Customization of a passive surgical support robot to specifications for ophthalmic surgery and preliminary evaluation.
To customize a passive surgery support robot for ophthalmic surgery and preliminarily evaluate its performance. Prospective observational study. The range of motion of the arm was analyzed during ophthalmic surgery and, based on this analysis, a commercially available passive robot was customized for surgical support for ophthalmic surgery; following which a prototype robot was constructed. To examine the effects on the brachial muscle during surgical operations with and without the prototype robot, surface electromyograms of the biceps and triceps were analyzed after performing continuous curvilinear capsulorrhexis (CCC) and suturing the sclerocorneal wound in a cataract surgery simulation. Six surgeons performed cataract surgery, and the degree of arm stability and muscle fatigue during surgery were evaluated using a visual analog scale. During surgery, the prototype robot enabled fixation of the elbow and wrist at any position within the surgeon's range of motion, expanding the range of motion of the hand and fingers and stabilizing operability. Surface electromyography showed a significant decrease in the mean amplitude value of the biceps brachii during both CCC and suturing (p < 0.0001). No significant difference was observed in the triceps brachii. The arm stability and muscle fatigue were improved by 83.3% on the visual analog scale with the prototype robot compared with that without protpotype robot. The use of a passive prototype robot may improve arm stability and reduce muscle fatigue during ophthalmic surgery.


Production of reducing sugar from Enteromorpha intestinalis by hydrothermal and enzymatic hydrolysis.
In this work, to evaluate the efficacy of marine macro-algae Enteromorpha intestinalis as a potential bioenergy resource, the effects of reaction conditions (solid-to-liquid ratio, reaction temperature, and reaction time) on sugars produced by a combined process of hydrothermal and enzymatic hydrolysis were investigated. As a result of the hydrothermal hydrolysis, a 7.3g/L (8% yield) total reducing sugar was obtained under conditions including solid-to-liquid ratio of 1:10, reaction temperature of 170°C, and reaction time of 60min. By subsequent (post-hydrothermal) enzymatic hydrolysis of samples treated at 170°C for 30min, a 20.1g/L (22% yield) was achieved.


Cytokine profiling, pretreatment with anakinra, and tolerance development in platinum-induced mixed hypersensitivity reactions.
Cytokine-release reactions (CRR) induced by platinum-based chemotherapy, manifesting with fever, chills, and rigors, are poorly understood and not easily prevented by usual premedication or desensitization. To gain a better understanding of platinum-induced CRR and to explore the use of anakinra as a tool to prevent its clinical manifestations. A cytokine and chemokine panel was obtained before and after platinum infusion in 3 cases with a mixed (immunoglobulin E-mediated and CRR) platinum-induced hypersensitivity reaction and in 5 controls either tolerant or with an immunoglobulin E-mediated platinum-induced hypersensitivity reaction. Anakinra was given as premedication in the 3 CRR cases. Cytokine-release reaction was associated with a marked release of interleukin (IL)-2, IL-5, IL-6, IL-10, and tumor necrosis factor-ɑ in all cases whereas only IL-2 and IL-10 increased in some controls after platinum infusion, and to a lesser extent than in cases. Anakinra seemed to block CRR symptoms in 2 cases. In the third case, who initially had CRR symptoms despite anakinra, tolerance to oxaliplatin appeared to develop after repeated re-exposures, as suggested by the decreasing levels of cytokines after oxaliplatin, except IL-10, and the capacity to progressively shorten the desensitization protocol and taper the premedication, in addition to the negativization of the oxaliplatin skin test result. In patients with platinum-induced CRR, anakinra could be a useful premedication to block its clinical manifestations, and monitoring of IL-2, IL-5, IL-6, IL-10, and tumor necrosis factor-ɑ could help predict tolerance development, thereby allowing safe adjustments to the desensitization protocol and premedication.


On the spectroscopic investigation of lipstick stains: Forensic trace evidence.
In forensic science, lipsticks are considered as crucial trace evidence because it helps in the linking of the criminal with the crime scene. In the present work, twenty-five lipstick samples are characterized and discriminated by using ATR-FTIR spectroscopy coupled with multivariate statistical methods. The utilized approach is non-destructive, fast, and provides reproducible results. It is observed from the FTIR spectra that lipstick contains various aliphatic and aromatic compounds e.g. Propyl ester of Hexanoic acid, Silicates, etc. Further, the discrimination power is calculated by using three approaches i.e. visual examination, cluster analysis (HCA and k-means) and factor analysis method. The multivariate method combined with t-statistics delivered a higher value of discriminating power i.e. 100% which is an improvement on the 99.00% discrimination power of visual comparison method. The developed method is validated by analyzing five duplicate samples and predicted them to their respective brands significantly. This study establishes a method which provides proof of concept discrimination of the lipstick samples. In the future, it can be quite possible to create an FTIR database of more lipstick samples for the identification of unknown/suspected lipstick samples.


Ununited humeral diaphyses.
A nonunion of a diaphyseal fracture of the humerus can present a major functional problem even in the elderly population. Advances in operative exposures combined with newer techniques of achieving stable internal fixation even in the presence of pathologic bone have enabled the surgeon to successfully treat even the most complex nonunions.


Spreading a medication administration intervention organizationwide in six hospitals.
Six hospitals from the San Francisco Bay Area participated in a 12-month quality improvement project conducted by the Integrated Nurse Leadership Program (INLP). A quality improvement intervention that focused on improving medication administration accuracy was spread from two pilot units to all inpatient units in the hospitals. INLP developed a 12-month curriculum, presented in a combination of off-site training sessions and hospital-based training and consultant-led meetings, to teach clinicians the key skills needed to drive organizationwide change. Each hospital established a nurse-led project team, as well as unit teams to address six safety processes designed to improve medication administration accuracy: compare medication to the medication administration record; keep medication labeled throughout; check two patient identifications; explain drug to patient (if applicable); chart immediately after administration; and protect process from distractions and interruptions. From baseline until one year after project completion, the six hospitals improved their medication accuracy rates, on average, from 83.4% to 98.0% in the spread units. The spread units also improved safety processes overall from 83.1% to 97.2%. During the same time, the initial pilot units also continued to improve accuracy from 94.0% to 96.8% and safety processes overall from 95.3% to 97.2%. With thoughtful planning, engaging those doing the work early and focusing on the "human side of change" along with technical knowledge of improvement methodologies, organizations can spread initiatives enterprisewide. This program required significant training of frontline workers in problem-solving skills, leading change, team management, data tracking, and communication.


A shorter and more specific oral sensitization-based experimental model of food allergy in mice.
Cow's milk protein allergy (CMPA) is one of the most prevalent human food-borne allergies, particularly in children. Experimental animal models have become critical tools with which to perform research on new therapeutic approaches and on the molecular mechanisms involved. However, oral food allergen sensitization in mice requires several weeks and is usually associated with unspecific immune responses. To overcome these inconveniences, we have developed a new food allergy model that takes only two weeks while retaining the main characters of allergic response to food antigens. The new model is characterized by oral sensitization of weaned Balb/c mice with 5 doses of purified cow's milk protein (CMP) plus cholera toxin (CT) for only two weeks and posterior challenge with an intraperitoneal administration of the allergen at the end of the sensitization period. In parallel, we studied a conventional protocol that lasts for seven weeks, and also the non-specific effects exerted by CT in both protocols. The shorter protocol achieves a similar clinical score as the original food allergy model without macroscopically affecting gut morphology or physiology. Moreover, the shorter protocol caused an increased IL-4 production and a more selective antigen-specific IgG1 response. Finally, the extended CT administration during the sensitization period of the conventional protocol is responsible for the exacerbated immune response observed in that model. Therefore, the new model presented here allows a reduction not only in experimental time but also in the number of animals required per experiment while maintaining the features of conventional allergy models. We propose that the new protocol reported will contribute to advancing allergy research.


Aggregation induced emission active fluorescent sensor for the sensitive detection of Hg2+ based on organic-inorganic hybrid mesoporous material.
We report the preparation of an organic-inorganic hybrid mesoporous material, PHC-SBA-15, derived from the coupling of a pyrene-based derivative PHC and mesoporous SBA-15 silica. Compared with the stable aggregation-induced emission (AIE) properties of PHC, those of PHC-SBA-15 were more promoted and active due to the fixation of PHC and the space limitation in mesoporous SBA-15. The aggregation and disaggregation activities can be tuned by controlling the concentrations in aqueous media and changing the fluorescence color from yellow to blue. In addition to the controllable AIE properties, PHC-SBA-15 was applied for the highly selective and sensitive detection of Hg2+ through the fluorescence quenching of monomeric pyrene in aqueous media. The fluorescence intensity at 395 nm was linearly proportional to that of Hg2+ in the concentration ranges of 0-1.0 × 10-5 and 1.0 × 10-5-10 × 10-5 M, showing a low detection limit of 1.02 × 10-7 M. This work provides an effective strategy for modulating the AIE properties from non-active to active by introducing AIE stable molecule into mesoporous silica material. This method also favors the development of fluorescent sensors for detecting targets with high sensitivity and selectivity in aqueous media with less synthetic difficulties.


Efficacy of platelet-rich plasma in arthroscopic repair of full-thickness rotator cuff tears: a meta-analysis.
The use of platelet-rich plasma (PRP) is an innovative clinical therapy, especially in arthroscopic rotator cuff repair. The purpose of this study was to compare the clinical improvement and tendon-to-bone healing with and without PRP therapy in arthroscopic rotator cuff repair. A systematic search was done in the major medical databases to evaluate the studies using PRP therapy (PRP+) or with no PRP (PRP-) for the treatment of patients with rotator cuff tears. We reviewed clinical scores such as the Constant score, the American Shoulder and Elbow Surgeons score, the University of California at Los Angeles (UCLA) Shoulder Rating Scale, the Simple Shoulder Test, and the failure-to-heal rate by magnetic resonance imaging between PRP+ and PRP- groups. Five studies included in this review were used for a meta-analysis based on data availability. There were no statistically significant differences between PRP+ and PRP- groups for overall outcome scores (P > .05). However, the PRP+ group exhibited better healing rates postoperatively than the PRP- group (P = .03) in small/moderate full-thickness tears. The use of PRP therapy in full-thickness rotator cuff repairs showed no statistically significant difference compared with no PRP therapy in clinical outcome scores, but the failure-to-heal rate was significantly decreased when PRP was used for treatment of small-to-moderately sized tears. PRP therapy may improve tendon-to-bone healing in patients with small or moderate rotator cuff tears.


