Retention and migration of alprostadil cream applied topically to the glans meatus for erectile dysfunction.
Retention and migration of a specially designed alprostadil transdermal cream was assessed after single-dose administration to the glans meatus of the penis. Seven men were enrolled in this two-way crossover study. Three subjects self-administered the radio-labeled alprostadil transdermal cream (approximately 100 mg of cream containing 300 microg alprostadil) by inserting the tip of the dispenser into the meatus. In three others, the dose was administered by dispensing the cream dropwise into the metal opening without touching the penis (the preferred and directed method). Retention and migration of the cream mass was measured in the penis with a gamma scintillation camera. The alprostadil transdermal cream was retained in the fossa navicularis at or near 99% in five of six subjects regardless of the method of dosing, thus indicating that the cream formulation performed as designed. A mild, transient burning sensation in the penis was the most common adverse event.


Familial multiple discoid fibromas: a look-alike of Birt-Hogg-Dubé syndrome not linked to the FLCN locus.
Previously, we proposed that familial multiple trichodiscomas (OMIM 190340) is distinct from Birt-Hogg-Dubé syndrome (BHD) (OMIM #135150). BHD is characterized by multiple fibrofolliculomas/trichodiscomas, lung cysts, pneumothorax, and renal cell cancer. Germline FLCN mutations can be detected in most but not all BHD families. We sought to evaluate familial multiple trichodiscomas at a clinical and genetic level. We now renamed this condition "familial multiple discoid fibromas" (FMDF) to emphasize the distinction from BHD. In 8 additional families with an autosomal dominant pattern of multiple discoid fibromas we assessed the clinical findings and the histopathological features of skin lesions. FLCN germline mutation analysis was completed in 7 families. In two of these families segregation analysis was performed using polymorphic DNA markers in and around the FLCN locus. The clinical findings in FMDF are different from those in BHD with early onset of skin lesions, prominent involvement of the pinnae, and discoid fibromas without the follicular epithelial component characteristic of the fibrofolliculoma/trichodiscoma spectrum of BHD. In addition, there were no evident pulmonary or renal complications. In none of the families were pathogenic FLCN germline mutations identified. Using segregation analysis we could exclude involvement of the FLCN locus in the two kindreds tested. The prevalence of FMDF is presently unknown. The underlying gene defect has not yet been identified. FMDF is clinically distinct from BHD and is not linked to the FLCN locus.


The maternity blues and Hong Kong Chinese women: an exploratory study.
The maternity blues have been studied world-wide and are generally regarded as a cross-cultural phenomenon. However, low prevalence rates of the blues have been reported recently in studies of Japanese women. The purposes of this study are, firstly, to establish whether the low prevalence noted in Japanese women is also found in another group of Asian women, that is, Hong Kong Chinese women, and secondly, to describe the manifestations of the blues in this group of women. A prospective survey involving a convenience sample of 88 women, recruited on the first day after normal or operative vaginal delivery. Participants completed a blues self-rating scale (Stein's Daily Scoring System) every day for the first 7 days after delivery. Data were analysed mainly in terms of descriptive statistics. 39 (44.3%) women experienced an episode of the blues during the first week after delivery. The manifestations of the blues showed a typical peaking on the 5th postnatal day. This is a short-term exploratory study. Further investigation is required into the factors influencing or precipitating the blues, particularly from the cultural perspectives of childbearing Hong Kong Chinese women. Hong Kong Chinese women experience the maternity blues in similar ways to those reported by studies of women in other countries and cultures, with the exception of those describing the blues in Japanese women.


Laparoendoscopic single-site (LESS) sacrocolpopexy: feasibility and efficacy of knotless procedure performed with conventional instruments.
The aim of this paper was to report a case of a patient with stage IV vaginal vault prolapse treated by laparoendoscopic single-site (LESS) sacrocolpopexy using an Alexis retractor and a surgical glove attached to three trocars through a 3.5-cm umbilical incision. Only conventional laparoscopic instruments were used for intrabdominal dissection of vagina and peritoneum. The mesh was fixed to the vaginal fornix and to the sacral periosteum from the promontory using running sutures hold in the extremities by polymer clips. The posterior peritoneum was closed over the mesh. LESS sacrocolpopexy performed with conventional instruments is a difficult but feasible and efficient technique to treat vaginal vault prolapse that respects the principles of conventional laparoscopic or open repairs. Alexis retractor associated with knotless sutures are technical options that simplify LESS reconstructive surgical maneuvers.


A randomized clinical study on the impact of Comprehensive Geriatric Assessment (CGA) based interventions on the quality of life of elderly, frail, onco-hematologic patients candidate to anticancer therapy: protocol of the ONCO-Aging study.
Age is considered as one of the most important risk-factor for many types of solid and hematological cancers, as their incidence increases with age in parallel to the ever-growing elderly population. Moreover, cancer incidence is constantly increasing as a consequence of the increase in life expectancy that favors the process of cellular senescence. Geriatric assessment has been increasingly recognized as predictive and prognostic instrument to detect frailty in older adults with cancer. In particular, the G8 score is a simple and reproducible instrument to identify elderly patients who should undergo full geriatric evaluation. Due to their frailty, elderly patients may be often under-treated and a therapeutic choice based also on a comprehensive geriatric assessment (CGA) is recommended. With these premises, we aim to test the impact of the CGA based interventions on the quality of life (QoL) of frail elderly onco-hematological patients, identified by the G8 screening, candidate for innovative target directed drugs or treatments including the combination of radiotherapy and chemotherapy (RT + CT). Patients aged > 65 years, candidate to target directed agents or to RT + CT treatments are screened for frailty by the G8 test; those patients classified as frail (G8 ≤ 14) are randomized to receive a CGA at baseline or to conventional care. The primary endpoint is QoL, assessed by EORTC QLQ-C30C. As collateral biological study, the potential prognostic/predictive role of T-cell senescence and myeloid derived suppressor cells (MDSC) are evaluated on plasma samples. This trial will contribute to define the impact of CGA on the management of frail elderly onco-hematologic patients candidate to innovative biological drugs or to integrated schedules with the association of RT + CT. Furthermore, the use of plasma samples to assess the potential prognostic value of imbalance of immune-competent cells is expected to contribute to the individualized care of elderly patients, resulting into a fine tuning of the therapeutic strategies. ClinicalTrials.gov ID: NCT04478916 . registered July 21, 2020 - retrospectively registered.


Detection of obestatin in seminal plasma and its relationship with ghrelin and semen parameters.
To investigate the occurrence of ghrelin and obestatin in human semen. Prospective study. University, center for research and therapy of male infertility. 112 consecutively selected men. Family history, clinical and physical examination, radioimmunoassay for ghrelin and obestatin determinations, semen analysis, annexinV/propidium iodide assay. Ghrelin and obestatin detected in the semen and relationships with semen parameters and conditions influencing semen quality (smoking, varicocele, ex varicocele, leukocytospermia). The levels of both peptides in semen were higher versus serum. Linear correlations between ghrelin and obestatin levels in serum and in semen were observed. Serum ghrelin levels were negatively correlated with the men's ages. Semen obestatin levels were positively correlated with sperm concentration and motility. Obestatin levels were decreased in the semen of smokers and in the presence of leukocytospermia. This is the first study on the presence of obestatin in human semen and its relationship with sperm concentration and motility, suggesting a possible role of the peptide in controlling cell proliferation and survival. Further investigations are required to explore the exact role of obestatin and ghrelin in human semen.


