx loss-of-function alleles in nature and supports the notion that they are advantageous in acidic soil pH conditions, a finding that might be exploited for crop breeding.


Late Pleistocene South American megafaunal extinctions associated with rise of Fishtail points and human population.
In the 1970s, Paul Martin proposed that big game hunters armed with fluted projectile points colonized the Americas and drove the extinction of megafauna. Around fifty years later, the central role of humans in the extinctions is still strongly debated in North American archaeology, but little considered in South America. Here we analyze the temporal dynamic and spatial distribution of South American megafauna and fluted (Fishtail) projectile points to evaluate the role of humans in Pleistocene extinctions. We observe a strong relationship between the temporal density and spatial distribution of megafaunal species stratigraphically associated with humans and Fishtail projectile points, as well as with the fluctuations in human demography. On this basis we propose that the direct effect of human predation was the main factor driving the megafaunal decline, with other secondary, but necessary, co-occurring factors for the collapse of the megafaunal community.


Promotion of proliferation of murine BALB/C3T3 fibroblasts mediated by nitric oxide at lower concentrations.
This study showed that nitric oxide (NO)-generating S-nitrosothiols, S-nitroso-N-acetylpenicillamine (SNAP) and S-nitrosoglutathione (GSNO), increased proliferation of BALB/c 3T3 (clone A31-1-1) fibroblasts in vitro. Treatment with SNAP at a relatively low concentration (0.005-0.02 mM) induced an increase in cell number compared to control. SNAP (0.005-0.02 mM) and GSNO (0.025-0.05 mM) both showed an increase of [3H]thymidine incorporation in exponentially growing cells in a dose-dependent manner. The maximal effect was observed at about 40 and 90% above control at 0.02 mM and 0.05 mM, respectively. The increase induced by 0.02 mM SNAP was abolished by the addition of 0.01 mM oxyhemoglobin, a scavenger of NO. [3H]Thymidine incorporation in stationary cells was also increased by SNAP. In addition, 0.02 mM SNAP produced a 1.8-3.2-fold increase of thymidine kinase activity in exponentially growing cells.


Spontaneous skin damage and delayed wound healing in SOD1-deficient mice.
Superoxide dismutase 1 (SOD1) is an important antioxidative enzyme that protects skin from oxidative stress. SOD1 (-/-) mice with a genetic background of b129Sv mice showed facial skin damage after 15 weeks of age. Eyelid swelling occurred as the initial symptom and caused impairment by triggering self-scratching. The period required for wound healing in the back was markedly delayed in 20-week SOD1 (-/-) mice. Oxidative stress markers, 4-hydroxynonenal and thiobarbituric acid-reactive substances, were unexpectedly lower in SOD1 (-/-) mice at day 1 after wounding. The decay rate of electron paramagnetic resonance signal intensity of intravenously injected nitroxide radical indicated that the half-life of the signal intensity was significantly prolonged in the wounded skin of SOD1 (+/+) mice. However, while the half-life of the signal intensity in control skin was a little longer in SOD1 (-/-) mice, it did not change in wounded skin. Taken together, these data suggest that the skin of SOD1 (-/-) mice is in redox imbalance and prone to damage by wounding.


Urological manifestations of HIV-related disease. A case of AIDS-associated testicular seminoma, Kaposi's sarcoma and possible intracranial lymphoma.
A wide variety of pathologies afflicting the genitourinary tract can be displayed by patients infected with the human immunodeficiency virus (HIV), including both infective and neoplastic conditions. Treatment can often be offered for such conditions using a combination of therapeutic approaches. These conditions should be looked for specifically in patients with HIV infection as treatment may improve their quality of life. A case is presented of a testicular seminoma (appearing in association with an intracranial mass and Kaposi's sarcoma) in a male patient with the acquired immune deficiency syndrome (AIDS); he made a good response to orchiectomy and radiotherapy for his seminoma. A short review is also given of the range of HIV-associated genitourinary pathologies which have been described to date.


Variable efficiency of three primer pairs for the diagnosis of Pneumocystis carinii pneumonia by the polymerase chain reaction.
The efficiency of three different primer pairs, complementary to different Pneumocystis carinii DNA regions, was compared in the polymerase chain reaction (PCR) for the diagnosis of Pneumocystis carinii pneumonia (PCP) on bronchoalveolar fluid (BALF) from patients with AIDS. PCR coupled with dot-blot hybridization (BLOT) using primers and probe from the mitochondrial 23SrDNA region showed the highest sensitivity, with a lower detection limit of 0.5-1 organisms microliter-1. When testing 47 BALF, PCR plus BLOT of the mitochondrial 23SrDNA region showed also the best diagnostic efficiency (97% sensitivity, 100% specificity). Sensitivity was significantly higher than with PCR and BLOT of the 5SrDNA region (81.5% sensitivity; P = 0.025, McNemar test); and of the dehydrofolate reductase (DHFR) gene region (75.6% sensitivity; P = 0.019). Sensitivity was also significantly higher than indirect immunofluorescence (75.8% sensitivity; P = 0.008). Using DHFR primers and probe, specificity was also reduced. The diagnostic sensitivity in clinical specimens paralleled the detection limit in the standard dilutions. The use of repeated DNA sequences of proven specificity as target of PCR amplification favourably influences sensitivity and specificity. This comparative study demonstrates that primer selection plays a significant role in the diagnosis of PCP by PCR.