The Triggering Receptor Expressed on Myeloid Cells 2 Binds Apolipoprotein E.
The triggering receptor expressed on myeloid cells 2 (TREM2) is an Ig-like V-type receptor expressed by populations of myeloid cells in the central nervous system and periphery. Loss-of-function mutations in TREM2 cause a progressive, fatal neurodegenerative disorder called Nasu-Hakola disease. In addition, a TREM2 R47H coding variant was recently identified as a risk factor for late-onset Alzheimer disease. TREM2 binds various polyanionic molecules but no specific protein ligands have been identified. Here we show that TREM2 specifically binds apolipoprotein E, a well established participant in Alzheimer disease. TREM2-Ig fusions efficiently precipitate ApoE from cerebrospinal fluid and serum. TREM2 also binds recombinant ApoE in solution and immobilized ApoE as detected by ELISA. Furthermore, the Alzheimer disease-associated R47H mutation, and other artificial mutations introduced in the same location, markedly reduced the affinity of TREM2 for ApoE. These findings reveal a link between two Alzheimer disease risk factors and may provide important clues to the pathogenesis of Nasu-Hakola disease and other neurodegenerative disorders.


[Andromastectomy].
Andromastectomy, that is to say the removal of the male mammary glands, should prevent the development of Gynaecomastia which is both painful and deforming and may occur subsequent to certain illnesses or hormone treatment.


Visualizing the spatial distribution and alteration of metabolites in continuously cropped Salvia miltiorrhiza Bge using MALDI-MSI.
Salvia miltiorrhiza Bge (SMB) has long been used in traditional Chinese medicine to treat cardiovascular and cerebrovascular diseases. Growing clinical usage has led to a huge demand for artificial planting of SMB. Thus, continuous cropping of SMB is an important challenge that needs to be addressed. Continuous cropping can alter the metabolic profile of plants, resulting in poor growth and low yield. In this study, we tried to image the spatial location and variation of endogenous metabolites in continuously cropped SMB using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). Spatially resolved expressions of tanshinones, salvianolic acids, polyamines, phenolic acids, amino acids, and oligosaccharides in normal and continuously cropped SMB roots were compared. The expressions of dihydrotanshinone I, tanshinone II A, dehydromiltirone, miltirone, dehydrotanshinone IIA, spermine, salvianolic acid B/E, tetrasaccharide, and pentasaccharide in continuously cropped SMB roots were much lower than those in normal roots. There was little difference in the expressions of caffeic acid and salvianolic acid A in normal and continuously cropped SMB roots. Ferulic acid was more widely distributed in xylem of normal SMB but strongly expressed in xylem, phloem, and cambium of continuously cropped SMB. The spatially resolved metabolite information enhances our understanding of the metabolic signature of continuously cropped SMB and also provides insights into the metabolic effects of continuous cropping in other plants.


Frailty: A cost incurred by reproduction?
Evolutionary theories of senescence, such as the 'disposable soma' theory, propose that natural selection trades late survival for early fecundity. 'Frailty', a multidimensional measure of health status, may help to better define the long-term consequences of reproduction. We examined the relationship between parity and later life frailty (as measured by the Frailty Index) in a sample of 3,534 adults aged 65 years and older who participated in the English Longitudinal Study of Ageing. We found that the most parous adults were the most frail and that the parity-frailty relationship was similar for both sexes. Whilst this study provided some evidence for a 'parity-frailty trade-off', there was little support for our hypothesis that the physiological costs of childbearing influence later life frailty. Rather, behavioural and social factors associated with rearing many children may have contributed to the development of frailty in both sexes.


The effect of diet and temperature on reproductive rate in Arcella vulgaris Ehrenberg (Sarcodina: Testacida).
The acceptability of bacterial, algal and fungal food cources as manifested by reproductive rate was investigated in Arcella vulgaris at 5°C intervals between 10°C-25°C. Bacteria and diets containing bacteria produced the highest rates of reproduction, a fungal diet induced the lowest rate of reproduction. On all diets reproductive rate increased with temperature up to 20°C, thereafter levelling out. Generation times were long, ranging from 64 h to 95 h, depending on diet and temperature. Consumption experiments using bacteria as food indicated that energy consumption was independent of temperature.


Metabolic syndrome in women with and without interstitial cystitis/bladder pain syndrome.
The aim of this study was to compare the frequency of metabolic syndrome (MetS) in patients with and without interstitial cystitis/bladder pain syndrome (IC/BPS). This case-control study evaluated the indicators of MetS in 287 females with IC/BPS and in 287 females without IC/BPS in West China Hospital between January 2010 and January 2020. Then, the number of voids per day, frequency of night urination, O'Leary-Sant Interstitial Cystitis Symptom/Problem Index, and visual analog scale were examined in the two groups. Based on both the National Cholesterol Education Program Adult Treatment Panel III recommendations and the International Diabetes Federation criteria, the distribution of MetS was statistically higher in patients with IC/BPS than in the control group, with 34.8% vs 17.8% (P < 0.0001) and 34.2% vs 20.9% (P = 0.0005), respectively. Regarding symptom scores, the IC/BPS group demonstrated significantly higher scores than the control group in all aspects (P < 0.0001). More patients with anxiety (P < 0.0001), insomnia (P < 0.0001), hypertension (P = 0.0001), and diabetes mellitus (P = 0.017) were observed in the IC/BPS group. Moreover, the findings indicated that patients with IC/BPS had a higher BMI (P = 0.0001) and larger waist circumference (P = 0.0001). Blood tests presented a significantly higher level of fasting glycemia, serum cystatin-C, and triglycerides in patients with IC/BPS. Furthermore, higher ORs for the occurrence of MetS among cases were observed, although this was not statistically significant. MetS frequency was relatively high in patients with IC/BPS. Further research is needed to understand the common pathophysiologic mechanism of IC/BPS and MetS.


Induction of periosteal bone formation by intraosseous BMP-2 injection in a mouse model of osteogenesis imperfecta.
Surgical interventions are routinely performed on children with osteogenesis imperfecta (OI) to stabilize long bones, often post fracture. We speculated that a combination of intramedullary reaming and intraosseous injection of recombinant bone morphogenetic protein-2 (BMP-2) could enhance periosteal ossification and ultimately cortical thickness and strength. This approach was conceptually tested in a preclinical model of genetic bone fragility. Six experimental groups were tested including no treatment, intramedullary reaming, and reaming with 5 µg BMP-2 injection performed in the tibiae of both wild type (WT) and Col1a2 G610C/+ (OI, Amish mutation) mice. Bone formation was examined at a two-week time point in ex vivo specimens by micro-computed tomography (microCT) analysis and histomorphometry with a dynamic bone label. MicroCT data illustrated increases in tibial cortical thickness with intramedullary reaming alone (Saline) and reaming plus BMP-2 injection (BMP-2) compared to no intervention controls. In the OI mice, the periosteal bone increase was not statistically significant with Saline but there was an increase of +192% (p = 0.053) with BMP-2 injection. Dynamic histomorphometry on calcein label was used to quantify new woven bone formation; while BMP-2 induced greater bone formation than Saline, the anabolic response was blunted overall in the OI groups. These data indicate that targeting the intramedullary compartment via reaming and intraosseous BMP-2 delivery can lead to gains in cortical bone parameters. It is suggested that the next step is to validate safety and functional improvements in a clinical OI setting.


Differential consequences of neurokinin receptor 1 and 2 antagonists in metastatic breast carcinoma cells; Effects independent of Substance P.
The biological action of Substance P (SP) is mediated mainly by NK-1 receptors (NK1R) followed by NK2 receptors (NK2R). Aberrant expression of NK1R and NK2R has been identified in various carcinomas. The role of Substance P and its receptors, especially NK2R in cancer progression is not entirely known and there are conflicting results in the literature demonstrating the need for further investigation. In the current study, we examined the effects of SP and antagonists selective for the NK1R and NK2R in breast carcinoma cells metastasize to vital organs. The effects of highly potent and selective non-peptide mouse NK1R and NK2R antagonists RP 67,580 and GR 159897, respectively, as well as SP and SP methyl ester, on both metastatic (4THM, 4TBM, 4TLM, 4T1) and non-metastatic (67NR) breast cancer cells were determined. NK1R and NK2R were over expressed in metastatic breast cells compared to non-metastatic cells. The NK1R antagonist at a 30 μM dose inhibited cell growth and induced cell death in metastatic cells while enhancing phosphorylation of Akt, the latter response not observed in the non-metastatic 67NR cells. Blocking the action of SP at the NK2R (30 μM antagonist) suppressed cellular proliferation in all the cell lines examined, with a response less prominent than that of the NK1R antagonist. Differently, the NK2R antagonist increased phosphorylation of p38 and enhanced MIP-2 secretion. SP and the SP methyl ester neither altered cell proliferation nor the effects of NK1R and NK2R antagonists in the metastatic cell lines. Increased sensitivity of metastatic breast carcinoma cells to NK1R and NK2R antagonists suggest potential therapeutic value of antagonists in metastatic disease. NK1R and NK2R in metastatic breast carcinoma cells react differently to agonists and antagonists. These findings together with previously published data demonstrate that differential consequences of receptor antagonists and SP may inhibit breast cancer growth and metastasis.


Mineralocorticoid receptor antagonist use and the effects of empagliflozin on clinical outcomes in patients admitted for acute heart failure: Findings from EMPULSE.
In patients hospitalized for acute heart failure (AHF) empagliflozin produced greater clinical benefit than placebo. Many patients with AHF are treated with mineralocorticoid receptor antagonists (MRAs). The interplay between empagliflozin and MRAs in AHF is yet to be explored. This study aimed to evaluate the efficacy and safety of empagliflozin versus placebo according to MRA use at baseline in the EMPULSE trial (NCT04157751). In this analysis all comparisons were performed between empagliflozin and placebo, stratified by baseline MRA use. The primary outcome included all-cause death, heart failure events, and a ≥5 point difference in Kansas City Cardiomyopathy Questionnaire (KCCQ) total symptom score at 90 days, assessed using the win ratio (WR). First heart failure hospitalization or cardiovascular death was a secondary outcome. From the 530 patients randomized, 276 (52%) were receiving MRAs at baseline. MRA users were younger, had lower ejection fraction, better renal function, and higher KCCQ scores. The primary outcome showed benefit of empagliflozin irrespective of baseline MRA use (WR 1.46, 95% confidence interval [CI] 1.08-1.97 and WR 1.27, 95% CI 0.93-1.73 in MRA users and non-users, respectively; interaction p = 0.52). The effect of empagliflozin on first heart failure hospitalization or cardiovascular death was not modified by MRA use (hazard ratio [HR] 0.58, 95% CI 0.30-1.11 and HR 0.85, 95% CI 0.47-1.52 in MRA users and non-users, respectively; interaction p = 0.39). Investigator-reported and severe hyperkalaemia events were infrequent (<6%) irrespective of MRA use. In patients admitted for AHF, initiation of empagliflozin produced clinical benefit and was well tolerated irrespective of background MRA use. These findings support the early use of empagliflozin on top of MRA therapy in patients admitted for AHF.