Tumor immunology and immunotherapy.
Tumor cells contain a variety of antigens, including tumor associated antigens. The tumor associated antigens can be clinically useful as markers for detection of cancer and some may also mediate host resistance against tumor growth. Much emphasis has been placed on the detection of circulating tumor associated markers, with radioimmunoassays for carcinoembryonic antigen (CEA) being extensively utilized. At present, CEA does not appear to be promising for initial detection of cancer, but may find an important place in the determination of prognosis and early detection of recurrent disease. Many cancer patients have depressed immunologic competence, yet they frequently have cell-mediated immunity against tumor associated antigens. Several different immunotherapeutic strategies have been developed, to either augment the immunologic responsiveness of the patient or to specifically increase the immune reactivity against tumor associated transplantation antigens.


Integrating Substance Misuse Specialists in a Youth Early Psychosis Service: Increasing Mental Health Clinicians' Knowledge and Confidence.
Substance misuse and mental health disorders are commonly occurring co-morbidities in young people. This paper reports on a pilot project to embed three specialist Alcohol and Other Drug (AoD) workers to be embedded in a youth early psychosis service to upskill mental health clinicians in managing substance misuse. Evaluation of the project used a mixed methods approach. Quantitative results showed that clinical staff members' knowledge of substance misuse, knowledge of AoD treatments and services, and overall confidence in working with young people with a substance misuse issue improved following implementation of the project. Qualitative results indicated four themes which emerged: defining the role of the AoD workers; support and upskilling of the mental health staff; openness and effective communication between the embedded workers and mental health teams; and barriers to collaboration. The results provide support for the embedding of specialist alcohol and drug workers in youth mental health services.


A comparison of the kinetics of low-density lipoprotein oxidation initiated by copper or by azobis (2-amidinopropane).
This article describes the kinetics of low density lipoprotein (LDL) oxidation catalyzed by azobis (2-amidinopropane) dihydrochloride, ABAP, or by copper. The LDLs were isolated from nonhuman primates fed diets enriched in one of three types of fatty acids: saturated fatty acids, monounsaturated fatty acids, predominantly, oleic acid, or polyunsaturated fatty acids, predominantly linoleic acid. Oxidation was followed by monitoring the formation of conjugated diene hydroperoxides from polyunsaturated fatty acids (PUFA). For both copper and ABAP-initiated oxidation, the rate of LDL oxidation depended on the concentrations of initiator, PUFA, and LDL. Except for the dependence on PUFA concentration the rate of LDL oxidation was not directly influenced by the fatty acid composition of the LDL particle. The two initiators had very different dependence on initiator concentration. Because LDL particles are essentially small, lipid-rich droplets, the kinetic descriptions of LDL oxidation assumed: (1), that there was only one chain per particle, and (2) that the radical chain was terminated when a second radical either entered or was formed in the particle. When two LDL samples having very different lag times were mixed, the oxidation profile was bimodal. This finding demonstrated that the oxidation of native LDL particles was independent of the oxidation state of the other native LDL particles in solution, i.e., LDL particles do not rapidly exchange radicals, for example, hydroperoxyl radicals. Oxidation initiated by ABAP was proportional to [ABAP]0.5, suggesting that hydroperoxyl radical recombination between the lipid hydroperoxyl radical and the ABAP-hydroperoxyl radical was the chain-terminating step. The reciprocal of the rate of copper oxidation was linearly related to the reciprocal copper concentration, demonstrating that the binding of copper to LDL was necessary to initiate oxidation. This binding constant showed considerable variability among LDL samples. The kinetic descriptions of LDL oxidation reflect the differences in the mechanisms of initiation and termination.


Formation of a PSI-PSII megacomplex containing LHCSR and PsbS in the moss Physcomitrella patens.
Mosses are one of the earliest land plants that diverged from fresh-water green algae. They are considered to have acquired a higher capacity for thermal energy dissipation to cope with dynamically changing solar irradiance by utilizing both the "algal-type" light-harvesting complex stress-related (LHCSR)-dependent and the "plant-type" PsbS-dependent mechanisms. It is hypothesized that the formation of photosystem (PS) I and II megacomplex is another mechanism to protect photosynthetic machinery from strong irradiance. Herein, we describe the analysis of the PSI-PSII megacomplex from the model moss, Physcomitrella patens, which was resolved using large-pore clear-native polyacrylamide gel electrophoresis (lpCN-PAGE). The similarity in the migration distance of the Physcomitrella PSI-PSII megacomplex to the Arabidopsis megacomplex shown during lpCN-PAGE suggested that the Physcomitrella PSI-PSII and Arabidopsis megacomplexes have similar structures. Time-resolved chlorophyll fluorescence measurements show that excitation energy was rapidly and efficiently transferred from PSII to PSI, providing evidence of an ordered association of the two photosystems. We also found that LHCSR and PsbS co-migrated with the Physcomitrella PSI-PSII megacomplex. The megacomplex showed pH-dependent chlorophyll fluorescence quenching, which may have been induced by LHCSR and/or PsbS proteins with the collaboration of zeaxanthin. We discuss the mechanism that regulates the energy distribution balance between two photosystems in Physcomitrella.


Overview of non-coding RNAs in breast cancers.
Breast cancer in women is the second most common cancer and the fifth leading cause of cancer death worldwide. Although earlier diagnosis and detection of breast cancer has resulted in lower mortality rates, further advances in prevention, detection, and treatment are needed to improve outcomes and survival for women with breast cancer as well as to offer a personalized therapeutic approach. It is now well-established that non-coding RNAs (ncRNAs) represent 98% of the transcriptome but in-depth knowledge about their involvement in the regulation of gene expression is lacking. A growing body of research indicates that ncRNAs are essential for tumorigenesis by regulating the expression of tumour-related genes. In this review, we focus on their implication in breast cancer genesis but also report the latest knowledge of their theragnostic and therapeutic role. We highlight the need for accurate quantification of circulating ncRNAs which is determinant to develop reliable biomarkers. Further studies are mandatory to finally enter the era of personalized medicine for women with breast cancer.


[Salmonella typhimurium--test system for detecting the mutagenic activity of environmental pollutants. II. Mutagenic effect of heavy metal salts in an in vitro system with metabolic activation].
Mutagenic effect of zinc chloride on Salmonella typhimurium strain was detected using in vitro metabolic activation system. Cadmium chloride showed no significant mutagenic activity in the same system. It is recommended to use both in vitro and in vivo metabolic activation systems in mutagenicity testing of chemicals.


Citrate anticoagulation and cell washing for intraoperative autotransfusion in the baboon.
Extracorporeal citrate was used for anticoagulation during autotransfusion of baboons. A cell-washing plasmaphoresis procedure was added in one group of animals in order to remove activated clotting materials. Both groups became hypocoagulable, but the cell-washed group had less evidence of disseminated intravascular coagulation as well as lower plasma hemoglobin levels. Citrate anticoagulation plus cell washing is a potential alternative to heparinization for autotransfusion.