Mortality was predicted by depression and functional dependence in a cohort of elderly adults of Italian descent from southern Brazil.
The older population has an increasing burden of non-communicable disease, which can potentially be associated with physical and mental disabilities and shorten life spam. To investigate whether depression, loss of functionality for activities of daily living, and lower social support are associated with all-cause mortality in the older population of Italian descent. This population-based cohort study was conducted in Veranópolis, a country city from southern Brazil, among individuals aged 60 years or older. Interviews were performed in a systematic random sampling regarding demographic, socioeconomic, and psychosocial variables, in addition to depression (Geriatric Depression Scale), activities of daily living (Barthel Index), and social support (Medical Outcomes Study scale). In the follow-up, participants were reinterviewed or, in case of death, the next of kin, and hospital records were revised. Hierarchical analysis was used to determine characteristics independently associated with all-cause mortality, using Poisson regression with robust variance, expressed as relative risk with 95% confidence intervals (RR; 95%CI). A total of 997 participants were enrolled and 882 participants completed the study, after 7.24 ± 2.41 years; with 581 remaining alive. The mean age was 73.12 ± 8.03 years, 4% were nonagenarians or centennials, and 62% were women. Symptoms of depression (RR: 1.04; 1.01-1.06) and functional dependence for ADL (RR: 1.00; 0.99-1.00) were associated with all-cause mortality, even after controlling for confounding factors. Lower social support was not associated with mortality (RR: 1.00; 0.99-1.01). Depression and functional dependence are independent predictors of all-cause mortality in the older population from Italian descent.


Analysis of factors that increase motorcycle rider risk compared to car driver risk.
As in other parts of the Western world, there is concern in New Zealand about increasing popularity of motorcycles because of potential increases in road trauma. This study sought to identify important factors associated with increased risk for motorcyclists to inform potential policy approaches to reduce motorcyclist injury, such as changes to motorcyclist licensing, training and education. Using data extracted from a register of all New Zealand licensed motor vehicles that were matched to crash data, statistical models were fitted to examine patterns of motorcycle risk in comparison with small cars. These showed generally elevated risks for motorcyclists compared to cars, but particularly elevated risks for motorcycle owners aged in their 20s or who lived in more urbanised settings. In crashes, motorcyclists have little protection from injury, putting the motorcyclist at high risk of injury. When comparing new motorcycles with new cars, the odds of fatal or serious injury to a motorcycle rider involved in an injury crash were almost eight times the odds for a car driver.


[Treatment of obstructive cardiomyopathy using myotomy in a 67-year-old patient. Pharmacological and angiographical studies].
The case is reported of a 67 year old man with obstructive cardiomyopathy treated by an extended myotomy. Serial phonomechanographic tracings and the pre- and post-operative angiograms show the steady progress of the disease towards a major disturbance of left ventricular compliance which became resistant to propranolol, and was partially reversed by myotomy.


[Immedeate and delayed-type reactivity to fungi and effects of antifungal drugs on atopic dermatitis].
To investigate immediate and delayed-type reactivity for fungi in atopic dermatitis (AD) patients and the effect of antifungal therapy. We examined immediate and delayed-type reactivity in AD patients for Candida albicans and Malassezia furfur by skin prick test (SPT), and estimated the effect of amphotericin B (AMPH) and itraconazole (ITCZ). Twenty eight of 40 patients showed positive immediate-type reaction and 10 of 27 patients did delayed-type reaction for Candida albicans. As for Malassezia furfur, positive immediate-type reaction was shown in 30 of 40 patients and positive delayed-type reaction did in 4 of 27 patients. The RAST score of specific IgE to Candida albicans was low in the patients with positive delayed-type skin reaction for Candida albicans, while the score was high in the patients with the negative delayed-type skin reaction. Both of AMPH and ITCZ were effective to the patients with positive immediate-type reaction for Candida albicans in SPT. The skin reaction for Malassezia furfur was stronger in the patients treated with ITCZ effectively than in the patients treated not effectively. In addition, ITCZ was effective in all patients except one, who showed positive reaction for Malassezia furfur accompanied with negative reaction for Candida albicans in SPT. Fungal allergy is one of the aggravation factors of AD, and SPT is useful to evaluate fungal allergy and to choose effective antifungal therapy.


Physical distancing implementation, ambient temperature and Covid-19 containment: An observational study in the United States.
Governments may relax physical distancing interventions for coronavirus disease 2019 (Covid-19) containment in warm seasons/areas to prevent economic contractions. However, it is not clear whether higher temperature may offset the transmission risk posed by this relaxation. This study aims to investigate the associations of the effective reproductive number (Rt) of Covid-19 with ambient temperature and the implementation of physical distancing interventions in the United States (US). This study included 50 states and one territory of the US with 4,532,650 confirmed cases between 29 January and 31 July 2020. We used an interrupted time-series model with a state-level random intercept for data analysis. An interaction term of 'physical distancing×temperature' was included to examine their interactions. Stratified analyses by temperature and physical distancing implementation were also performed to analyse the modifying effects. The overall median (interquartile range) Rt was 1.2 (1.0-2.3). The implementation of physical distancing was associated with a 12% decrease in the risk of Rt (relative risk [RR]: 0.88, 95% confident interval [CI]: 0.86-0.89), and each 5 °C increase in temperature was associated with a 2% decrease (RR: 0.98, 95%CI: 0.97-0.98). We observed a statistically significant interaction between temperature and physical distancing implementation, but all the RRs were small (close to one). The containing effects of high temperature were attenuated by 5.1% when physical distancing was implemented. The association of COVID-19 Rt with physical distancing implementation was more stable (0.88 vs. 0.89 in days when temperature was low and high, respectively). Increased temperature did not offset the risk of Covid-19 Rt posed by the relaxation of physical distancing implementation. Our study does not recommend relaxing the implementation of physical distancing interventions in warm seasons/areas.