Analysis of the HLA-ABC linkage disequilibrium: decreasing strength of gametic association with increasing map distance.
1242 HLA-ABC haplotypes of the North German population (Hambrug) as deduced by family analyses are described. They are in perfect agreement with recently published data by Mayr (1977) from Austria (Vienna) in all parameters tested: frequency of the single HLA-alleles, haplotype distribution and linkage disequilibrium values. Gametic association studies revealed that 69.4% of the B and C genes (map distance 0.2cM) 36.9% of the A and C genes (0.6 cM), but only 23.2% of the A and B genes (0.8 cM) were significantly more often combined than expected due to their frequencies. From these findings it seems likely that the linkage disequilibrium within the MHC is rather due to a short evolutionary period than to selective forces. Some observations as to the most common European haplotype A1,B8 are discussed.


Metformin downregulates the mitochondrial carrier SLC25A10 in a glucose dependent manner.
Metformin, a commonly used agent in the treatment of type 2 diabetes, is also associated with reduced risk of cancer development and improvement in cancer survival. Although much is known about metformin, the mechanisms behind its anti-cancer properties are not fully understood. In this study we addressed the role of a mitochondrial transporter commonly upregulated in cancer cells, SLC25A10, for cell survival and metabolism in the presence of metformin. SLC25A10 is a carrier in the mitochondrial inner membrane that transports malate and succinate out of the mitochondria, in exchange of phosphate and sulfate. We show that metformin treatment results in decreased gene expression of the SLC25A10 carrier both in lung cancer A549 mock cells and A549 SLC25A10 knockdown (siSLC25A10) cells. The decrease was even more pronounced when cells were grown at low glucose concentrations. The expression levels of key enzymes in glucose metabolism showed slightly altered mean values for all genes tested in both control cells and siSLC25A10 cells upon metformin treatment. The gene expression of the metabolic regulator glutamic-oxaloacetic transaminase 1 decreased in wild type cells upon metformin treatment whereas there was a trend of increased expression in the siSLC25A10 cells upon metformin treatment. In addition, the gene expression of the cyclin-dependent kinase inhibitor 1A was markedly increased in the siSLC25A10 compared to control A549 cells, and with even larger increases in the presence of metformin and at low glucose concentration. Our data show that in siSLC25A10 cell lines, metformin significantly alters the SLC25A10 carrier at both mRNA and protein levels and can thereby affect the supply of nutrients and the metabolic state of cancer cells.


Association prediction of CircRNAs and diseases using multi-homogeneous graphs and variational graph auto-encoder.
As a non-coding RNA molecule with closed-loop structure, circular RNA (circRNA) is tissue-specific and cell-specific in expression pattern. It regulates disease development by modulating the expression of disease-related genes. Therefore, exploring the circRNA-disease relationship can reveal the molecular mechanism of disease pathogenesis. Biological experiments for detecting circRNA-disease associations are time-consuming and laborious. Constrained by the sparsity of known circRNA-disease associations, existing algorithms cannot obtain relatively complete structural information to represent features accurately. To this end, this paper proposes a new predictor, VGAERF, combining Variational Graph Auto-Encoder (VGAE) and Random Forest (RF). Firstly, circRNA homogeneous graph structure and disease homogeneous graph structure are constructed by Gaussian interaction profile (GIP) kernel similarity, semantic similarity, and known circRNA-disease associations. VGAEs with the same structure are employed to extract the higher-order features by the encoding and decoding of input graph structures. To further increase the completeness of the network structure information, the deep features acquired from the two VGAEs are summed, and then train the RF with sparse data processing capability to perform the prediction task. On the independent test set, the Area Under ROC Curve (AUC), accuracy, and Area Under PR Curve (AUPR) of the proposed method reach up to 0.9803, 0.9345, and 0.9894, respectively. On the same dataset, the AUC, accuracy, and AUPR of VGAERF are 2.09%, 5.93%, and 1.86% higher than the best-performing method (AEDNN). It is anticipated that VGAERF will provide significant information to decipher the molecular mechanisms of circRNA-disease associations, and promote the diagnosis of circRNA-related diseases.


Surgical treatment of intracranial Erdheim-Chester disease.
We review the clinical presentation, radiological and histological characteristics, and the natural history, of intracranial Erdheim-Chester disease (ECD). ECD is a rare form of non-Langerhans histiocytosis that affects multiple organs. It is clinically characterized by leg pain, exophthalmos and diabetes insipidus (DI). Central nervous system involvement is rare, with only 27 patients reported in the international literature. DI and cerebellar signs represent the most common neurological symptoms. Its treatment is controversial. Intracranial surgical procedures for ECD have been reported in 11 patients with a complete surgical resection performed in six, and an intracerebral biopsy performed in five patients. In seven patients the cranial procedures represented the initial diagnostic method. Surgical resection and radiation therapy have been used in the further management of these cerebral lesions.


Anti-hepatitis B virus activities of triterpenoid saponin compound from Potentilla anserine L.
The Tibetan herb Potentilla anserina L. has been widely used in China for many thousands of years to treat hepatitis-B. Bioassay-guided fractionation of the ethanol extract of the rhizomes led to the isolation of a triterpenoid saponin (TS) that was determined to be 2alpha,3beta,19alpha-trihydroxyurs-12-en-28-oic acid beta-D-glucopyranosyl ester. Using models of HBV infection, this compound was evaluated for its effect on HBV antigene expression in the 2.2.15 cell line in vitro and anti-hepatitis B virus (HBV) activities in Peking ducklings in vivo. Results showed that it could decrease the expression levels of HBsAg, HBeAg and HBVDNA in the 2.2.15 cell culture and the inhibitory effect was not due to the cytotoxity of the triterpenoid saponin. The antiviral study in vivo on Peking ducklings also demonstrated that this compound inhibits duck hepatitis B virus (DHBV) DNA replication.


The frequency, magnitude and timing of post-diagnosis body weight gain in Dutch breast cancer survivors.
To evaluate the association between systemic treatments and post-diagnosis weight gain in breast cancer patients during longer follow-up periods, we conducted a retrospective cohort study (n=271). Information on adjuvant systemic treatments and repeated body weight measurements was obtained from medical records, and analysed using multi-level regressions. During the first year, a mean weight change of +2.0kg (SD 4.9) was observed. Overall, 29% of all breast cancer patients had gained 5kg or more in body weight during total follow-up (median: 3 years). In multi-level analyses, women who received combined systemic treatment gained significantly more weight as compared with women who received no systemic treatment (4.5kg versus 2.0kg at 5 years post-diagnosis, p<0.05). Significant weight gain occurs in breast cancer patients in the Netherlands during the first year post-diagnosis. After the first year, further weight gain mainly occurs in women who receive chemotherapy in combination with endocrine therapy.


New developments at the University of Ottawa Community Legal Clinic.
This is another in our series of articles about Canadian legal clinics that provide specialized services to people with HIV/AIDS. Vanessa Gruben describes new trends in legal issues observed by the University of Ottawa Community Legal Clinic since the last article by the Clinic in 1999, as well as other programs and projects undertaken by the Clinic over the last year.


Global survey of physician testing practices for nontuberculous mycobacteria.
Certain patients are at greater risk of developing nontuberculous mycobacterial pulmonary disease (NTM-PD), including those with lung conditions such as bronchiectasis. Testing for nontuberculous mycobacteria (NTM) in patients at risk is necessary to identify NTM-PD and start appropriate management. The aim of this survey was to evaluate current testing practices for NTM and identify testing triggers. Physicians (n=455) who see at least one patient with NTM-PD in a typical 12-month period and test for NTM as part of practice from Europe, USA, Canada, Australia, New Zealand and Japan participated in a 10-min anonymised survey on NTM testing practices. Bronchiectasis, COPD and use of immunosuppressants were the factors most likely to prompt testing among physicians in this survey (90%, 64% and 64%, respectively), with radiological findings the most common reason leading to considering NTM testing in patients with bronchiectasis and COPD (62% and 74%, respectively). Macrolide monotherapy in patients with bronchiectasis and inhaled corticosteroid use in patients with COPD were not important triggers for testing (15% and 9% of physicians, respectively). Persistent cough and weight loss triggered testing in >75% of physicians. Testing triggers were markedly different for physicians in Japan, with cystic fibrosis prompting testing in fewer physicians compared with other regions. Testing for NTM is influenced by underlying disease, clinical symptoms or radiological changes, but clinical practice varies considerably. Adherence to guideline recommendations for NTM testing is limited in certain patient subgroups and varies across regions. Clear recommendations on NTM testing are needed.


3 TESLA MR imaging in adults with focal onset epilepsy.
The finding of cerebral epileptogenic lesions in magnetic resonance (MR) has demonstrated to be a relevant prognostic factor for potential surgical candidates. In a series of consecutive adults with focal onset epilepsy, we investigated the yield of 3T MR imaging for detecting epileptogenic cerebral lesions. We prospectively recruited 161 adult patients with a diagnosis of focal epilepsy, all of whom underwent standardized MR imaging study performed with a 3T magnet. Lesion-related epilepsy was observed in 48% of patients, and 12% of cryptogenic patients showed subtle or non-specific lesions related to the epileptogenic source. The most common findings were focal cortical dysplasia and vascular lesions, followed by mesial temporal sclerosis, tumors, and scars from previous cerebral injuries. Patients older than 72 years were more likely to have vascular epilepsy. Diagnostic assessment using a standardized 3T MR imaging protocol for focal-onset epilepsy detects lesions in nearly half the patients. Our results indicate that elders with focal epilepsy should be searched for vascular lesions.


Characterization of the developmental stages of cypress zygotic embryos by two-dimensional electrophoresis and by cytochemistry.
Biochemical changes that characterize megagametophyte and zygotic embryo development in the conifer Cupressus sempervirens L. (Cupressaceae) were studied by complementary methods of cytochemistry and two-dimensional electrophoresis (2-DE). These analyses revealed that early in their development megagametophytes and embryos were characterized by the predominant elaboration of starch in association with a low protein content. As their development proceeded, starch content gradually decreased while protein body synthesis progressively intensified, both in the megagametophyte and the embryo. In parallel, an increase in protein level as well as an accumulation of specific polypeptides could be observed in the two tissues. During maturation, protein bodies accumulated to high levels both in megagametophyte and embryo cells, whereas starch could no longer be detected. Protein levels were high in mature seeds and reached 12% and 8% of the megagametophyte and embryo DW, respectively. Some sets of polypeptides accumulated more specifically at this time in both megagametophyte and embryo. Some of these began to first accumulate in the megagametophyte during embryo development before their concentration rose in the embryo at cotyledonary stage. Others displayed a more specific-embryo accumulation pattern.