Comparison of the effect of sodium hyaluronate (Ophthalin) and hydroxypropylmethylcellulose (HPMC-Ophtal) on corneal endothelium, central corneal thickness, and intraocular pressure after phacoemulsification.
To prospectively evaluate the effects of 2% hydroxypropyl-methylcellulose (HPMC-Ophtal) and sodium hyaluronate 1% (Ophthalin) on intraocular pressure, corneal thickness, and endothelial cell loss in small incision cataract surgery with implant. A total of 110 patients undergoing routine phacoemulsification with implant received either 2% hydroxypropyl methylcellulose or sodium hyaluronate 1% as ophthalmic viscosurgical device. Pre- and postoperative slitlamp examination, intraocular pressure measurement (preoperatively and at 1-4 hours, 1 day, and 7 days postoperatively), ultrasonic pachymetry (preoperatively and at 1 week, 4-6 weeks, and 12 weeks post operatively), and corneal endothelial cell count (preoperatively and 12 weeks postoperatively) were performed. Data were analyzed using two-way analysis of variance. All measurements were comparable between the two groups preoperatively. Intraocular pressure was significantly lower in the Ophthalin group at 1 day post operatively, while no significant difference was found between the two groups on the 1-4 hours and 7 days examination. The central corneal thickness was not significantly different between the two groups at any postoperative visit . However, the mean cell density demonstrated a significant fall of 11.76% for Ophthalin and 4.27% for HPMC-Ophtal at 12 weeks post-operatively, the difference between the two being significant (p=0.009). 2% Hydroxypropyl methylcellulose, compared with sodium hyaluronate 1%, is superior in protecting the corneal endothelial cells, has the same effect on central corneal thickness, and is associated with slightly higher intraocular pressure 1 day post operatively. It compares favorably with sodium hyaluronate 1% and can be used as an effective and cheaper alternative in routine small incision cataract surgery with implant.


Opioid and benzodiazepine use during therapeutic hypothermia in encephalopathic neonates.
To evaluate the use of sedatives and analgesics during therapeutic hypothermia in encephalopathic neonates and assess associations between medication exposure and hospital outcomes. We identified neonates ≥35 weeks gestational age treated with therapeutic hypothermia at 125 neonatal intensive care units between 2007 and 2015. We compared characteristics and hospital outcomes between unexposed neonates and neonates exposed to opioids and/or benzodiazepines. Opioids were administered to 1 677/2 621 (64%) neonates, and exposure increased from 38% in 2008 to 68% in 2015. Sedation/analgesia varied widely between centers. Opioid-exposed neonates experienced greater durations of respiratory support and were more likely to receive inotropes and inhaled nitric oxide. Mortality during postnatal days 0-3 was lower among opioid-exposed neonates (31/625 [5%]) than unexposed neonates (64/714 [9%]). Sedation/analgesia during therapeutic hypothermia is prevalent but not uniform across centers. Prospective studies are needed to assess if exposure independently predicts intensity and duration of physiologic support.


Peptide Vectors Carry Pyrene to Cell Organelles Allowing Real-Time Quantification of Free Radicals in Mitochondria by Time-Resolved Fluorescence Microscopy.
Real-time quantification of reactive nitrogen and oxygen species (ROS) in cells is of paramount importance as they are essential for cellular functions. Their excessive formation contributes to the dysfunction of cells and organisms, ultimately leading to cell death. As ROS are mostly produced in the mitochondria, we have synthesized a fluorescent probe able to reach this organelle to detect and quantify, in real time, the variation of ROS by time-resolved microfluorimetry. The new probes are based on the long fluorescence lifetime of pyrene butyric acid (PBA). Two PBA isomers, attached at their 1- or 2-positions to a peptide vector to target mitochondria, were compared and were shown to allow the measurement of free radical species and oxygen, but not non-radical species such as H2 O2 .


regentrans: a framework and R package for using genomics to study regional pathogen transmission.
Increasing evidence of regional pathogen transmission networks highlights the importance of investigating the dissemination of multidrug-resistant organisms (MDROs) across a region to identify where transmission is occurring and how pathogens move across regions. We developed a framework for investigating MDRO regional transmission dynamics using whole-genome sequencing data and created regentrans, an easy-to-use, open source R package that implements these methods (https://github.com/Snitkin-Lab-Umich/regentrans). Using a dataset of over 400 carbapenem-resistant isolates of Klebsiella pneumoniae collected from patients in 21 long-term acute care hospitals over a one-year period, we demonstrate how to use our framework to gain insights into differences in inter- and intra-facility transmission across different facilities and over time. This framework and corresponding R package will allow investigators to better understand the origins and transmission patterns of MDROs, which is the first step in understanding how to stop transmission at the regional level.


Closure of radial forearm free flap donor site: A comparative study between keystone flap and skin graft.
The aim was to investigate the feasibility of radial forearm free flap (RFFF) donor site closure by keystone flap (KF) and compare its outcomes to those of skin graft (SG) closure. One hundred and one patients who underwent RFFF for head and neck reconstruction were included (35 KF closure and 65 SG closure). Duration of wound healing and donor site complications was collected. After a minimal follow-up of 1 year, patients were questioned about functional and esthetic impairment. Coverage of donor site by KF was successful in all cases. The duration of wound healing was longer after SG than after KF (32 days vs 18 days, P < .001). Healing complications, esthetic and functional results were not statistically different. Forearm donor site closure by KF is a feasible alternative to the traditional SG. Its main advantages are the reduced wound healing time and the avoidance of a second donor site.


Aromatase, 17 beta-hydroxysteroid dehydrogenase and intratissular sex hormone concentrations in cancerous and normal glandular breast tissue in postmenopausal women.
In a study of the origin of estrogens in patients with breast cancer, the concentrations of estrogens and their androgen precursors, and aromatase and 17 beta-hydroxysteroid dehydrogenase (E2DH) activities were determined in normal glandular and cancerous breast tissue. The correlation between tissue estrogens, precursor concentrations, enzyme activities and plasma levels and/or receptor status were calculated. In both normal glandular and carcinomatous breast tissue, the concentrations of androstenedione (A), dehydroepiandrosterone (DHEA), 5 androstene-3 beta, 17 beta-diol (5-Adiol), estrone (E1), estradiol (E2) and progesterone (P) were significantly higher than plasma concentrations. While testosterone (T) concentrations were similar, dehydroepiandrosterone (DHCA) and estrone sulphate (E1S) concentrations were lower in tissue than in plasma. In carcinomatous tissue androgen concentrations were lower, but estrogen concentrations were higher than in glandular breast tissue. Estradiol (E2) concentration was positively correlated with the receptor concentration with the mean E2 concentration corresponding to an estimated receptor occupancy of about 25%, probably sufficient for a submaximal biological response. Aromatase and E2DH (E2----E1) activities were observed in all breast cancer and glandular breast tissues, activities being higher in carcinoma than in glandular breast tissues; nevertheless, aromatase activity accounts probably only for a small fraction of tissue estrogen concentration. E2DH, but not aromatase activity, was significantly higher in estrogen receptor positive than in estrogen receptor negative tissues and was negatively correlated with tissue dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) concentration; the latter two steroids are non competitive inhibitors of E2DH which inactivates E2 to E1. This effect of DHEA(S) may constitute a mechanism by which these androgens stimulate cancer growth and a rationale (besides suppression of estrogen precursors) for medical or surgical adrenalectomy in hormone sensitive metastatic mammary cancer. E2DH activity might constitute an additional marker of hormone dependency of mammary cancer.