Quantitation of stone burden: imaging advances.
The accurate diagnosis and quantitation of nephrolithiasis in patients with primary hyperoxaluria (PH) often directly impacts the medical and surgical management for individuals with both symptomatic and asymptomatic calculi. Traditionally, depiction of the size, location and appearance of urinary calculi has been provided by kidney, ureter and bladder plain film radiographs with or without tomography. Given advances in imaging technology there is a shift from conventional radiographs to cross-sectional imaging technology, namely unenhanced computed tomography (CT), CT urography, ultrasound and magnetic resonance imaging. These diagnostic techniques provide differing advantages and disadvantages for imaging stone disease. This review outlines imaging advances in the accurate diagnosis and quantitation of patients with metabolically active stone disease such as PH.


Mucus fishing syndrome.
Twenty-five patients are described with a variety of external ocular diseases including keratoconjunctivitis sicca, blepharitis, and allergic conjunctivitis, who presented with persistence of symptoms of irritation, foreign body sensation, and apparent excessive mucus production, with mild conjunctival inflammation despite appropriate treatment of the underlying disease. All patients were found to have evidence of trauma to the conjunctival epithelium due to mechanical removal of the excess mucus from the surface of the globe or inferior cul-de-sac. The surface irritation created by the mechanical damage led to a further increase in mucus production, creating a cycle that we have termed mucus fishing syndrome. Cessation of this behavior coupled with ongoing therapy of the underlying disease led to resolution of signs and symptoms in all patients.


Loan applications in adult patients with congenital heart disease: a French study.
Improvements in the treatment of children with congenital heart disease have led to most of these patients reaching adulthood. Despite the increase in lifespan, very little is known about their quality of life - in particular, their ability to obtain a mortgage or consumer loan. To investigate the outcome of mortgage and loan applications made by adults with differential severities of congenital heart disease. Four hundred and seventy-six patients were invited to participate in a questionnaire-based interview by phone. Of these patients, one hundred and forty-two responded. Respondents were classified into three categories ('significant', 'complex' and 'mild') based on congenital heart disease severity according to the Bethesda conference. Ninety patients (64%) had applied for loans; 17 (16.5%) did not report their heart disease to the insurance company, 13 were refused insurance and 39 were asked to pay surplus fees. The imposed fees concerned patients classified in the 'significant' and 'complex' groups (P<0.0001 and P<0.003, respectively, compared with those classified in the 'mild' group). Age, sex, other diseases, cardiovascular risk factors and duration of the loan had no influence on loan application outcomes. Adults with congenital heart disease are considerably more likely to have difficulty obtaining a mortgage or loan, independent of their congenital heart disease severity. Moreover, despite an increased obtainment of a loan in patients classified as 'mild', the refusal rates were identical for patients classified as having 'significant' or 'complex' congenital heart disease, although their prognosis is different.


Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials.
Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has demonstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.5% and 54.0%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3+, CD4+, CD8+, CD19+, CD116+CD56+, and CD123+ immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up.


The analgesic efficacy of intravenous versus oral tramadol for preventing postoperative pain after third molar surgery.
The aim of this study was to compare the analgesic efficacy of single-dose preoperative intravenous versus oral tramadol for preventing pain after third molar surgery. Seventy-two patients undergoing elective third molar surgery were randomized to receive either intravenous (n = 36) or oral (n = 36) tramadol 50 mg. The intravenous group received an oral placebo capsule followed by intravenous tramadol 50 mg preoperatively. The oral tramadol group received a 50-mg oral tramadol capsule followed by intravenous placebo saline preoperatively. In both groups, a standard intravenous sedation technique was administered and the impacted third molars were removed under local anesthesia. The difference in postoperative pain was assessed by 4 primary end points: hourly pain intensity as measured by a 100-mm visual analog scale for 8 hours, time to rescue analgesic, postoperative acetaminophen consumption, and a 5-point global assessment scale (0 = poor, 1 = fair, 2 = good, 3 = very good, and 4 = excellent). Throughout the 8-hour investigation period, patients reported significantly lower pain intensity scores in the intravenous versus oral group (15.9 +/- 9.6 mm versus 36.9 +/- 17.2 mm, P = .03). Patients also reported significantly longer time to rescue analgesic (7.0 hours versus 3.5 hours, P = .00001), lesser postoperative acetaminophen consumption (1,823 +/- 1,266 mg versus 3,558 +/- 1,418 mg, P = .000006), and better global assessment (2.6 +/- 0.9 versus 1.1 +/- 0.8, P = .01) for the intravenous versus oral group. We conclude that preoperative intravenous tramadol is superior to oral tramadol for preventing postoperative pain following third molar surgery. However, it should be noted that there is a difference in the bioavailability between the 2 formulations of up to 30%, which may explain the findings.