Survey of Canadian vascular surgeons and trainees finds work-related musculoskeletal pain and discomfort is common.
Occupational injuries and disability are a source of surgeon morbidity. The purpose of this study was to assess the physical toll of working in operating rooms by Canadian vascular surgeons. To assess workplace musculoskeletal (MSK) complaints and challenges faced by Canadian vascular surgeons and trainees and their implications on surgical practice and occupational longevity. An online survey was distributed to resident and surgeon members of the Canadian Society of Vascular Surgery. The survey collected data on demographics, operative volume, and work-related MSK symptoms. The survey was distributed to 188 surgeons and trainees. After three e-mailings, 109 surveys were returned (58% response rate). Of the responders, 87% were male, 51% were 45 years or older, and 56% had been in practice for 10 or more years. Workplace MSK symptoms were reported by 83% of the responders. The most common locations were the low back (78%), neck (74%), and shoulder (30%). Most responders (83%) believed that these symptoms were related to their operative environment. Almost half (48%) sought medical care. As a result of these MSK symptoms, 25% experience chronic pain with 8% reporting time off work as a consequence. Another 11% reported an impact on their operative performance with 14% considering early retirement. A lack of operating room system changes to prevent workplace injury and disability was noted by 85% of the responders although only 3% reported their disability to their department. Occupational MSK symptoms and disability are common among Canadian vascular surgeons. Further research is needed to create programs to improve surgeon morbidity.


Partial duplication of the jaw: case reports and review of relevant publications.
Craniofacial duplication is a rare congenital malformation with a wide phenotypic range. The signs and symptoms range from partial craniofacial duplication to bicephalus. We describe two cases of partial duplication of jaw: a girl with a duplication of the maxilla, and a boy with duplication of the mandible. We review the relevant publications and discuss the pathogenesis.


Complete Genome Sequence of the Type Strain of the Acetogenic Bacterium Moorella thermoacetica DSM 521T.
Here we report the closed genome sequence of the type strain Moorella thermoacetica DSM 521(T), an acetogenic bacterium, which is able to grow autotrophically on H2 + CO2 and/or CO, using the Wood-Ljungdahl pathway. The genome consists of a circular chromosome (2.53 Mb).


Traumatic retropharyngeal hematoma and prevertebral edema induced by whiplash injury.
Whiplash injury commonly results in cervical spine trauma. We report a case of a 58-year-old man, who sustained a whiplash injury from contact with the headrest of his seat after his car was involved in a rear-end collision. He presented with sore throat, hoarseness, difficulty in swallowing and progressing dyspnea. The diagnostic work-up comprising lateral radiograph, CT and MR imaging disclosed the rare constellation of a retropharyngeal hematoma and prevertebral edema without further injury of the cervical spine structures. Compression of the upper airways was evident. A careful history and an appropriate diagnostic approach are essential for the work-up and management of such a life-threatening situation.


Impact of wait times on late postprocedural mortality after successful transcatheter aortic valve replacement.
Wait times are associated with mortality on waiting list for transcatheter aortic valve replacement (TAVR). Whether longer wait times are associated with long term mortality after successful TAVR remains unassessed. Consecutive patients successfully treated with elective TAVR in our center between January 2013 and August 2019 were included. The primary end point was one-year all-cause mortality. TAVR wait times were defined as the interval from referral date for valve replacement to the date of TAVR procedure. A total of 383 patients were included with a mean wait time of 144.2 ± 83.87 days. Death occurred in 55 patients (14.4%) at one year. Increased wait times were independently associated with a relative increase of 1-year mortality by 2% per week after referral (Adjusted Hazard Ratio 1.02 [1.002-1.04]; p = 0.02) for TAVR. Chronic kidney disease, left ventricular ejection fraction ≤ 30%, access site and STS score were other independent correlates of 1-year mortality. Our study shows that wait times are relatively long in routine practice and associated with increased 1-year mortality after successful TAVR. Such findings underscore the need of strategies to minimize delays in access to TAVR.


Clinical study of cisplatin hyperthermic intraperitoneal perfusion chemotherapy in combination with docetaxel, 5-flourouracil and leucovorin intravenous chemotherapy for the treatment of advanced-stage gastric carcinoma.
The purpose of this study is to observe and compare the preliminary efficacy and side effects of docetaxel, 5-fluorouracil and leucovorin intravenous chemotherapy in combination with cisplatin hyperthermic intraperitoneal perfusion chemotherapy for the treatment of advanced gastric cancer. Retrospectively analyzed 101 patients with advanced gastric cancer receiving docetaxel, 5-fluorouracil, leucovorin and cisplatin intravenous chemotherapy or intravenous administration of docetaxel, 5-fluorouracil and leucovorin combined with cisplatin hyperthermic intraperitoneal perfusion chemotherapy, 49 patients in intravenous chemotherapy (VC) group, 52 patients in hyperthermic intraperitoneal perfusion chemotherapy (HIPEC) group. The response rate was 44.9% (22/49) in VC group and 65.4% (34/52) in HIPEC group, among which there was 1 case of CR, and the difference was statistically significant (p= 0.038). For CBR evaluation, the effective rate was 65.3% (32/49) in VC group and 82.7% (43/52) in HIPEC group, and the difference was statistically significant (p= 0.0458). The median progress free survival time (PFS) was 3.4 months in VC group and 4.6 months in HIPEC group, the difference was statistically significant (p= 0.045). The median overall survival time (OS) was 6.7 months in VC group and 7.5 months in HIPEC group, the difference was not statistically significant (p= 0.201). The main side effects in two groups were well tolerated, and there was no statistically significant difference. The short-term efficacy and PFS of HIPEC plus intravenous chemotherapy were better than single intravenous chemotherapy, and there was no significant improvement in OS, the side effects were similar in two groups with good tolerability.


Highly effective, easily accessible screw-sense-determining end group in the asymmetric polymerization of 1,2-diisocyanobenzenes.
Enantiopure helical poly(quinoxaline-2,3-diyl) was formed stereoselectively in the polymerization of 1,2-diisocyanobenzene using a new organopalladium initiator bearing the (4S,5S)-N-acyl-4,5-dihydro-4,5-diphenyl-1H-imidazol-2-yl group as the polymer-end screw-sense-determinant.


Optimization of azeotropic protein separations in gradient and isocratic ion-exchange simulated moving bed chromatography.
The separation of dilute binary mixtures of proteins by salt aided ion-exchange simulated moving bed (SMB) chromatography is optimized with respect to throughput, desorbent consumption and salt consumption. The optimal flow-rate ratios are analytically determined via an adopted "triangle theory". Azeotropic phenomena are included in this procedure. The salt concentrations in the feed and recycled liquid are subsequently determined by numerical optimization. The azeotropic separation of bovine serum albumin and a yeast protein is used to illustrate the procedure. Gradient operation of the SMB is generally preferred over isocratic operation. A feed of azeotropic salt concentration can only be separated in a gradient SMB. Desorbent and salt consumption are always lower in gradient than in isocratic SMB chromatography.


An analysis of glaucoma repeat measures assessment results: Are core competencies enough?
The need to validate core competency skills in qualified optometrists wishing to take part in extended roles in glaucoma care has been questioned. This analysis examines the ability of qualified optometrists to perform relevant core competency skills under standardised objective assessment conditions to explore whether such validation is justified. It also investigates if there are associations between performance, gender and length of time since qualification. Anonymised data from the Cardiff University assessment programme for the Wales Optometry Postgraduate Education Centre (WOPEC) Local Optical Committee Support Unit glaucoma referral filtering and monitoring pathway delivered between January 2017 and March 2020 were analysed. Results were combined with demographic data from the General Optical Council register of optometrists in the UK to investigate associations between performance and practitioner characteristics, namely length of time since qualification and gender. The assessment results of 2215 optometrists practising in England (approximately 15% of all UK registered optometrists and 30% of all optometrists registered in England) were analysed. Failure rates for first time assessment in each of five objective structured clinical examination style practical assessments were 8.5% (van Herick); 8.8% (slit lamp binocular indirect ophthalmoscopy); 10.1% (Goldmann applanation tonometry calibration); 21.9% (Goldmann applanation tonometry) and 23.3% (case scenario interpretation and management). There were either no associations or at most very weak associations between performance and practitioner characteristics. Our results suggest that these competencies are not universally present in optometrists practising in England and that ongoing training and assessment of these competencies is justified for entry into extended roles. There are no meaningful associations between performance in these assessments and gender or time since qualification.


Spatial tumour gene signature discriminates neoplastic from non-neoplastic compartments in colon cancer: unravelling predictive biomarkers for relapse.
Opting for or against the administration of adjuvant chemotherapy in therapeutic management of stage II colon cancer remains challenging. Several studies report few survival benefits for patients treated with adjuvant therapy and additionally revealing potential side effects of overtreatment, including unnecessary exposure to chemotherapy-induced toxicities and reduced quality of life. Predictive biomarkers are urgently needed. We, therefore, hypothesise that the spatial tissue composition of relapsed and non-relapsed colon cancer stage II patients reveals relevant biomarkers. The spatial tissue composition of stage II colon cancer patients was examined by a novel spatial transcriptomics technology with sub-cellular resolution, namely in situ sequencing. A panel of 176 genes investigating specific cancer-associated processes such as apoptosis, proliferation, angiogenesis, stemness, oxidative stress, hypoxia, invasion and components of the tumour microenvironment was designed to examine differentially expressed genes in tissue of relapsed versus non-relapsed patients. Therefore, FFPE slides of 10 colon cancer stage II patients either classified as relapsed (5 patients) or non-relapsed (5 patients) were in situ sequenced and computationally analysed. We identified a tumour gene signature that enables the subclassification of tissue into neoplastic and non-neoplastic compartments based on spatial expression patterns obtained through in situ sequencing. We developed a computational tool called Genes-To-Count (GTC), which automates the quantification of in situ signals, accurately mapping their position onto the spatial tissue map and automatically identifies neoplastic and non-neoplastic tissue compartments. The GTC tool was used to quantify gene expression of biological processes upregulated within the neoplastic tissue in comparison to non-neoplastic tissue and within relapsed versus non-relapsed stage II colon patients. Three differentially expressed genes (FGFR2, MMP11 and OTOP2) in the neoplastic tissue compartments of relapsed patients in comparison to non-relapsed patients were identified predicting recurrence in stage II colon cancer. In depth spatial in situ sequencing showed potential to provide a deeper understanding of the underlying mechanisms involved in the recurrence of disease and revealed novel potential predictive biomarkers for disease relapse in colon cancer stage II patients. Our open-access GTC-tool allowed us to accurately capture the tumour compartment and quantify spatial gene expression in colon cancer tissue.