Higher Incidence Rates of Comorbidities in Patients with Psoriatic Arthritis Compared with the General Population Using U.S. Administrative Claims Data.
Psoriatic arthritis (PsA) is associated with multiple comorbid conditions, including cardiovascular (CV) comorbidities that impose a considerable burden on patients. Effective management of PsA requires an understanding of comorbidity profiles. To compare the frequency and incidence rates of comorbidities and hospitalizations among newly diagnosed PsA patients and a matched general population without PsA, using large national claims databases in the United States. This retrospective observational study used MarketScan databases from January 1, 2008, to September 30, 2015, to identify adult patients with newly diagnosed PsA (i.e., no PsA diagnosis during the 1 year before the first observed PsA diagnosis). The earliest date of PsA diagnosis was defined as the index date. Patients with no PsA diagnosis any time during the study period (controls) were directly matched to PsA patients with demographic characteristics. All patients had ≥ 2 years of medical and pharmacy coverage before the index date and ≥ 1 year of follow-up. Incident rates per 100 person-years for comorbidities of interest were evaluated. The hazard ratios of having various comorbid conditions for PsA patients were estimated by Cox proportional hazards models. All-cause and CV-related hospitalizations during the follow-up period were evaluated. A total of 14,898 PsA patients and 35,037 matched controls met the study criteria. Compared with controls, PsA patients had a higher risk of CV disorders (incidence rate = 6.5 vs. 5.8; HR = 1.46; 95% CI = 1.37-1.56) and a higher risk of the majority of the specific CV disorders (hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, peripheral vascular disease). PsA patients also had a higher risk for any autoimmune disease (incidence rate = 8.4 vs. 1.6; HR = 18.26; 95% CI = 17.18-19.40) and most autoimmune categories (psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and other autoimmune disorders). Rates of other PsA-related comorbidities (diabetes, anxiety, fatigue, smoking, alcohol use, obesity or overweight, depression, osteoporosis, uveitis, eczema, and gout) were also significantly higher for PsA patients. The all-cause hospitalization rate was higher among PsA patients than controls (24.9% vs. 16.2%; P < 0.001). The CV-related hospitalization rate varied depending on whether the CV condition was the primary discharge diagnosis only or was any diagnosis on the inpatient claims. The rates of coronary artery disease hospitalizations were significantly higher in PsA patients than in controls with both methods of analysis (primary diagnosis: 0.8% vs. 0.5%; P < 0.001; nonprimary diagnosis: 3.2% vs. 2.2%; P < 0.001). This retrospective U.S.-based claims study found that PsA patients had a high comorbidity burden. Compared with the non-PsA population, PsA patients were associated with a higher incidence of CV comorbidities, autoimmune diseases, and other PsA-related comorbidities and a higher rate of all-cause and CV-related hospitalizations. Understanding these comorbidity profiles may provide insight on the effect of comorbid conditions on disease management and health care utilization associated with PsA. This study was funded by Novartis. Kaine is a paid consultant for Novatis. Hur and Palmer are Novartis employees and stockowners. Song and Kim work for Truven Health Analytics, which received funding from Novartis to conduct this study.


The use of pethidine as pre-medication to prevent anoxic spells in patients with tetralogy of Fallot.
The aim of this study was to determine whether morphine-HCl or pethidine-HCl differ as pre-medication to prevent anoxic spell in patients with tetralogy of Fallot (TOF) at catheterization. A 3 year retrospective case notes review study of 46 consecutive patients who underwent cardiac catheterization from 1998 to 2001 was conducted. In a prospective 1 year randomized control study, 10 patients diagnosed as TOF and admitted to Tokyo Women's Medical University, The Heart Institute of Japan, Tokyo, in 2002 were randomized to receive morphine or pethidine as pre-medication for cardiac catheterization. The incidence of anoxic spell before and after cardiac catheterization was investigated in both studies. In the case notes review, a total of 10 out of the 46 patients showed anoxic spell study: eight out of 24 patients in the morphine group and two out of 22 in the pethidine group. The difference in the incidence was statistically significant (P < 0.05, Fisher's exact test). Four patients in the prospective study showed anoxic spell: three out of six in the morphine group and one out of four in the pethidine group (odds ratio = 3.0). Overall, 14 out of 56 patients had anoxic spell: 11 out of 30 in the morphine group and three out of 26 in the pethidine group (P = 0.03). The incidence of hypoxic spells in patients with TOF undergoing cardiac catheterization is reduced by the use of pethidine-HCl as pre-medication compared to morphine. This has important clinical implications.


Does self-reported symptom questionnaire play a role in nonadherence to colonoscopy for risk-increased population in the Tianjin colorectal cancer screening programme?
A colorectal cancer screening programme (CCSP) was implemented from 2012 to 2017 in Tianjin, China. Residents with a positive faecal immunochemical test (FIT) or positive self-reported symptom questionnaire (SRSQ) were recommended to undergo colonoscopy. The objective was to investigate the potential factors associated with nonadherence to colonoscopy among a risk-increased population. Data were obtained from the CCSP database, and 199,522 residents with positive FIT or positive SRSQ during two screening rounds (2012-2017) were included in the analysis. Logistic regression analysis was performed to assess the association between nonadherence to colonoscopy and potential predictors. A total of 152,870 (76.6%) individuals did not undergo colonoscopy after positive FIT or positive SRSQ. Residents with positive SRSQ but without positive FIT were more likely not to undergo colonoscopy (negative FIT: OR, 2.35; 95% CI, 2.29-2.41, no FIT: OR, 1.27; 95% CI, 1.24-1.31). Patients without a cancer history were less likely to undergo colonoscopy even if they received risk-increased reports based on the SRSQ. In the CCSP, seventy-seven percent of the risk-increased population did not undergo colonoscopy. FIT should be recommended since positive FIT results are related to improved adherence to colonoscopy. Residents with negative FIT but positive SRSQ should be informed of the potential cancer risk to ensure adherence to colonoscopy.


Chloroplast division machinery as revealed by immunofluorescence and electron microscopy.
The division of chloroplasts (plastids) is critical for the viability of photosynthetic eukaryotes. Previously we reported on the chloroplast division apparatus, which consists of inner and outer double or triple rings (PD rings). Chloroplasts are assumed to arise from bacterial endosymbionts, while bacterial division is instigated by a bacterial cytokinesis Z-ring protein (FtsZ). Here we present immunofluorescence and electron-microscopic evidence of chloroplast division via complex machinery involving the FtsZ and PD rings in the higher plant Pelargonium zonale Ait. Prior to invagination, the FtsZ protein was attached to a ring at the stromal division site. Following formation of the FtsZ ring, the inner stromal and outer cytosolic PD rings appeared, signifying the initiation of invagination. The FtsZ ring and the PD rings were found at the leading edge of chloroplast constriction throughout division. During chloroplast division, neither the FtsZ nor the inner rings changed width, but the volume of the outer ring gradually increased. We suggest that the FtsZ ring determines the division region, after which the inner and outer PD rings are formed as a lining for the FtsZ ring. With the outer ring providing the motivating force, the FtsZ and inner PD rings ultimately decompose to their base components.


Radiotherapy: Neurocognitive considerations in the treatment of brain metastases.
The results of a randomized, controlled trial investigating the neurocognitive effects of stereotactic radiosurgery (SRS), with or without whole-brain radiation therapy (WBRT), to treat brain metastases demonstrated a significant reduction in learning and memory, associated with the addition of WBRT to SRS. the results indicate that SRS monotherapy is an effective and safe initial management strategy for brain metastases.