Computational and experimental studies on the inhibitory mechanism of hydroxychloroquine on hERG.
Hydroxychloroquine (HCQ) was noted to produce severe cardiac arrhythmia, an adverse effect as its use against severe acute respiratory syndrome caused by coronavirus 2 (SAES-CoV-2). HCQ is an antimalarial drug with quinoline structure. Some other quinoline compounds, such as fluoroquinolone antibiotics (FQs), also lead to arrhythmias characterized by QT prolongation. QT prolongation is usually related to the human ether-a-go-go-related gene (hERG) potassium channel inhibitory activity of most drugs. In this research, molecular docking was used to study the potential inhibitory activities of HCQ as well as other quinolines derivatives and hERG potassium channel protein. The possible causes of these QT prolongation effects were revealed. Molecular docking and patch clamp experiments showed that HCQ could bind to hERG and inhibit the efflux of potassium ion preferentially in the repolarization stage. The IC50 of HCQ was 8.6 μM ± 0.8 μM. FQs, which are quinoline derivatives, could also bind to hERG molecules. The binding energies of FQs varied according to their molecular polarity. It was found that drugs with a quinoline structure, particularly with high molecular polarity, can exert a significant potential hERG inhibitory activity. The potential side effects of QT prolongation during the development and use of quinolines should be carefully considered.


Delivering motivational interviewing early post stroke: standardisation of the intervention.
We applied Motivational Interviewing (MI) techniques, early after stroke, to facilitate psychological adjustment to life post-stroke. In our trial, MI-plus-usual-care increased the likelihood of normal mood at 3-months post-stroke, compared to usual-care alone. Whilst appropriate training, manuals, and supervision may increase adherence to core principles of this complex intervention, unintended variability in implementation inevitably remains. We aimed to explore the impact of variability on participant outcome. Using our trial data (411 participants), we explored variation in MI delivery, examining: therapist characteristics (stroke care expertise/knowledge, psychology training); MI content (fidelity to MI techniques assessed with Motivational Interviewing Treatment Integrity code, describing therapist behaviours as MI-consistent, MI-neutral or MI-inconsistent); and MI dose (number/duration of sessions). The four MI therapists (two nurses/two psychologists) had varying expertise and MI delivery. Across therapists, mean average session duration ranged 29.5-47.8 min. The percentage of participants completing the per-protocol four sessions ranged 47%-74%. These variations were not related to participant outcome. There were uniformly high frequencies (>99%) of MI-consistent and MI-neutral interactions, and low frequencies (<1%) of MI-inconsistent interactions. Variation in therapist characteristics and MI dose did not affect participant outcome. These may have been tolerated due to high fidelity to MI principles.IMPLICATIONS FOR REHABILITATIONMotivational Interviewing (MI) can help reduce depression in stroke survivors when delivered early after stroke.The effectiveness of our MI intervention depends on the delivery of high quality MI; in particular, interactions with low levels of MI-inconsistency, and high global MI ratings, ideally delivered over more than one session, each lasting at least 30 minutes.Provided high quality MI is being delivered, the intervention can still have a beneficial effect on participant outcome, even with flexibility and variation in therapist characteristics, and duration and number of sessions, which may be inevitable in a clinical context.


Habitat fragmentation promotes malaria persistence.
Based on a Ross-Macdonald type model with a number of identical patches, we study the role of the movement of humans and/or mosquitoes on the persistence of malaria and many other vector-borne diseases. By using a theorem on line-sum symmetric matrices, we establish an eigenvalue inequality on the product of a class of nonnegative matrices and then apply it to prove that the basic reproduction number of the multipatch model is always greater than or equal to that of the single patch model. Biologically, this means that habitat fragmentation or patchiness promotes disease outbreaks and intensifies disease persistence. The risk of infection is minimized when the distribution of mosquitoes is proportional to that of humans. Numerical examples for the two-patch submodel are given to investigate how the multipatch reproduction number varies with human and/or mosquito movement. The reproduction number can surpass any given value whenever an appropriate travel pattern is chosen. Fast human and/or mosquito movement decreases the infection risk, but may increase the total number of infected humans.


[A paraneoplastic Sharp syndrome reversible after resection of a benign schwannoma: a paraneoplastic syndrome?].
Paraneoplastic syndromes commonly occur in malignancies and often precede the first symptoms of the tumor. By definition, paraneoplastic syndromes are only associated with malignancies although some exceptions have been reported, occurring with benign tumors. We report a patient presenting with a clinical and serological Sharp syndrome, followed a few months later by a cervical schwannoma. Curative surgical resection of the mass resulted in a clinical and serological healing from the Sharp syndrome. To our knowledge, this is the first report of a benign schwannoma complicated by a possible paraneoplastic Sharp syndrome.