Cotinine, a major nicotine metabolite, induces cell proliferation on urothelium in vitro and in vivo.
Tobacco smoking is a major risk factor for human cancers including urinary bladder carcinoma. In a previous study, nicotine enhanced rat urinary bladder carcinogenesis using a rat urinary bladder two-stage carcinogenesis model. In the present study, nicotine metabolites (cotinine, trans-3'-hydroxy cotinine and N'-nitrosonornicotine) were evaluated in a cell proliferation assay using urinary bladder urothelial cell lines. Cotinine (0.1 to 1 mM) induced the highest cell proliferation compared to the others, including nicotine, in three bladder cancer cell lines (RT4, T24 and UMUC3 cells). By Western blot, cotinine induced phosphorylation of Stat3 and expression of cyclin D1 in UMUC3 cells. The cell proliferation induced by cotinine was blocked by inhibitors of nicotinic receptors (10 nM SR16584 or 10 μM methyllycaconitine citrate) and Stat3 (100 nM stattic). In an in vivo study, cotinine (13, 40 and 120 ppm) in drinking water also induced cell proliferation and simple hyperplasia in urinary bladder and renal pelvis urothelium of rats, but to a lesser degree compared to nicotine (40 ppm). Cytotoxicity detected by scanning electron microscopy and apoptosis in the bladder urothelium were induced by nicotine but not cotinine. These data suggest that cotinine is able to induce urothelial cell proliferation both in vitro and in vivo, and high urinary concentrations may enhance urothelial carcinogenesis.


Effects of intradermal administration of streptococcal preparation OK-432 on interferon and natural killer cell activities in patients with oral cancer.
The streptococcal preparation OK-432 was used by intradermal administration as an immunotherapy in 18 patients with oral cancer, and the sera from patients during OK-432 treatment were serially assayed for interferon (IFN) activity by the plaque-reduction method with vesicular stomatitis virus in FL cells derived from human amniotic membrane. The type of serum IFN was characterized by acid-treatment and neutralization test with anti-IFN-alpha and anti-IFN-beta antisera. IFN-gamma was expressed for its titer as the residual IFN activity after neutralization with both antisera. An intradermal injection of OK-432 transiently induced IFN activity and 3 patterns in the type and level of the produced IFN were observed. Although most of the patients induced IFN-gamma and acid-stable IFN or only IFN-gamma, 2 patients seemed to be unresponsive to OK-432. When we examined the relationship between natural killer (NK) activity and IFN titer, a sharply declined NK activity was found immediately post OK-432 administration, and then NK activity stayed around the pretreatment level. Most of the tested patients' induced IFN-gamma, preceding the step toward the gradual increase in NK activity, decreased with OK-432. However, even in the patients showing no IFN induction with OK-432, a significant decrease of NK activity occurred.


The synthesis, biological activity and metabolism of 15-[6,7-14C2]- and 15-[21-3H]methyl retinone, 15-methyl retinol and 15-dimethyl retinol in rats.
15-Methyl retinone, 15-methyl retinol and 15-dimethyl retinol were synthesized from all-trans retinoic acid. The absorption maxima and molar absorption coefficients (epsilon) in ethanol are: 15-methyl retinone (372 nm, 47 400), 15-methyl retinol (325 nm, 72 000) and 15-dimethyl retinol (325 nm, 72 200). The latter two compounds show fluorescence at 470 nm when excited around 320 nm, but with intensities 40 and 70%, respectively, that of retinol. All react with trifluoroacetic acid in chloroform, and the alcohols are dehydrated in ethanolic HCl. Relative to all-trans retinyl acetate, the biological activities in rat growth assay (+/-S.E.) are: 15-methyl retinone (4.7 +/- 1.5%), 15-methyl retinol (16.2 +/- 2.3%) and 15-dimethyl retinol (0.34 +/- 0.07%). The monomethyl derivatives actively support testicular development and spermatogenesis, but none of the three analogues prevents degeneration of the retina in retinoate-treated vitamin A-deficient rats. By using [6,7-14C2]-, [11,12-3H2]- and [21-3H]-labeled analogues, the 15-methyl derivatives were shown to be well absorbed in the gut but poorly stored (1-3% of the dose) in the liver. Metabolites are excreted extensively (25-65%) in the bile, however, largely as glucuronides, and to some extent (15%) in the urine. 15-Methyl retinone is reduced to 15-methyl retinol in the intestinal mucosa but not in the liver, and fatty acyl esters of the alcohols are present in liver. Insofar as we could judge, none of these 15-methyl analogues is converted into retinol. Both monomethyl and dimethyl retinols are transported in plasma in vivo in the retinol-binding protein fraction. Interestingly, the dosages required for half saturation and saturation of the plasma transport system are inversely related, in a rough way, to the biological activities in growth.


Predictive score for early preterm birth in decisions about emergency cervical cerclage in singleton pregnancies.
To develop a simple score for assessing the risk of early preterm delivery before 32 weeks in women with singleton pregnancies receiving emergency cervical cerclage. Retrospective study. French tertiary care center from 1994 to 2006. A total of 134 pregnant women underwent emergency cervical cerclage procedure at 15-26 weeks. The analysis concerned 85 singleton pregnancies after exclusion of women with a dilated cervix without visible membranes, or presenting for revision of failed prophylactic cerclage, or who had either preterm premature rupture of membranes or clinical signs of chorioamnionitis. Multivariate logistic regression methods with rounded coefficients were used to develop a score to predict early preterm delivery before 32 weeks. Early preterm delivery before 32 weeks. The score, ranging from 0 to 15 points, was based on the following four criteria independently associated with early preterm delivery: obstetric history; cervical dilatation; membranes bulging into the vagina; and infection. Each score value was associated with a predicted probability of early preterm birth. The score and its associated early preterm probabilities may be a valuable tool to help physicians in advising women about the need for emergency cerclage.


Conditional mutual information-based feature selection for congestive heart failure recognition using heart rate variability.
Feature selection plays an important role in pattern recognition systems. In this study, we explored the problem of selecting effective heart rate variability (HRV) features for recognizing congestive heart failure (CHF) based on mutual information (MI). The MI-based greedy feature selection approach proposed by Battiti was adopted in the study. The mutual information conditioned by the first-selected feature was used as a criterion for feature selection. The uniform distribution assumption was used to reduce the computational load. And, a logarithmic exponent weighting was added to model the relative importance of the MI with respect to the number of the already-selected features. The CHF recognition system contained a feature extractor that generated four categories, totally 50, features from the input HRV sequences. The proposed feature selector, termed UCMIFS, proceeded to select the most effective features for the succeeding support vector machine (SVM) classifier. Prior to feature selection, the 50 features produced a high accuracy of 96.38%, which confirmed the representativeness of the original feature set. The performance of the UCMIFS selector was demonstrated to be superior to the other MI-based feature selectors including MIFS-U, CMIFS, and mRMR. When compared to the other outstanding selectors published in the literature, the proposed UCMIFS outperformed them with as high as 97.59% accuracy in recognizing CHF using only 15 features. The results demonstrated the advantage of using the recruited features in characterizing HRV sequences for CHF recognition. The UCMIFS selector further improved the efficiency of the recognition system with substantially lowered feature dimensions and elevated recognition rate.


An Evaluation of the Clinical and Economic Burden Among Older Adult Medicare-Covered Beneficiaries With Treatment-Resistant Depression.
To compare the clinical and economic burden of treatment-resistant depression (TRD) among older adult patients with major depressive disorder (MDD) to non-TRD MDD and non-MDD patients. Retrospective cohort study using 5% Medicare data (January 1, 2012-December 31, 2015) for MDD patients aged ≥65 years who were defined as TRD if they received ≥2 antidepressant treatments in the current episode. MDD patients not meeting TRD criteria were deemed non-TRD MDD; those without an MDD diagnosis were categorized as non-MDD. All were required to have continuous health plan enrollment for ≥6 months pre- and ≥12 months postindex date (index: first antidepressant claim/random [non-MDD]). Three cohorts were matched, and generalized linear and Cox proportional hazards models were used to compare medication use, healthcare resource utilization, costs, and risks of initial hospitalization and readmission ≤30 days postdischarge from initial hospitalization. After matching, 178 patients from each cohort were analyzed. During 12 months of follow-up, TRD patients had higher use of different antidepressants and antipsychotics, higher inpatient and emergency room visits, longer inpatient stays, and higher total healthcare costs ($24,543 versus $16,059, $8,058) than non-TRD MDD and non-MDD cohorts, respectively (all p <0.05). Risk of initial hospitalization was higher in the TRD (hazard ratio [HR] = 3.60, 95% confidence interval [CI] = 2.08-6.23) and non-TRD MDD cohorts (HR = 1.82, 95% CI = 1.02-3.25) than the non-MDD cohort. The burden of MDD among older adult Medicare beneficiaries is substantial, and even greater among those with TRD compared to non-TRD MDD, demonstrating the need for more effective treatments than those currently available.


Physiological mechanisms of thermoregulation in reptiles: a review.
The thermal dependence of biochemical reaction rates means that many animals regulate their body temperature so that fluctuations in body temperature are small compared to environmental temperature fluctuations. Thermoregulation is a complex process that involves sensing of the environment, and subsequent processing of the environmental information. We suggest that the physiological mechanisms that facilitate thermoregulation transcend phylogenetic boundaries. Reptiles are primarily used as model organisms for ecological and evolutionary research and, unlike in mammals, the physiological basis of many aspects in thermoregulation remains obscure. Here, we review recent research on regulation of body temperature, thermoreception, body temperature set-points, and cardiovascular control of heating and cooling in reptiles. The aim of this review is to place physiological thermoregulation of reptiles in a wider phylogenetic context. Future research on reptilian thermoregulation should focus on the pathways that connect peripheral sensing to central processing which will ultimately lead to the thermoregulatory response.