Interleukin 1 beta gene polymorphism and risk of cervical cancer.
To determine whether a polymorphism at position +3953 in exon 5 of the lL-1beta gene (IL-1beta +3953), a condition associated with an increased risk for a number of inflammatory diseases, is also involved in the development of cervical cancer. We isolated DNA from peripheral blood in 150 women with cervical cancer and 200 healthy controls, and IL-1beta +3953 allele polymorphism was determined by polymerase chain reaction. Genotypes A1/A2 and A2/A2+A1/A2 were associated with increased risk of cervical cancer (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.78-4.67; P<0.001 and OR, 2.85; 95% CI, 1.77-4.6; P<0.001, respectively). The risk in a passive smoker with A2/A2 or A1/A2 genotype was increased more than 5-fold (OR, 5.69; 95% CI, 2.61-12.50; P<0.001) compared with a nonsmoker with the A1/A1 genotype. This study provides evidence of an association between lL-1beta +3953 polymorphism and risk of cervical cancer.


Level IV tumor thrombus in non-metastatic renal cell cancer? No, thanks. Level II is better. Lessons learned from a case report.
Up to 19% of patients with renal cell carcinoma present with a venous thrombus at diagnosis and 1% have a thrombus extending above the diaphragm. The higher the thrombus level, the more challenging the surgery. Cavoatrial tumor thrombus usually requires circulatory arrest and sometimes cardiopulmonary by-pass. We present a case of non-metastatic renal cell carcinoma with a cavoatrial tumor thrombus in a patient who was unfit for cardiac surgery. Eight months of targeted molecular therapy downsized the tumor thrombus to inferior vena cava and allowed us to perform a radical nephrectomy with minimal cavothomy for thrombus resection.


Anti-platelet or anti-coagulant agent for the prevention of ischemic stroke in patients with end-stage renal disease and atrial fibrillation--a nation-wide database analyses.
The risk/benefit profiles of anti-coagulant or anti-platelet agents in patients with end-stage renal disease (ESRD) and atrial fibrillation (AF) remained unclear. We aimed to investigate the stroke risks in these patients with or without anti-coagulant/anti-platelet therapy by using our national database. By using our national health insurance ESRD claim database, we searched patients with AF, more than 18 years old and without prior history of ischemic stroke. Medication information as well as the events of ischemic stroke, hemorrhagic stroke, and transient ischemic accident during follow-up were identified from the database. Propensity score method was used to match all the potential confounders between patients with and without anti-platelets/warfarin treatment. A total of 134,410 ESRD patients were identified in the database. Among them, patients with non-valvular AF, over 18 years old, without prior history of ischemic stroke and received monotherapy with anti-platelets (1622) or warfarin (294) served as case groups while patients (2983) without taking any anti-platelets and warfarin served as control groups. The incidences of ischemic stroke or transient ischemic attack (TIA) were not different among the control (6.6%), anti-platelet (6.2%) and warfarin (5.1%) groups in a follow-up period of approximately 4 years. The results remained unchanged after propensity match. Cox-regression analyses also showed no beneficial effect of anti-platelet or warfarin therapy in overall and any subgroups. In this nationwide cohort analyses, we found that anti-platelet or warfarin treatment could not lower the risk of ischemic stroke in patients with ESRD.


Relaxivity-iron calibration in hepatic iron overload: Predictions of a Monte Carlo model.
R2* (1/T2*) and single echo R2 (1/T2) have been calibrated to liver iron concentration (LIC) in patients with thalassemia and transfusion-dependent sickle cell disease at 1.5T. The R2*-LIC relationship is linear, whereas that of R2 is curvilinear. However, the increasing popularity of high-field scanners requires generalizing these relationships to higher field strengths. In this study, we tested the hypothesis that numerical simulation can accurately determine the field dependence of iron-mediated transverse relaxation rates. We previously replicated the calibration curves between R2 and R2* and iron at 1.5T using Monte Carlo models incorporating realistic liver structure, iron deposit susceptibility, and proton mobility. In this paper, we extend our model to predict relaxivity-iron calibrations at higher field strengths. Predictions were validated by measuring R2 and R2* at 1.5T and 3T in six β-thalassemia major patients. Predicted R2* increased twofold at 3T from 1.5T, whereas R2 increased by a factor of 1.47. Patient data exhibited a coefficient of variation of 3.6% and 7.2%, respectively, to the best-fit simulated data. Simulations over the range 0.25T-7T showed R2* increasing linearly with field strength, whereas R2 exhibited a concave-downward relationship. A model-based approach predicts alterations in relaxivity-iron calibrations with field strength without repeating imaging studies. The model may generalize to alternative pulse sequences and tissue iron distribution.


An enzyme-mediated protein-fragment complementation assay for substrate screening of sortase A.
Enzyme-mediated protein conjugation has gained great attention recently due to the remarkable site-selectivity and mild reaction condition affected by the nature of enzyme. Among all sorts of enzymes reported, sortase A from Staphylococcus aureus (SaSrtA) is the most popular enzyme due to its selectivity and well-demonstrated applications. Position scanning has been widely applied to understand enzyme substrate specificity, but the low throughput of chemical synthesis of peptide substrates and analytical methods (HPLC, LC-ESI-MS) have been the major hurdle to fully decode enzyme substrate profile. We have developed a simple high-throughput substrate profiling method to reveal novel substrates of SaSrtA 7M, a widely used hyperactive peptide ligase, by modified protein-fragment complementation assay (PCA). A small library targeting the LPATG motif recognized by SaSrtA 7M was generated and screened against proteins carrying N-terminal glycine. Using this method, we have confirmed all currently known substrates of the enzyme, and moreover identified some previously unknown substrates with varying activities. The method provides an easy, fast and highly-sensitive way to determine substrate profile of a peptide ligase in a high-throughput manner.


Methyl phosphonate as a 31P-NMR probe for intracellular pH measurements in Dictyostelium amoebae.
Methyl phosphonate at concentrations up to 20 mM was found to be non toxic towards the growth of Dictyostelium amoebae and the starvation-induced differentiation program. In contrast, phenyl phosphonate at the same concentrations was found to inhibit growth. Methyl phosphonate possessed good 31P-NMR characteristics for use as a pH probe in Dictyostelium. The entry of methyl phosphonate into the cytoplasm required about 150 min of incubation before an equilibrium was reached with added extracellular methyl phosphonate. A semilogarithmic plot of the efflux of methyl phosphonate out of the amoebae was linear as a function of time, and the kinetic first-order constant was k = 0.016 min-1. The kinetic parameters were consistent with an uptake of methyl phosphonate by fluid-phase pinocytosis. The pH calculated from the chemical shift of the internalized methyl phosphonate signal was found to be pH 7.4 in aerobic Dictyostelium amoebae. The intracellular methyl phosphonate environment turned more acidic in response to anaerobiosis (delta pH = 0.8) or in the presence of a weak acid such as propionate. These pH determinations were in agreement with the values of cytosolic pH derived from the chemical shift of Pi. Methyl phosphonate should be a useful probe for pH measurements in 31P-NMR studies of Dictyostelium in situations where the signal of Pi cannot be attributed with certainty.


Screening, Diagnosis and Early Intervention in Autism Spectrum Disorders.
The increment of prevalence is among the most important changes that have taken place in recent years with regard to Autism Spectrum Disorder (ASD); in the 1970s and 1980s of the 20th century, the prevalence of ASD was estimated to be 4/10,000 [...].