Sharing special birth stories. An explorative study of online childbirth narratives.
Increasingly, pregnant women, as active online media users, incorporate media driven values on childbirth that may not agree with professional midwifery values. In Dutch midwifery practice, online searching for other women's stories is often discouraged. However, online birth stories attract women as a means to learn from one another's experiences of childbirth. This study aims to explore Dutch women's use of an online social media platform (Instagram) to represent childbirth by analyzing their narrative strategies. A collection of 110 Instagram-linked childbirth narratives (2015-2017) were analyzed applying an approach of interpretative repertoires. The Dutch women in this study linked birth stories on their Instagram accounts that represented impactful experiences of childbirth. In their narratives, three interconnected repertoires are played out: sharing your story, going into details, and doing it yourself. This study highlights that narrative details of the online birth stories illustrate the physical and procedural obstacles that women overcame in giving birth. Reporting their emotional experiences in detail, women's online sharing of birth stories puts a focus on their personal preferences and decision making, and may ease the way for medical interventions. Without giving explicit advice, personal online birth stories could be instrumental in reformulating the standards of what childbirth is, or should be, like. Social media networks allow women to exchange stories that structure narrating women's childbirth experiences and offer a structure for the lived or future experiences of others. This may have an impact on women's decision-making during pregnancy and childbirth.


Effects of nuclear receptor transactivation on boar taint metabolism and gene expression in porcine hepatocytes.
The accumulation of the testicular steroid androstenone (AND) and tryptophan degradation product skatole (3MI) in fat results in boar taint, an off odor and flavor in boar meat. Increasing boar taint metabolism in the liver may help limit the deposition of AND and 3MI in fat, thereby improving meat quality. The effects of transactivation of the nuclear receptors constitutive androstane receptor (CAR), pregnane X receptor (PXR), and farnesoid X receptor (FXR) on the expression levels of several transcripts of interest and the metabolism of AND and 3MI in primary porcine hepatocytes were tested. Primary cells were isolated from mature boars, and transcript expression levels were assayed using real-time PCR. The transcripts of interest included porcine orthologs of common phase I and phase II metabolic enzymes and transcripts previously shown to be differentially expressed in boars with high boar taint levels. Transactivation of CAR, PXR, or FXR resulted in altered expression of several transcripts, including increased expression of cytochrome P450 (CYP) 2B22 by CAR, of CYP2A19, CYP2B22, CYP2C33, and CYP2C49 by PXR, of CYP2C33 and CYP2E1 by FXR, and of CYP19A2 by all three receptors. Only transactivation of PXR had a significant effect on AND metabolism, resulting in 7.5±1.5% of the initial level of AND remaining compared to 21.4±3.1% remaining with control dimethyl sulfoxide (DMSO) treatment. FXR had the greatest effect on 3MI metabolism, increasing the expression of CYP2E1 by 1.29-fold and increasing the production of the key metabolite 6-hydroxy-3-methylindole (6-OH-3MI), while decreasing 5-hydroxy-3-methylindole (5-OH-3MI) production. 3-Hydroxy-3-methyloxindole (HMOI) production was increased by CAR transactivation, while indol-3-carbinol (I3C) production was increased by PXR and FXR transactivation, and by treatment with 5β-dihydrotestosterone (5β-DHT). From this, it can be concluded that selective transactivation of PXR and FXR may be a viable means of decreasing boar taint by increasing the hepatic metabolism of AND and 3MI.


Mechanism of inactivation of rat liver microsomal cytochrome P-450c by 2-bromo-4'-nitroacetophenone.
The mechanism by which 2-bromo-4'-nitroacetophenone (BrNAP) inactivates cytochrome P-450c, which involves alkylation primarily at Cys-292, is shown in the present study to involve an uncoupling of NADPH utilization and oxygen consumption from product formation. Alkylation of cytochrome P-450c with BrNAP markedly stimulated (approximately 30-fold) its rate of anaerobic reduction by NADPH-cytochrome P-450 reductase, as determined by stopped flow spectroscopy. This marked stimulation in reduction rate is highly unusual in that Cys-292 is apparently not part of the heme- or substrate-binding site, and its alkylation by BrNAP does not cause a low spin to high spin state transition in cytochrome P-450c. Under aerobic conditions the rapid oxidation of NADPH catalyzed by alkylated cytochrome P-450c was associated with rapid reduction of molecular oxygen to hydrogen peroxide via superoxide anion. The intermediacy of superoxide anion, formed by the one-electron reduction of molecular oxygen, established that alkylation of cytochrome P-450c with BrNAP uncouples the catalytic cycle prior to introduction of the second electron. The generation of superoxide anion by decomposition of the Fe2+ X O2 complex was consistent with the observations that, in contrast to native cytochrome P-450c, alkylated cytochrome P-450c failed to form a 430 nm absorbing chromophore during the metabolism of 7-ethoxycoumarin. Alkylation of cytochrome P-450c with BrNAP did not completely uncouple the catalytic cycle such that 5-20% of the catalytic activity remained for the alkylated cytochrome compared to the native protein depending on the substrate assayed. The uncoupling effect was, however, highly specific for cytochrome P-450c. Alkylation of nine other rat liver microsomal cytochrome P-450 isozymes with BrNAP caused little or no increase in hydrogen peroxide formation in the presence of NADPH-cytochrome P-450 reductase and NADPH.