Prostasomes are heterogeneous regarding size and appearance but affiliated to one DNA-containing exosome family.
Prostate acinar epithelial cells release microvesicles (prostasomes) that possess pleiotropic biological effects relevant for successful fertilization. Prostasomes are formed in a similar way as exosomes but are heterogeneous as regards size and appearance. Like exosomes they are thought to be mediators of intercellular communication. We prepared seminal prostasomes in accordance with the prevailing protocol for exosome preparation including passage through a 0.2 µm filter and centrifugation in a sucrose gradient. We compared the "filterable prostasomes" with those trapped on the filter ("nonfilterable prostasomes") and, qualitatively, no conspicuous differences were apparent regarding ultrastructure and SDS-PAGE banding pattern. Moreover, both types of prostasomes contained DNA fragments and Western blot revealed presence of prostate specific membrane antigen (PSMA), CD38, and annexin A1. Reasonably, prostasomes could be included in the exosome family and be regarded as one entity containing chromosomal DNA.


NRF2-dependent stress defense in tumor antioxidant control and immune evasion.
The transcription factor NRF2 is known as the master regulator of the oxidative stress response. Tumor entities presenting oncogenic activation of NRF2, such as lung adenocarcinoma, are associated with drug resistance, and accumulating evidence demonstrates its involvement in immune evasion. In other cancer types, the KEAP1/NRF2 pathway is not commonly mutated, but NRF2 is activated by other means such as radiation, oncogenic activity, cytokines, or other pro-oxidant triggers characteristic of the tumor niche. The obvious effect of stress-activated NRF2 is the protection from oxidative or electrophilic damage and the adaptation of the tumor metabolism to changing conditions. However, data from melanoma also reveal a role of NRF2 in modulating differentiation and suppressing anti-tumor immunity. This review summarizes the function of NRF2 in this tumor entity and discusses the implications for current tumor therapies.


[Woman with type 1 diabetes mellitus and rapidly progressive edema].
A 47-year-old woman with type 1 diabetes mellitus was presented for evaluation of progressive oedema, fatigue and weight gain. Her medical history was significant for arterial hypertension and autoimmune thyroiditis requiring substitution therapy with levothyroxine. Physical examination revealed bilateral malleolar and crural oedema, swelling of the eyelids and two-sided pleural effusions. DIAGNOSTIC, TREATMENT AND COURSE: The blood level of albumin was very low, urine analysis showed proteinuria of > 8 g/day. The kidney biopsy revealed only slight changes. This led in combination with the blood and urine results to the diagnosis of minimal change glomerulopathy. After initiation of high dose prednisolone the patient achieved near total remission within four weeks. Prednisolone therapy was tapered over several months. In patients with diabetes mellitus and suddenly occurring nephrotic syndrome other diseases than diabetic nephropathy have to be considered. In most cases a kidney biopsy is mandatory.


Study on daptomycin use and implementation of an antimicrobial stewardship program.
Treatment of Gram-positive pathogens remains a major health issue due to the presence of methicillin-resistant Staphylococcus aureus (MRSA) and Vancomycin-Resistant Enterococcus spp. Daptomycin offers an alternative after therapeutic failure using glycopeptides. Yet its use requires strict control given its financial impact and environmental risks. Since 2014, the use of daptomycin within our hospital has intensified, occasionally outside the scope of its approved indications. The aim of this study is to analyze the appropriateness of daptomycin prescriptions. This work was conducted in a 1500-bed University Hospital. A descriptive retrospective study was conducted from November 2013 to July 2014. All patients having received at least 2 days of treatment were included. Analysis of the appropriateness of daptomycin prescriptions was conducted by a multidisciplinary team comprised of infectious diseases specialists, pharmacists and a microbiologist. The appropriateness of daptomycin prescriptions was established based on Infectious Diseases Society of America recommendations published in 2011. The indicators chosen to determine appropriateness of prescription were: treatment indication, prescribed dose and other antibiotics associated with the daptomycin prescription. 19 patients (14 men/5 women) were included. Observed indications were: bone and joint infection (n = 6; 32 %), infectious endocarditis (n = 5; 26 %), bacteremia (n = 5; 26 %) and complicated skin and soft tissue infection (n = 3; 16 %). Identified pathogens were: MRSA (n = 14; 74 %), methicillin-resistant coagulase-negative Staphylococcus (n = 4; 21 %) and Streptococcus mitis (n = 1; 5 %). Daptomycin was prescribed as first-line treatment in 32 % of cases (n = 6). The mean dosage was 9 mg/kg/day (5-11 mg/kg/day) for a mean duration of 11 days (2; 55 days). Clinical success was observed in 42 % of cases (n = 8). Appropriateness for daptomycin use was only established for 15 % of prescriptions (n = 3). Faced with a lack of recent recommendations on the subject, our multidisciplinary team issued a local consensus, defining the indications and dosage modalities for this reserve antibiotic. This multidisciplinary approach enables improved use of recent anti-MRSA drugs.


Flavonoids protect U-937 macrophages against tert-butylhydroperoxide induced oxidative injury.
The study was carried out to determine the relative efficacies of polyphenolic flavonoids, quercetin, catechin and epicatechin against tert-BOOH induced oxidative stress in human macrophage, U-937 cell line. Exposure of the cells to tert-BOOH oxidative stress resulted in a significant increase in cytotoxicity and reactive oxygen species (ROS) generation. Further, a significant decrease in mitochondrial membrane potential and increase in lipid peroxidation and DNA damage was observed in cells exposed to tert-BOOH. Pretreatment of cells with quercetin, catechin and epicatechin significantly inhibited tert-BOOH induced cytotoxicity by inhibiting ROS generation. The flavonoids inhibited DNA damage induced by tert-BOOH and preserved the mitochondrial transmembrane potential significantly. Epicatechin and catechin were found to be more efficient than quercetin in inhibiting tert-BOOH induced cellular damage.


Explicit and implicit remembering: when is learning preserved in amnesia?
Amnesic patients can learn and retain a variety of skills. To investigate what distinguishes tasks that are within the learning abilities of amnesic patients from those that are not, we administered two tests to individuals with Korsakoff's syndrome and two control groups. One was a visual reaction time task with an embedded repeating sequence of stimulus positions. Response times of Korsakoff patients indicated that they learned this sequence and retained it normally for a week. The second task was a tactual stylus maze in which all blind alleys were blocked. Korsakoff patients were impaired in learning this maze, as assessed by the time required to trace it. Differences between the two tasks are outlined and the implications of these differences are discussed.


Coronary artery bypass graft surgery using the radial artery as a secondary conduit improves patient survival.
The clinical benefits of the left internal thoracic artery-to-left anterior descending coronary artery graft are well established in coronary artery bypass graft surgery (CABG). However, limited data are available regarding the long-term outcome of the radial artery (RA) as a secondary conduit over the established standard of the saphenous venous graft. We compared the 12-year survival outcome in a set of propensity-matched CABG patients who received either the RA or the saphenous vein as a secondary conduit. A multivariable logistic regression that included 18 baseline characteristics was used to define the propensity of receiving an RA graft. The propensity model resulted in 260 matched pairs who underwent first-time isolated CABG from 1996 to 2001 with similar preoperative characteristics (C statistic=0.86). The cumulative 12-year survival estimated by use of the Kaplan-Meier method was higher for the RA graft patients (hazard ratio 0.76; P=0.03). This survival advantage was especially significant in diabetics (P=0.005), in women (P=0.02), and in the elderly (P=0.04.) The protective effect appeared beginning at year 5 post surgical intervention. The RA as a secondary conduit provided superior long-term survival after CABG, especially in diabetic patients, women, and the elderly. This effect was most pronounced >5 years after surgery.


Enantioselective construction of stereogenic quaternary centres via Rh-catalyzed asymmetric addition of alkenylboronic acids to alpha,beta-unsaturated pyridylsulfones.
The highly enantioselective construction of all-carbon quaternary stereogenic centres via Rh-catalyzed Chiraphos-mediated conjugate addition of alkenylboronic acids to beta,beta-disubstituted alpha,beta-unsaturated 2-pyridylsulfones is described.


MicroRNA-134 regulates poliovirus replication by IRES targeting.
Global poliovirus eradication efforts include high vaccination coverage with live oral polio vaccine (OPV), surveillance for acute flaccid paralysis, and OPV "mop-up" campaigns. An important objective involves host-directed strategies to reduce PV replication to diminish viral shedding in OPV recipients. In this study, we show that microRNA-134-5p (miR-134) can regulate Sabin-1 replication but not Sabin-2 or Sabin-3 via direct interaction with the PV 5'UTR. Hypochromicity data showed miR-134 binding to Sabin-1 and 3 but not Sabin-2 IRES. Transfection of a miR-134 mimic repressed translation of Sabin-1 5'UTR driven luciferase validating the mechanism of miR-134-mediated repression of Sabin-1. Further, site directed mutagenesis of the miR-134 binding site in Sabin-1 IRES relieved miR-134-mediated repression indicating that these regulatory molecules have an important role in regulating the host gene response to PV. Binding of miR-134 to Sabin-1 IRES caused degradation of the IRES transcript in a miR-134 and sequence specific manner. The miR-134 binding site was found to be highly conserved in wild type PV-1 as well as EV71 strains indicating that miR-134 may regulate function of these IRES sequences in circulation.


Strain ATCC 4720T is the authentic type strain of Agrobacterium tumefaciens, which is not a later heterotypic synonym of Agrobacterium radiobacter.
The original type strains of Agrobacterium radiobacter and Agrobacterium tumefaciens recorded in the eighth edition of Bergey's Manual of Determinative Bacteriology published in 1974 were NCIB 9042T and ATCC 4720T, respectively. However, in the list of the valid names of bacteria compiled in 1980, both strains were changed, A. radiobacter NCIB 9042T to ATCC 19358T and A. tumefaciens ATCC 4720T to ATCC 23308T. These changes were unjustified, particularly in the case of A. tumefaciens whose type strain was replaced by another strain from the same collection, although the original type strain ATCC 4720T was never lost and it is currently available in several culture collections. Therefore, we request that the type strain of A. tumefaciens be corrected from ATCC 23308T to ATCC 4720T.


Memories of being a dental student in Liverpool Dental Hospital and School 1962-1966.
Recollections of being an undergraduate dental student in Liverpool during the 1960s.