Soymilk phenolic compounds, isoflavones and antioxidant activity as affected by in vitro gastrointestinal digestion.
The aim of this research was to evaluate changes in the phenolic compounds, isoflavones and antioxidant activity of soymilk following in vitro gastrointestinal digestion (including dialysis). Gastric digestion significantly influenced the release of bioactive substances from the soymilk matrix, increasing the concentration of total phenolic components (35% as the sum of individuals and 14% by Folin-Ciocalteu [F-C] method), total isoflavone content (22%) and total antioxidant activity (76%). The concentration of all those compounds was reduced significantly in the duodenal fraction in comparison to gastric digestion and their lowest concentration was observed in the dialysed fraction, where phenolic acids were not detected. The bioaccessibility of soymilk phenolic compounds was 15% as the sum of individuals and 20% by F-C assay; isoflavones 36% and constituents with antioxidant activity 27%. Results suggest that most of these compounds were sufficiently available to be absorbed and could contribute health benefits.


Activity of 2,6,9-trisubstituted purines as potent PDGFRα kinase inhibitors with antileukaemic activity.
Receptor tyrosine kinase PDGFRα is often constitutively activated in various tumours and is regarded as a drug target. Here, we present a collection of 2,6,9-trisubstituted purines with nanomolar potency against PDGFRα and strong and selective cytotoxicity in the human eosinophilic leukaemia cell line EOL-1 that expresses the FIP1L1-PDGFRA oncogene. In treated EOL-1 cells, the example compound 14q inhibited the autophosphorylation of PDGFRα and the phosphorylation of STAT3 and ERK1/2. Interestingly, we observed pronounced and even increased effects of 14q on PDGFRα and some of its downstream signalling pathways after drug washout. In accordance with suppressed PDGFRα signalling, treated cells were arrested in the G1 phase of the cell cycle and eventually underwent apoptosis. Our results show that substituted purines can be used as specific modulators of eosinophilic leukaemia.


Human health risk assessment of selected metal(loid)s via crayfish (Faxonius virilis; Procambarus acutus acutus) consumption in Missouri.
Farmed crustaceans are an important component in addressing the rising animal protein demand. The present study determined the concentrations of fourteen elements (Ag, As, Be, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Sn, Pb, and Zn) in the edible abdominal muscle of cultured freshwater crayfish species (Faxonius virilis; Procambarus acutus acutus) from Missouri. Also, this paper describes the dietary intake and the human health risks from the consumption of crayfish muscle in the adult population. Overall, 172 animals were captured between February 2017 and January 2018 for assessment. Concentrations of metals (Ag, Be, Cd, Cu, Co, Cr, Fe, Mn, Ni, Pb, Sn, Mo, and Zn) and metalloid (As) in the muscle tissue were determined after microwave-assisted acid digestion by ICP - OES. Health indices (EDI/EWI: estimated daily/weekly intakes; THQ: target hazard quotient; TTHQ: total target hazard quotient; ILCR: incremental lifetime cancer risk; and ∑ILCR: cumulative lifetime cancer risk) were calculated and compared to thresholds. Of all samples, the highest concentrations (mg kg -1 wet weight) of metal(loid)s in muscle were Ag (0.11), As (3.15), Be (0.21), Cd (0.11), Co (0.32), Cr (1.22), Cu (107), Fe (23.0), Mn (8.54), Mo (0.62), Ni (2.65), Pb (1.76), Sn (5.91), and Zn (19.2). In both species, the average As, Cd, and Zn concentrations were below the legal limits. However, the levels of Cu, Pb, and As, in some samples, were in exceedance of the maximum levels. In both species, a significant correlation (p < 0.05) was observed between the carapace length (CL) and animal body weight (BW). In P. acutus, CL, BW, and animal total length were homogenous (p > 0.05) among the sexes. Non-parametric Kruskal-Wallis test results indicated significant differences (p < 0.05) in the levels of As, Be, and Zn in F. virilis, and Be and Cr in P. a. acutus among the genders. Significant inter-species differences (p < 0.05) were observed in the levels of Be, Ni, and Pb and the growth factors. The EDI/EWI values were below the permissible limits. THQ and TTHQ values, being below 1.0, indicated no probabilistic health risk. Regarding carcinogenic risk, only As and Ni indicated cancer risk (ILCR >10-5 and ∑ILCR >10-5) to the adult population. High metals/metalloid exposure from crayfish muscle consumption posed potential health hazards to the adult population.


"Practical suggestions on facial plastic surgery--how i do it". The lower blepharoplasty.
The above-described operation is the musculocutaneous ("skin-muscle") flap procedure of blepharoplasty for the lower lid. The author is pleased to state that he has been very satisfied with this technique and that he has experienced no serious complications with it. Although the scar may be somewhat low by most standards, after several weeks it is hardly discernible (Fig. 7).


Differential physiological and biochemical responses of two cyanobacteria Nostoc muscorum and Phormidium foveolarum against oxyfluorfen and UV-B radiation.
In the present study, degree of tolerance and tolerance strategies of two paddy field cyanobacteria viz. Nostoc muscorum and Phormidium foveolarum against oxyfluorfen (10 and 20 μg ml(-1)) and UV-B (7.2 kJ m(-2)d(-1)) stress were investigated. Oxyfluorfen and UV-B decreased growth, photosynthesis, nutrient uptake, nitrate reductase, acid and alkaline phosphatase activities, which accompanied with the increase in the level of oxidative stress. However, growth was more affected in N. muscorum than P. foveolarum. Antioxidants exhibited differential responses against oxyfluorfen and UV-B stress. Ascorbate and proline levels were higher in P. foveolarum. A protein of 66 kDa was expressed in N. muscorum, however, it was absent in P. foveolarum than those of N. muscorum. Besides this, a protein of 29 kDa appeared in P. foveolarum under all the treatments, but it was present only in control cells of N. muscorum cells. Overall results indicated resistant nature of P. foveolarum against oxyfluorfen and UV-B stress in comparison to N. muscorum.


Normal variations of oral anatomy and common oral soft tissue lesions: evaluation and management.
Examination of the oral cavity can provide significant diagnostic information regarding the general health of the patient. The oral cavity is affected by a multitude of pathologic conditions of variable cause and significance; however, there are numerous normal variations of oral soft tissue structures that may resemble a pathologic state. Understanding these variations assists practitioners to discriminate between normal versus abnormal findings and determine the appropriate course of management, if necessary.


Solvent effects on host-guest residence time and kinetics: further insights from metadynamics simulation of Toussaintine-A unbiding from chitosan nanoparticle.
Solvents play an important role in host-guest intermolecular interactions. The kinetics and residence time of Toussaintine-A (TouA) unbinding from chitosan was investigated by means of well-tempered metadynamics and thermodynamic integration using two solvents, polar aprotic (DMSO), and polar protic (water). The kinetic rates were found to be strongly dependent on the solvent polarity; hence, the unbinding rate proceeded much faster in DMSO compared to water. DMSO tends to participate less in a chemical reaction by weakening the intermolecular interaction between chitosan and TouA due to lack of acidic hydrogen resulting in a reduction of the transition state. On the other hand, water, which ought to donate hydrogen atoms, sustains a strong interaction and hence large barrier heights. Consequently, this reduces the unbinding rate and increases the residence time. Binding free energy from thermodynamic integration suggests a thermodynamic stable chitosan-TouA complex in water than in DMSO. Graphical abstract.