Pseudohurleytrema yolandae n. sp., the first monorchiid trematode reported from the Triacanthidae (Tetraodontiformes).
Prior to the present study, species of the trematode family Monorchiidae Odhner, 1911 had been reported from four of the ten families of tetraodontiform fishes: the Balistidae, Monacanthidae, Ostraciidae and Tetraodontidae. Here we report the first monorchiid from the family Triacanthidae, Pseudohurleytrema yolandae n. sp. infecting Tripodichthys angustifrons (Hollard), from Moreton Bay, Queensland, Australia. The species conforms well to the morphological concept of the subfamily Hurleytrematinae Yamaguti, 1958, and the genus Pseudohurleytrema Yamaguti, 1954, in the possession of filamented eggs, a bipartite terminal organ, and a unipartite seminal vesicle. Relative to the other three recognised species of Pseudohurleytrema, the present species is distinctive in the size of the testis and eggs, position of the ovary, and the form of the vitellarium and excretory vesicle. We consider Pseudohurleytrema magnum Kaikabad & Bilqees in Bilqees, 1991 as a species inquirenda. Sequence data for the 28S ribosomal RNA gene and cox1 mitochondrial gene were generated for P. yolandae, providing the first molecular data for the genus. Phylogenetic analysis showed that P. yolandae does not form a clade with the other three hurleytrematine genera for which there are molecular data (Helicometroides Yamaguti, 1934, Hurleytrematoides Yamaguti, 1953 and Provitellus Dove & Cribb, 1998), forming a poorly-supported clade with Proctotrema addisoni Searle, Cutmore & Cribb, 2014 within the clade of the subfamily Monorchiinae Odhner, 1911. The four hurleytrematine genera resolved as four distinct clades, indicating that the current subfamilial classification requires comprehensive revision.


The role of treatment regimen and duration in treating patients with Mycobacterium avium complex lung disease: A real-world experience and case-control study.
The treatment advantage of guideline-based therapy (GBT) in Mycobacterium avium complex lung disease (MAC-LD) is well-known. However, GBT is not always feasible. The aim of the study was to analyze the relationship of treatment regimens and duration with outcomes. This study screened patients with MAC-LD from Jan 2011 to Dec 2020 and enrolled those who received treatment. The treatment regimens were categorized to triple therapy (three active drugs) and non-triple therapy. The favorable outcomes included microbiological cure or clinical cure if no microbiologic persistence. A total of 106 patients with MAC-LD were enrolled. Among them, 88 subjects (83 %) received triple therapy, 58 (54.7 %) had MAC treatment >12 months, and 66 (62.3 %) had favorable outcomes. Patients receiving triple therapy (90.9 % vs. 67.5 %, p = 0.008) and treatment >12 months (62.1 % vs. 42.5 %, p = 0.07) had higher proportion of favorable outcomes than unfavorable outcomes. Multivariable logistic regression analysis showed that age >65, comorbidities of COPD and prior tuberculosis, low hemoglobin, and high MAC burden were independent risk factors of unfavorable outcome. In contrast, triple therapy (OR: 0.018, 95 % CI: 0.04-0.78, p = 0.022) and treatment duration >12 months (OR: 0.20, 95 % CI: 0.055-0.69, p = 0.012) were protective factors against unfavorable outcome. Triple therapy including GBT, and treatment more than 12 months achieved more favorable outcome. Maintenance of triple therapy, but not reducing the number of active drugs, might be an acceptable alternative of GBT.


Gene Editing Technologies for Biofuel Production in Thermophilic Microbes.
Thermophilic microbes are an attractive bioproduction platform due to their inherently lower contamination risk and their ability to perform thermostable enzymatic processes which may be required for biomass processing and other industrial applications. The engineering of microbes for industrial scale processes requires a suite of genetic engineering tools to optimize existing biological systems as well as to design and incorporate new metabolic pathways within strains. Yet, such tools are often lacking and/or inadequate for novel microbes, especially thermophiles. This chapter focuses on genetic tool development and engineering strategies, in addition to challenges, for thermophilic microbes. We provide detailed instructions and techniques for tool development for an anaerobic thermophile, Caldanaerobacter subterraneus subsp. tengcongensis, including culturing, plasmid construction, transformation, and selection. This establishes a foundation for advanced genetic tool development necessary for the metabolic engineering of this microbe and potentially other thermophilic organisms.


Identification of two-pore domain potassium channels as potent modulators of osmotic volume regulation in human T lymphocytes.
Many functions of T lymphocytes are closely related to cell volume homeostasis and regulation, which utilize a complex network of membrane channels for anions and cations. Among the various potassium channels, the voltage-gated K(V)1.3 is well known to contribute greatly to the osmoregulation and particularly to the potassium release during the regulatory volume decrease (RVD) of T cells faced with hypotonic environment. Here we address a putative role of the newly identified two-pore domain (K(2P)) channels in the RVD of human CD4(+) T lymphocytes, using a series of potent well known channel blockers. In the present study, the pharmacological profiles of RVD inhibition revealed K(2P)5.1 and K(2P)18.1 as the most important K(2P) channels involved in the RVD of both naïve and stimulated T cells. The impact of chemical inhibition of K(2P)5.1 and K(2P)18.1 on the RVD was comparable to that of K(V)1.3. K(2P)9.1 also notably contributed to the RVD of T cells but the extent of this contribution and its dependence on the activation status could not be unambiguously resolved. In summary, our data provide first evidence that the RVD-related potassium efflux from human T lymphocytes relies on K(2P) channels.