Evaluating reverse speech as a control task with language-related gamma activity on electrocorticography.
Reverse speech has often been used as a control task in brain-mapping studies of language utilizing various non-invasive modalities. The rationale is that reverse speech is comparable to forward speech in terms of auditory characteristics, while omitting the linguistic components. Thus, it may control for non-language auditory functions. This finds some support in fMRI studies indicating that reverse speech resulted in less blood-oxygen-level-dependent (BOLD) signal intensity in perisylvian regions than forward speech. We attempted to externally validate a reverse speech control task using intracranial electrocorticography (ECoG) in eight patients with intractable focal epilepsy. We studied adolescent and adult patients who underwent extraoperative ECoG prior to resective epilepsy surgery. All patients received an auditory language task during ECoG recording. Patients were presented 115 audible question stimuli, including 30 reverse speech trials. Reverse speech trials more strongly engaged bilateral superior temporal sites than did the corresponding forward speech trials. Forward speech trials elicited larger gamma-augmentation at frontal lobe sites not attributable to sensorimotor function. Other temporal and frontal sites of significant augmentation showed no significant difference between reverse and forward speech. Thus, we failed to validate reported evidence of weaker activation of temporal neocortices during reverse compared to forward speech. Superior temporal lobe engagement may indicate increased attention to reverse speech. Reverse speech does not appear to be a suitable task for the control of non-language auditory functions on ECoG.


The progenitor cell marker NG2/MPG promotes chemoresistance by activation of integrin-dependent PI3K/Akt signaling.
Chemoresistance represents a major problem in the treatment of many malignancies. Overcoming this obstacle will require improved understanding of the mechanisms responsible for this phenomenon. The progenitor cell marker NG2/melanoma proteoglycan (MPG) is aberrantly expressed by various tumors, but its role in cell death signaling and its potential as a therapeutic target are largely unexplored. We have assessed cytotoxic drug-induced cell death in glioblastoma spheroids from 15 patients, as well as in five cancer cell lines that differ with respect to NG2/MPG expression. The tumors were treated with doxorubicin, etoposide, carboplatin, temodal, cisplatin and tumor necrosis factor (TNF)alpha. High NG2/MPG expression correlated with multidrug resistance mediated by increased activation of alpha3beta1 integrin/PI3K signaling and their downstream targets, promoting cell survival. NG2/MPG knockdown with shRNAs incorporated into lentiviral vectors attenuated beta1 integrin signaling revealing potent antitumor effects and further sensitized neoplastic cells to cytotoxic treatment in vitro and in vivo. Thus, as a novel regulator of the antiapoptotic response, NG2/MPG may represent an effective therapeutic target in several cancer subtypes.


Low baseline plasma PCSK9 level is associated with good clinical outcomes of immune checkpoint inhibitors in advanced non-small cell lung cancer.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a crucial protein involved in the metabolism of low-density lipoprotein cholesterol. However, the role of plasma PCSK9 in predicting the efficacy of ICIs in advanced non-small cell lung cancer (NSCLC) remains to be clarified. We retrospectively reviewed the medical records of NSCLC patients who presented at Shanghai Pulmonary Hospital between April 2019 and June 2020. ELISA was conducted to detect the concentration of PCSK9. Clinical efficacy was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). A total of 55 patients were enrolled in the study. The median progression-free survival (PFS) following treatment with ICIs in all patients was 9.9 months. The optimal threshold of baseline plasma PCSK9 was 232.2 ng/ml. Patients with low baseline plasma PCSK9 had a longer PFS (NR vs. 7.37 months, p = 0.017, HR = 0.207, 95% CI: 0.086-0.498) and a better response (ORR 71.4% vs. 43.9%, p = 0.075, DCR 100% vs. 80.5%, p = 0.098) to ICIs. Younger patients (≤66 years) with a lower PCSK9 had a significantly longer PFS and higher treatment response than those with a high baseline level of PCSK9 (NR vs. 5.83 months, p = 0.021, HR = 0.134, 95% CI: 0.044-0.409; ORR 66.7% vs. 30.0%, p = 0.106, DCR 100% vs. 75%, p = 0.153). The situation was similar in patients who received first-line therapy (NR vs. 8.97 months, p = 0.022, HR = 0.138, 95% CI: 0.047-0.400; ORR 63.6% vs. 46.4%, p = 0.480, DCR 100% vs. 89.3%, p = 0.545). Multivariate analysis showed that low PCSK9 concentration was independently associated with PFS (p = 0.032, HR = 0.201). Low baseline plasma PCSK9 level may predict good outcomes in patients with advanced NSCLC treated with ICIs.


Pulmonary nodule volumetric accuracy of a deep learning-based reconstruction algorithm in low-dose computed tomography: A phantom study.
To compare the image properties and pulmonary nodule volumetric accuracies among deep learning-based reconstruction (DLR), filtered back projection (FBP), and hybrid iterative reconstruction (hybrid IR) in low-dose computed tomography (LDCT). A multipurpose chest phantom containing artificial spherical pulmonary nodules with 5-, 8-, 10-, and 12-mm diameters and Hounsfield units (HUs) of -630 and +100 HU was scanned 20 times at a standard dose, based on a low-dose screening CT trial, and at 1/2, 1/6, and 1/12 of the standard dose. To assess noise reduction performance and volumetric accuracy, the standard deviations (SDs) of the pixel values and volumetric percentage errors (PEs) were compared among FBP, hybrid IR, and DLR. The noise non-stationarity index (NNSI) was calculated from 20 image replicates and compared among FBP, hybrid IR, and DLR to evaluate noise stationarity. The SD reduction rates for FBP in hybrid IR and DLR were 62 %-85 % and 79 %-90 %, respectively. For the four nodules with +100 HU, the PE of all reconstruction methods was <±25 % (not clinically relevant). For the four nodules with -630 HU, the PEs were equivalent or lower for hybrid IR and DLR than for FBP, and the PE difference between hybrid IR and DLR ranged from 0 % to 7%. The NNSI was significantly higher for DLR than for FBP and hybrid IR (p < 0.01). Greater noise suppression was achieved with DLR than with hybrid IR without compromising nodule volumetric accuracy in LDCT despite the representative noise non-stationarity.


The isolation of novel inhibitory polypeptides of protein phosphatase 1 from bovine thymus nuclei.
Nuclei from bovine thymus contain a high level of partially latent protein phosphatase 1 (PP-1). More than 90% of this PP-1 is associated with the insoluble chromatin/matrix fraction and can be extracted with 0.3 M NaCl. The salt extract also contains three heat- and acid-stable inhibitory proteins of PP-1 that can be resolved on Mono Q. We have purified two of these nuclear inhibitors of PP-1 (NIPP-1a and NIPP-1b) until homogeneity. They are acidic proteins (pI = 4.4) with a molecular mass of 18 kDa (NIPP-1a) and 16 kDa (NIPP-1b) on SDS-PAGE. Judged from the larger molecular mass that was deduced from gel filtration (35 kDa), NIPP-1a and NIPP-1b appear to be asymmetric or dimeric proteins. The nuclear inhibitors totally inhibited the phosphorylase phosphatase activity of PP-1, but even at a 250-fold higher concentration they did not affect the activities of the other major serine/threonine protein phosphatases (PP-2A, PP-2B, and PP-2C). NIPP-1a and NIPP-1b inhibited the catalytic subunit of PP-1 with an extrapolated Ki of about 1 pM, which is some three orders of magnitude better than the cytoplasmic proteins inhibitor 1/DARPP-32 and modulator. The nuclear inhibitors were not inactivated by incubation with protein phosphatases that inactivate inhibitor 1 and DARPP-32. Unlike modulator, they were not able to convert the catalytic subunit of PP-1 into a MgATP-dependent form. Remarkably, the extent of inhibition of PP-1 by NIPP-1b depended on the nature of the substrate. The phosphorylase phosphatase and casein phosphatase activities of PP-1 were completely blocked by NIPP-1b, whereas the dephosphorylation of basic proteins was either not at all inhibited (histone IIA) or only partially (myelin basic protein). These data may indicate that the acidic NIPP-1b is inactivated through complexation by basic proteins. Indeed, nonphosphorylated histone IIA antagonized the inhibitory effect of NIPP-1b on the casein phosphatase activity of PP-1. Our data show that the nucleus contains specific and potent inhibitory proteins of PP-1 that differ from earlier described cytoplasmic inhibitors. We suggest that these novel proteins may control the activity of nuclear PP-1 on its natural substrate(s).


Substantia nigra and ventral tegmental area projections to cortex: topography and collateralization.
The substantia nigra and ventral tegmental area of the rat were examined by retrograde transport methods to determine the topography and collateralization patterns of projections to cortex and certain subcortical sites. The topographical relationships between cells and their terminal fields were confirmed and clarified by the horseradish peroxidase retrograde transport technique. The collateralization of axons was analyzed by the use of multiple fluorescent tracers. These experiments indicated that individual ventral tegmental area cells do not collateralize extensively to either subcortical or cortical terminal fields. Substantia nigra cells, however, give rise to more highly collateralized axons and single cells may simultaneously innervate different regions of cortex as well as subcortical sites. Substantia nigra cells can be divided with respect to their cortical collateralization patterns into three groups: (1) those that innervate cingulate cortices, (2) those that project to prefrontal and suprarhinal cortices, and (3) those that innervate entorhinal cortex.


Discriminative stimulus properties of the benzodiazepine receptor antagonist flumazenil.
Rats were trained to discriminate the stimulus properties of the benzodiazepine (BZ) receptor antagonist flumazenil using a conditioned taste aversion procedure. On drug trials, fluid-restricted rats were injected with flumazenil (32 mg/kg), given access to a 0.25% saccharin solution for 30 min, and injected with LiCl (1.8 mEq/kg IP). On saline trials, injections of saline bracketed the period of saccharin consumption. Acquisition of the discriminated taste aversion, as measured by differential effects on drinking between saline and drug trials, developed after only five pairings of flumazenil with the LiCl injections. Flumazenil did not alter saccharin consumption in unconditioned controls (N = 9) that never received LiCl. The discrimination was also measured by flumazenil's ability to reduce the preference for saccharin over tap water using two-bottle choice tests. Flumazenil demonstrated dose-dependent generalization upon decreasing the training dose as low as 1 mg/kg. Two other BZ receptor antagonists of different chemical structure, CGS 8216 and ZK 93426, substituted completely for the flumazenil stimulus. Partial generalization was exhibited to the partial inverse agonists FG 7142 and beta-CCE, while the full inverse agonists DMCM and PTZ failed to substitute for the flumazenil stimulus. The BZ receptor agonists diazepam and alprazolam failed to substitute for the flumazenil stimulus, although partial generalization was shown with CDP. The results suggest that the BZ receptor antagonist flumazenil may produce intrinsic discriminative stimulus effects that are independent from those of BZ receptor agonists or inverse agonists.