Response to Pearl's comments on principal stratification.
Dr. Pearl invites researchers to justify their use of principal stratification. This comment explains how the use of principal stratification simplified a complex mediational problem encountered when evaluating a smoking cessation intervention's effect on reducing smoking withdrawal symptoms.


[Teratoma of the 4th ventricle and precocious puberty. Case report].
A case of precocious puberty and diabetes insipidus in a 7 years old boy due to a malignant teratoma in the IVth ventricle is reported. The tumor had grown into the IIIrd and lateral ventricles as found on the necropsy. The original site of the tumor and the possible physiopathological mechanisms for the precocious puberty are discussed.


Cadmium stimulates prostaglandin E2 synthesis in osteoblast-like cells, MC3T3-E1.
The effect of Cd on prostaglandin E2 production in osteoblasts was studied using cloned osteoblast-like cells, MC3T3-E1, which were established from new-born mouse calvaria. Treatment of the cells with Cd caused a dose- (0-10 microM) and time- (0-24 h) dependent increase in the release of prostaglandin E2 from the cells into the culture medium. A lag time of 4 h was required for the onset of the phenomenon. The release of [14C]arachidonic acid from prelabeled cell membrane was little influenced by the Cd treatment, while conversion of [14C]arachidonic acid to prostaglandin E2 by the homogenate of the cells treated with Cd was enhanced as compared to that by untreated cells. The stimulatory effect of Cd on prostaglandin E2 production was abolished in the presence of cycloheximide (100 ng/ml). By Western blot analysis with polyclonal rabbit anti-cyclooxygenase antibody, it was revealed that Cd treatment augmented the amount of immunoreactive cyclooxygenase in the cells. These results strongly suggest that Cd stimulates prostaglandin E2 production through the induction of cyclooxygenase in MC3T3-E1 cells. This effect of Cd may be involved in the mechanisms of Cd-induced bone injury.


Generation of optical vector beams with a diffractive optical element interferometer.
We present a novel approach to generating radially and azimuthally polarized vector beams that utilize an interferometer constructed from two identical diffractive optical elements. The measured polarization properties of four vector beam states and their phase relationships are in good agreement with theoretical expectations. This interferometer is passively phase stable and robust, making it suitable for linear and nonlinear optical (superresolution) microscopy.


Kinetic urine creatinine determination with the Gemsaec analyzer.
A rapid automated method for urinary creatinine with the Jaffé reaction is described. Interferences by protein, glucose and ketones are circumvented by the reaction rate kinetics. The precision and accuracy of this centrifugal method on the ENI-Gemsaec analyzer are comparable to the manual end-point Jaffé reaction with deproteinization and to the common Auto-Analyzer technique.


Can we prevent sudden cardiac death in young athletes: the debate about preparticipation sports screening.
All high school athletes in the United States require a preparticipation screening examination. The American Heart Association recommends a focused history and physical examination. The European Society of Cardiology recommends that all examinations include an electrocardiogram (ECG). We review the risks and costs of screening, discuss legal ramifications and analyse the ethical implications of these considerations. There are too many unknown about ECG screening to require it as routine testing for all high school athletes. Doctors must inform young athletes and their parents about the option of ECG screening and about the debate over its efficacy. Patients and parents may then choose to have an ECG or not. Mandatory universal screening is not warranted at this time.


Simple and compact cannula system for mice.
A small and simple device is described for applying substances to the brain of freely moving mice. The effectiveness of the technique was evaluated by intraventricular injections of d-amphetamine sulfate. It was observed that intraventricular injections of d-amphetamine (50-200 microgram) produced a dose dependent increase in activity.


Metal and pH-Dependent Aptamer Binding of Tetracyclines Enabling Highly Sensitive Fluorescence Sensing.
Tetracyclines are a widely used group of antibiotics, many of which are currently only used in veterinary medicine and animal husbandry due to their adverse side effects. For the detection of tetracyclines, we previously reported a DNA aptamer named OTC5 that binds to tetracycline, oxytetracycline, and doxycycline with similar KD's of ~100 nM. Tetracyclines have an intrinsic fluorescence that is enhanced upon binding to OTC5, which can be used as a label-free and dye-free sensor. In this work, the effect of pH and metal ions on the sensor was studied. Mg2+ ions are required for the binding of OTC5 to its target with an optimal concentration of 2 mM. Other metal ions including Ca2+ and Zn2+ can also support aptamer binding. Although Mn2+ barely supported binding, the binding can be rescued by Mg2+. ITC studies confirmed that OTC5 had a KD of 0.2 μM at a pH of 6.0 and 0.03 μM at a pH of 8.3. Lower pH (pH 6) showed better fluorescence enhancement than higher pH (pH 8.3), although a pH of 6.0 had slightly higher KD values. Under optimized sensing conditions, sensors with limit of detections (LODs) of 0.1-0.7 nM were achieved for tetracycline, oxytetracycline, and doxycycline, which are up to 50-fold lower than previously reported. Milk samples were also tested yielding an LOD of 16 nM oxytetracycline at a pH of 6.0.


Reaction center and UQH2:cyt c2 oxidoreductase act as independent enzymes in Rps. sphaeroides.
Turnover of the ubiquinol oxidizing site of the UQH2:cyt c2 oxidoreductase (b/c1 complex) of Rps. sphaeroides can be assayed by measuring the rate of reduction of cyt b561 in the presence of antimycin (AA). Oxidation of ubiquinol is a second-order process, with a value of k2 of about 3 X 10(5)M-1. The reaction shows saturation at high quinol concentrations, with an apparent Km of about 6-8mM (with respect to the concentration of quinol in the membrane). When the quinone pool is oxidized before illumination, reduction of the complex shows a substantial lag (about 1 ms) after a flash, indicating that the quinol produced as a result of the photochemical reactions is not immediately available to the complex. We have suggested that the lag may be due to several factors, including the leaving time of the quinol from the reaction center, the diffusion time to the complex, and the time for the head group to cross the membrane. We have suggested a minimal value for the diffusion coefficient of ubiquinone in the membrane (assuming that the lag is due entirely to diffusion) of about 10(-9) cm-2 sec-1. The lag is reduced to about 100 microseconds when the pool is significantly reduced, showing that quinol from the pool is more rapidly available to the complex than that from the reaction center. With the pool oxidized, similar kinetics are seen when the reduction of cyt b561 occurs through the AA-sensitive site (with reactions at the quinol oxidizing site blocked by myxothiazol).(ABSTRACT TRUNCATED AT 250 WORDS)


Bioethanol production from tension and opposite wood of Eucalyptus globulus using organosolv pretreatment and simultaneous saccharification and fermentation.
During tree growth, hardwoods can initiate the formation of tension wood, which is a strongly stressed wood on the upper side of the stem and branches. In Eucalyptus globulus, tension wood presents wider and thicker cell walls with low lignin, similar glucan and high xylan content, as compared to opposite wood. In this work, tension and opposite wood of E. globulus trees were separated and evaluated for the production of bioethanol using ethanol/water delignification as pretreatment followed by simultaneous saccharification and fermentation (SSF). Low residual lignin and high glucan retention was obtained in organosolv pulps of tension wood as compared to pulps from opposite wood at the same H-factor of reaction. The faster delignification was associated with the low lignin content in tension wood, which was 15% lower than in opposite wood. Organosolv pulps obtained at low and high H-factor (3,900 and 12,500, respectively) were saccharified by cellulases resulting in glucan-to-glucose yields up to 69 and 77%, respectively. SSF of the pulps resulted in bioethanol yields up to 35 g/l that corresponded to 85-95% of the maximum theoretical yield on wood basis, considering 51% the yield of glucose to ethanol conversion in fermentation, which could be considered a very satisfactory result compared to previous studies on the conversion of organosolv pulps from hardwoods to bioethanol. Both tension and opposite wood of E. globulus were suitable raw materials for organosolv pretreatment and bioethanol production with high conversion yields.