The effects of elevated CO2 on clonal growth and nutrient content of submerge plant Vallisneria spinulosa.
An approximately four months long glasshouse experiment was conducted to examine the effects of elevated carbon dioxide (CO(2)) concentration (1,000 +/- 50 micromol mol(-1)) in the atmosphere on biomass accumulation and allocation pattern, clonal growth and nitrogen (N), phosphorus (P) accumulation by the submerged plant Vallisneria spinulosa Yan. Elevated CO(2) significantly increased V. spinulosa total fresh biomass ( approximately 130%) after 120 days, due to more biomass accumulation in all morphological organs than in those at ambient CO(2) (390 +/- 20 micromol mol(-1)). About 75% of the additional total biomass at elevated CO(2) was accounted for by leaf and rhizome (above ground) biomass and only 25% of it belonged to root and turion (below ground). However, the turions biomass exhibited a greater increase rate than that of organ above ground, which caused reduction in the above/below ground biomass ratio. The clonal growth of V. spinulosa responded positively to elevated CO(2). The number of primary ramets increased up to 1.4-folds at elevated CO(2) and induced a dense growth pattern. For nutrients absorption, concentration of N in leaf and in turion was significantly (p <or= 0.05) reduced by 13.4% and by 15.7% in elevated CO(2) and were not affected in both root and rhizome. Percent P, in contrast, was significantly (p <or= 0.05) enhanced in all of the organs, ranging from 35% to 147%, except for turion. Compared with those in ambient CO(2), the mean accumulation per ramet of N and P significantly higher in elevated CO(2). These results showed that elevated CO(2) could promote submerged plant biomass accumulation, and it should be an adaptive strategy for clonal plants to increase the nutrient absorption efficiency of root and reproduce more clonal ramets to exploit enough resources to match with higher growth in elevated CO(2).


Novologues containing a benzamide side chain manifest anti-proliferative activity against two breast cancer cell lines.
Hsp90 represents a promising target for the development of both anti-cancer and neuroprotective agents. Structure-activity relationship studies on novobiocin and novobiocin analogues, led to the development of KU-32 and recently, KU-596, as lead compounds for the potential treatment of neurodegenerative diseases. Similar to KU-32, we have demonstrated that upon replacement of the acetamide side chain present in KU-32 with a benzamide, this neuroprotective agent was transformed into a scaffold that manifests anti-proliferative activity. To assess structure-activity relationships for this new scaffold, a library of benzamide-containing novologues was prepared and evaluated against two breast cancer cell lines. Compound 14a manifested the most potent anti-proliferative activity from these studies and induced Hsp90-dependent client protein degradation in a concentration-dependent manner.


Serendipitous discovery of light-induced (In Situ) formation of an Azo-bridged dimeric sulfonated naphthol as a potent PTP1B inhibitor.
Protein tyrosine phosphatases (PTPs) like dual specificity phosphatase 5 (DUSP5) and protein tyrosine phosphatase 1B (PTP1B) are drug targets for diseases that include cancer, diabetes, and vascular disorders such as hemangiomas. The PTPs are also known to be notoriously difficult targets for designing inihibitors that become viable drug leads. Therefore, the pipeline for approved drugs in this class is minimal. Furthermore, drug screening for targets like PTPs often produce false positive and false negative results. Studies presented herein provide important insights into: (a) how to detect such artifacts, (b) the importance of compound re-synthesis and verification, and (c) how in situ chemical reactivity of compounds, when diagnosed and characterized, can actually lead to serendipitous discovery of valuable new lead molecules. Initial docking of compounds from the National Cancer Institute (NCI), followed by experimental testing in enzyme inhibition assays, identified an inhibitor of DUSP5. Subsequent control experiments revealed that this compound demonstrated time-dependent inhibition, and also a time-dependent change in color of the inhibitor that correlated with potency of inhibition. In addition, the compound activity varied depending on vendor source. We hypothesized, and then confirmed by synthesis of the compound, that the actual inhibitor of DUSP5 was a dimeric form of the original inhibitor compound, formed upon exposure to light and oxygen. This compound has an IC50 of 36 μM for DUSP5, and is a competitive inhibitor. Testing against PTP1B, for selectivity, demonstrated the dimeric compound was actually a more potent inhibitor of PTP1B, with an IC50 of 2.1 μM. The compound, an azo-bridged dimer of sulfonated naphthol rings, resembles previously reported PTP inhibitors, but with 18-fold selectivity for PTP1B versus DUSP5. We report the identification of a potent PTP1B inhibitor that was initially identified in a screen for DUSP5, implying common mechanism of inhibitory action for these scaffolds.


Intracardiac echocardiography: use during transcatheter device closure of a patent ductus arteriosus in a dog.
Intracardiac echocardiography (ICE) is used in humans for percutaneous interventional procedures, such as transcatheter device closures. Intracardiac echocardiography provides high-resolution imaging of cardiac structures with two-dimensional, M-mode, Doppler, and also three-dimensional modalities. The present report describes application of ICE during transcatheter occlusion of patent ductus arteriosus using a canine ductal occluder in a dog for which transesophageal echocardiography could not provide an optimal acoustic window.