The effects of stress on wound healing in male tree lizards (Urosaurus ornatus).
Exposure to stress can affect an organism's partitioning of resources among immune function and other organismal functions. However, measuring immune function is often difficult. Recent studies show that the rate of cutaneous wound healing in laboratory rodents is a simple, integrated measure of stress-sensitive immune function. We investigated the use of this technique in tree lizards to test the hypotheses (1) that stress compromises wound healing and (2) that this effect is at least partially mediated by corticosterone. Laboratory-housed male tree lizards randomly assigned to the experimental and control treatment groups received a 3.5 mm cutaneous biopsy on the dorsal surface of the pelvis. Experimental group males were restrained in cloth bags for 60 min every day for 21 days during the healing profile, whereas control males were left in their cages. Wound sizes were measured every other day by image analysis. Control animals healed faster than stressed animals. The difference in wound surface area between the groups was most pronounced early in the healing profile. Stressed animals also had higher corticosterone levels and corticosterone was negatively correlated with healing rate in the stressed animals. These observations support both hypotheses that stress compromises healing and that corticosterone may act to mediate the effects of stress.


Patient-Reported Outcomes in Adult Idiopathic Inflammatory Myopathies.
Idiopathic inflammatory myopathies (IIM) have considerable impact on patient symptoms and quality of life. We have reviewed the evolution of patient-centered care and use of patient-reported outcome measures (PROMs) for adults with IIM. Use of PROMs in myositis care and research is limited, although the importance of incorporation into routine practice and trials has become increasingly recognized. Several key domains/measures have been identified including the patient global assessment of disease activity, physical function as measured by the health assessment questionnaire-disability index (HAQ-DI), Short Form Health Survey-36 (SF-36), or the Patient-Reported Outcome Measurement Information System ® (PROMIS®) in adult IIM. Data are limited for these instruments concerning their reliability, content and construct validity, and responsiveness. Incorporation of the patient perspective into clinical care and research may be used to address the unmet/unaddressed needs of the patient living with myositis. Several ongoing projects aim to bring validated PROMs to the IIM community.


The long, the short, and the micro: a polyA tale of Pax3 in satellite cells.
The use of alternative polyadenylation sites is emerging as an important regulator of gene expression. In this issue of Cell Stem Cell, Boutet et al. (2012) report that alternative 3'UTRs of the Pax3 transcript restrict its expression to axial satellite cells through miR-mediated targeting of one of the isoforms.


Transient cyclical methylation of promoter DNA.
Methylation of CpG dinucleotides is generally associated with epigenetic silencing of transcription and is maintained through cellular division. Multiple CpG sequences are rare in mammalian genomes, but frequently occur at the transcriptional start site of active genes, with most clusters of CpGs being hypomethylated. We reported previously that the proximal region of the trefoil factor 1 (TFF1, also known as pS2) and oestrogen receptor alpha (ERalpha) promoters could be partially methylated by treatment with deacetylase inhibitors, suggesting the possibility of dynamic changes in DNA methylation. Here we show that cyclical methylation and demethylation of CpG dinucleotides, with a periodicity of around 100 min, is characteristic for five selected promoters, including the oestrogen (E2)-responsive pS2 gene, in human cells. When the pS2 gene is actively transcribed, DNA methylation occurs after the cyclical occupancy of ERalpha and RNA polymerase II (polII). Moreover, we report conditions that provoke methylation cycling of the pS2 promoter in cell lines in which pS2 expression is quiescent and the proximal promoter is methylated. This coincides with a low-level re-expression of ERalpha and of pS2 transcripts.


2-Methyl-5-tert-butylthiophenol--an odorless deprotecting reagent useful in synthesis of oligonucleotides and their analogs.
A solution of 2-methyl-5-tert-butylthiophenol and triethylamine in acetonitrile efficiently removed the methyl protecting groups from phosphate and phosphorothioate triesters and yielded oligonucleotides of high quality. This inexpensive odorless liquid is not toxic and is a suitable replacement for hazardous thiophenol and other reagents often used for this purpose.


Morphological and morphometric study of the scapulae of Korean wild deer.
Korean water deer (Hydropotes inermis argyropus; Heude, 1884) and Siberian roe deer (Capreolus pygargus; Pallas, 1771) are Korean wild deer classified in the tribe Capreolini. C. pygargus in Korea were previously considered a single species; however, it was recently suggested that roe deer living on Jeju Island (Jeju roe deer; Capreolus pygargus jejuensis) is a distinct subspecies from roe deer living on the Korean peninsula (mainland roe deer; Capreolus pygargus tianschanicus) based on several studies demonstrating genetic and morphological features. In this study, we suggests that the scapular morphology and osteometric data can be used for interspecies discrmination between Korean wild deer. To compare the morphological characteristics of scapula among the three groups of deer, we analyzed the features and nine osteomorphological measurements of 31 H. i. argyropus (14 males and 17 females), 18 C. p. jejuensis (4 males and 14 females), and 23 C. p. tianschanicus (16 females and 7 males). The estimated ages of the deer were over 32-35 months. Data were analyzed by one-way repeated measures analysis of variance with post hoc Duncan test and discriminant functional analysis (DFA). H. i. argyropus and C. p. tianschanicus had the smallest and largest scapulae, respectively. The scapulae of the three Korean wild deer had a similar triangular shape, which was obscured by the tuber of the scapular spine, pointed acromion, broad infraspinous fossa, narrow supraspinous fossa, and partial ossification of scapular cartilage in older deer. H. i. argyropus had certain distinctive features, including a caudally pointed acromion, a notch between the supraglenoid tubercle and glenoid cavity (NBSG), a glenoid notch, and no sexual dimorphism, except for the longest dorsal length (Ld) and the scapular index (SI). C. p. jejuensis had a larger scapular index (SI) (61.74 ± 0.74%), compared with the SIs of H. i. argyropus and C. p. tianschanicus. The unique features of the scapula in C. p. jejuensis include its S-shaped cranial border. The C. p. jejuensis had a cranially pointed acromion, less frequent presence of glenoid notch and NBSG, short length of supraglenoid tubercle, and no sexual dimorphism. The C. p. tianschanicus had elevated cranial margin of the glenoid cavity, and frequent presence of glenoid notch and NBSG, similar to the H. i. argyropus. Similar to C. p. jejuensis, C. p. tianschanicus had a cranially pointed acromion. However, sexual dimorphism was observed in C. p. tianschanicus. DFA using osteometric data showed 97.22% of specimens were classified correctly into their species, meaning the osteometric parameters can be used for interspecies discrimination of Korean wild deer. Our findings indicate that the scapular morphologies of the three Korean wild deer have certain similarities and differences, suggesting that C. p. jejuensis are distinct from C. p. tianschanicus.


New World Stictocladius Edwards (Diptera: Chironomidae).
The orthocladiine Chironomidae genus Stictocladius Edwards was described originally from South America. Although recognised subsequently as present also in Australia and New Zealand, the true diversity in the Neotropics has remained unclear. After more than a decade of collections of both isolated adults and aquatic immature stages, we can recognise several new taxa and associate some immature stages. Thus, we describe Stictocladius prati n. sp. as male, female, pupa and larva; Stictocladius acutus n. sp. and Stictocladius acrilobus n. sp. as male, female and pupa; Stictocladius fimbriatus n. sp. as male and female; Stictocladius fovigus n. sp. and Stictocladius nudiventer n. sp. as male and pupa; and Stictocladius privicalcar n. sp. and Stictocladius prostatus n. sp. each as male imago alone. The male and female of Stictocladius pulchripennis Edwards is redescribed and the pupa described. The male and female of Stictocladius flavozonatus Edwards and the male of Stictocladius calonotum Edwards are described. Five pupal types are described: Stictocladius sp. A (near S. acrilobus), Stictocladius sp. B (possibly S. calonotum), Stictocladius sp. C (near S. calonotum), Stictocladius sp. D (possibly S. flavozonatus) and Stictocladius sp. E with uncertain affinity. A larva from Chile of the Stictocladius 'sofour type' (Stictocladius sp. F) and an unreared larva from North America (Stictocladius sp. G) possibly belonging to S. acutus are described. Keys to named Neotropical male and female imagines of Stictocladius and to all pupal forms of Neotropical Stictocladius are provided. Some data concerning fourth instars of Stictocladius are presented. Means of differentiation from putative sister taxon Lopescladius are discussed.


Influence of the level of the transmembrane potential on the dynamics of the extinction of the amplitude of the synaptic reactions of the snail under voltage clamping conditions.
The influence of the level of the transmembrane potential on the dynamics of the extinction of the amplitudes of summary excitatory postsynaptic currents arising in identified giant parietal neurons in response to rhythmic stimulation of the intestinal nerve was investigated in a preparation of the isolated CNS of the common snail in order to identify the possibility of the participation of the postsynaptic element in synaptic plasticity. It was demonstrated that, at a greater value of the transmembrane potential, the decrease in the amplitudes of the postsynaptic currents which have been induced by rhythmic stimulation takes place more rapidly. It was also demonstrated that at a higher frequency of stimulation of the nerve, the effect of the influence of the membrane potential level on the dynamics of the synaptic reactions is more prominent. The data obtained may be regarded as an argument in favor of the possibility of the participation of the post-synapse in plasticity.


Low- and high-cocaine locomotor responding rats differ in reinstatement of cocaine seeking and striatal mGluR5 protein expression.
Behavioral responsiveness to initial cocaine use varies among individuals and may contribute to differential vulnerability to cocaine addiction. Rats also exhibit individual differences in cocaine's effects and can be classified as low or high cocaine responders (LCRs or HCRs, respectively), based on their initial cocaine-induced locomotor activity (10 mg/kg, i.p.). Here, we used the extinction/reinstatement model to address whether or not LCRs and HCRs differ in (i) extinction/reinstatement of cocaine self-administration behavior and (ii) levels of metabotropic glutamate receptors (mGluRs) following these behaviors. During the earliest acquisition sessions, LCRs exhibited significantly greater cocaine intake (0.8 mg/kg/infusion) and cocaine-paired lever responding than HCRs, but intake and lever responding converged by the end of the cocaine self-administration portion of the study. LCRs and HCRs did not differ in cocaine seeking during the first extinction session and extinguished cocaine seeking similarly. HCRs exhibited greater reinstatement than LCRs to lower (2.5 and 5 mg/kg), but not higher (10 mg/kg), i.p. priming doses of cocaine. The effect of drug-paired cues on reinstatement following extinction was complex, with HCRs and LCRs showing the greater effect of cue depending on the order in which cue- and drug-primed tests were given. Western blot analysis revealed that mGluR5 heteromers were significantly higher in the dorsal striatum of HCRs than LCRs following reinstatement testing. Although our previous findings with the LCR/HCR model have uniformly supported the idea that lower initial cocaine-induced activation predicts more ready development of cocaine addiction-like behaviors, here, we show a more complex relationship with cocaine reinstatement.