Accuracy evaluation of direct navigation with an isocentric 3D rotational X-ray system.
Minimally invasive interventions are often performed under fluoroscopic guidance. Drawbacks of fluoroscopic guidance are the fact that the presented images are 2D projections and that both the patient and the clinician are exposed to radiation. Image-guided navigation using pre-interventionally acquired 3D MR or CT data is an alternative. However, this often requires invasive anatomical landmark-based, marker-based or surface-based image-to-patient registration. In this paper, a coupling between an image-guided navigation system and an intraoperative C-arm X-ray device with 3D imaging capabilities (3D rotational X-ray (3DRX) system) that enables direct navigation without invasive image-to-patient registration on 3DRX volumes, is described and evaluated. The coupling is established in a one-time preoperative calibration procedure. The individual steps in the registration procedure are explained and evaluated. The acquired navigation accuracy using this coupling is approximately one millimeter.


Tracheal stenosis caused by congenital vascular ring anomaly misinterpreted as asthma for 45 years.
Dyspnoeic conditions simulating asthma are not uncommon in adult and paediatric practice. Vascular ring anomalies in particular may be misdiagnosed, resulting in unnecessary delay before corrective surgery. We report a rare case of symptomatic double aortic arch in an adult which emphasises the above points.


Increasing uptake of live attenuated influenza vaccine among children in the United States, 2008-2014.
The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all persons in the United States aged ≥6 months. On June 25, 2014, ACIP preferentially recommended live attenuated influenza vaccine (LAIV) for healthy children aged 2-8 years. Little is known about national LAIV uptake. To determine uptake of LAIV relative to inactivated influenza vaccine, we analyzed vaccination records from six immunization information system sentinel sites (approximately 10% of US population). LAIV usage increased over time in all sites. Among children 2-8 years of age vaccinated for influenza, exclusive LAIV usage in the collective sentinel site area increased from 20.1% (2008-09 season) to 38.0% (2013-14). During 2013-14, at least half of vaccinated children received LAIV in Minnesota (50.0%) and North Dakota (55.5%). Increasing LAIV usage suggests formulation acceptability, and this preexisting trend offers a favorable context for implementation of ACIP's preferential recommendation.


Comparative performance analysis of 2D and 3D gamma metrics for patient specific QA in VMAT using Octavius 4D with 2D-Array 1500.
Gamma pass percentage (GPP) is the predominant metric used for Patient Specific Quality Assurance (PSQA) in radiation therapy. The dimensionality of the measurement geometry in PSQA has evolved from 2D planar to 3D planar, and presently to state-of-the-art 3D volumetric geometry. We aim to critically examine the performance of the three-dimensional gammas vis-à-vis the older gamma metrics of lower dimensionality to determine their mutual fungibility in PSQA, using clinically approved Volumetric Arc Therapy (VMAT) plans. Gamma pass percentages derived from PSQA for VMAT plans using Octavius 4D phantom with 2D-Array 1500 and its proprietary software were recorded. 2D planar, 3D planar, and 3D volumetric gamma pass percentages were retrospectively extracted for multiple treatment plans at three sites, using three acceptance limits, and for two modes of normalization. The differences in mean pass percentages, and the pairwise correlation between geometries were calculated within limits of statistical significance. A significant increase in mean pass rates was observed from 2D planar to 3D planar geometries. The difference was less pronounced from 3D planar to 3D volumetric. 2D planar v/s 3D planar showed a significant degree of correlation among themselves, which was not seen against most of the 3D volumetric pass rates. The mean gamma pass rates show conclusive evidence of the benefits of shifting from 2D planar to higher dimensions measurement geometries, but the benefits of using 3D volumetric compared to 3D planar is not always unequivocal. The correlations show mixed results regarding the interdependence of pass percentages at different geometries.


Approaches to graft-vs-host disease.
Graft-vs-host disease (GVHD) is one of the most difficult problems in stem cell transplantation. It is best considered in the context of the normal immune response. The role of the immune system is to identify and eliminate foreign antigens. In the case of GVHD, the antigens are minor histocompatibility antigens (mHA) recognized in an inflammatory milieu. The immune system cannot reasonably be expected to selectively recognize microbial antigens and ignore mHA. This approach would require the generation of selective tolerance--something that clearly occurs but which we have frustratingly little control over. While we can often treat and remit even life-threatening GVHD, the consequence has been the development of fatal opportunistic infections. The challenge is to change our style of thinking about GVHD to allow a transition from a 'nuclear winter' approach that controls GVHD at the price of infection, to a more selective patient approach that recognizes the limitations of immunosuppressive therapy.


Contribution of vasoconstriction to the origin of atherosclerosis: a conceptual study.
Research during the past century has clearly shown that endothelial injury (EI) and/or endothelial dysfunction (ED) are among the major events determining the onset of atherosclerosis. Included in the events that may elicit endothelial damage, vasoconstriction (VC) has received relatively little attention. This conceptual review attempts to show that in elastic and conduit arteries, VC is not only capable of producing EI/ED, but is also closely associated with many recognized proatherogenic stimuli. Of related interest is the observation that a number of suspected antiatherogenic stimuli oppose VC by their vasodilatory effects, lending further support to this relationship. In addition, recent developments in the knowledge of the molecular basis of VC (including the role of specific inhibitors) are discussed, and their potential for preventing lesion formation and thus becoming novel therapeutic alternatives against the onset of atherosclerosis are highlighted.