Index transposition after resection of the long finger ray.
Ten patients underwent index-to-long-finger ray transposition for repair after resection of the long finger ray. Care was taken to preserve the second web space and prevent painful neuromas. Rigid internal fixation was achieved with a T plate, and mobilization was started immediately. There were no nonunions. Postoperative motion was equal to preoperative motion in acute cases and equal or better in chronic cases. Mean grip strength was 0.65, and pinch strength was 0.78 compared with the uninjured hand. There were no painful neuromas, hypersensitive scars, or deterioration of monofilament or two-point sensibility. The breadth and appearance of the first and second web spaces were equal bilaterally. Digit alignment and rotation were normal. The six patients receiving worker's compensation returned to work in between 3 and 24 weeks, and the other patients returned in between 11 days and 12 weeks.


Methods for ensuring the highest DNA concentration and yield in future and retrospective trace DNA extracts.
In forensic laboratories, increased extraction efficiency of trace evidence is paramount because analytical success is intrinsically dependent on the quantity of DNA recovered. Moreover, highly concentrated nucleic acids are vital for effective downstream analysis and high quality results. This study investigated the efficiency of extraction with the Qiagen® QIAamp® DNA Investigator kit, and explored improvements to the methodology that would maximise the recovery of low concentration forensic samples. Controlled amounts of starting cellular material were used to mimic trace (or low level) DNA deposits prior to DNA extraction with the Investigator kit. Addition of the provided carrier RNA along with conducting two successive elutions of 50 µL improved the net recovery of DNA to 95%. Concentration with centrifugal filters post-extraction were able to concentrate DNA but a large net loss was observed. For the concentration of historic, retrospectively extracted DNA, centrifugal methods are able to concentrate DNA extracts previously too dilute for analysis. These concentrated volumes, however are small, allowing for minimal downstream analysis attempts before the sample is exhausted.


Mental imagery. Effects on static balance and attentional demands of the elderly.
Several studies have demonstrated the effectiveness of mental imagery in improving motor performance. However, no research has studied the effectiveness of such a technique on static balance in the elderly. This study evaluated the efficiency of a mental imagery technique, aimed at improving static balance by reducing postural oscillations and attentional demands in the elderly. Twenty subjects aged 65 to 90 years old, divided into two groups (8 in Control group and 12 in Experimental group) participated in the study. The experimental participants underwent daily mental imagery training for a period of six weeks. Antero-posterior and lateral oscillations, reaction times during the use of the double-task paradigm were measured, and the Berg Balance Scale, Activities-specific Balance Confidence Scale, and VMIQ questionnaire were answered during both pre-test and post-test. Attentional demands and postural oscillations (antero-posterior) decreased significantly in the group with mental imagery training compared with those of the Control group. Subjects in the mental imagery group became significantly better in their aptitudes to generate clear vivid mental images, as indicated by the VMIQ questionnaire, whereas no significant difference was observed for the Activities-specific Balance Confidence Scale or Berg Scale. The results support psychoneuromuscular and motor coding theories associated with mental imagery.


Function and regulation of large conductance Ca(2+)-activated K+ channel in vascular smooth muscle cells.
Large conductance Ca(2+)-activated K(+) (BK(Ca)) channels are abundantly expressed in vascular smooth muscle cells. Activation of BK(Ca) channels leads to hyperpolarization of cell membrane, which in turn counteracts vasoconstriction. Therefore, BK(Ca) channels have an important role in regulation of vascular tone and blood pressure. The activity of BK(Ca) channels is subject to modulation by various factors. Furthermore, the function of BK(Ca) channels are altered in both physiological and pathophysiological conditions, such as pregnancy, hypertension and diabetes, which has dramatic impacts on vascular tone and hemodynamics. Consequently, compounds and genetic manipulation that alter activity and expression of the channel might be of therapeutic interest.


Nitric oxide, 2-amino-4-phosphonobutyric acid and light/dark adaptation modulate short-wavelength-sensitive synaptic transmission to retinal horizontal cells.
Light-induced changes in the input resistance (Rin) of external, luminosity (i.e. H1) type horizontal cell (HC) perikarya were studied by the bridge-balance method in light-adapted and dark-adapted retinae of carp. Changes in input resistance (delta Rin) induced by short-(460 nm) and long-wavelength (674 nm) flashes, adjusted in intensity to elicit equal-amplitude membrane voltage responses (equal-voltage condition), were measured. In light-adapted retinae, long-wavelength stimuli increased Rin consistently; in contrast, the increase was much less with short-wavelength stimuli. This equal-voltage chromatic delta Rin difference was lost in dark-adapted retinae whereby the delta Rin (an increase) became the same for short- and long-wavelengths. The chromatic delta Rin difference could be recovered by light adaptation or application of sodium nitroprusside to the dark-adapted retinae. Conversely, the equal-voltage chromatic delta Rin difference was eliminated by injection of NG-monomethyl-L-arginine into H1HCs of the light-adapted retinae or by treating the retinae with 2-amino-4-phosphonobutyrate (APB). These results suggest that H1HCs of the carp retina possess distinct postsynaptic mechanisms which mediate short- and long-wavelength signal transmission. Furthermore, it appears that the short-wavelength-sensitive pathway is active only during the light-adapted state of the retina. Taken together, therefore, the short-wavelength transmission to H1HCs probably operates on an APB-sensitive glutamate receptor, with nitric oxide as a light-adaptive messenger.


Primordial Follicle Formation - Some Assembly Required.
Formation of primordial follicles occurs when germ cell nests break apart and individual oocytes become surrounded by pregranulosa cells. Why mammalian germ cells develop in germ cell nests is not fully understood but recent work has provided evidence that some oocytes serve as nurse cells supporting other oocytes in the cyst. Headway has also been made in understanding interactions that occur between cyst cells that must change as individual oocytes separate to associate with pregranulosa cells. As germ cell nests undergo breakdown some oocytes are lost by programmed cell death that has been attributed to apoptosis, but newer studies have implicated autophagy in counteracting apoptosis to promote cell survival and maintain the ovarian reserve. Work in the past few years has added to already known pathways regulating primordial follicle formation and has identified new players including signaling molecules, transcription factors and RNA binding proteins.


A decade of proteomics accomplished! Central and Eastern European Proteomic Conference (CEEPC) celebrates its 10th Anniversary in Budapest, Hungary.
The Central and Eastern European Proteomic Conference (CEEPC) proudly celebrated its 10th Anniversary with an exciting scientific program inclusive of proteome, proteomics and systems biology in Budapest, Hungary. Since 2007, CEEPC has represented 'state-of the-art' proteomics in and around Central and Eastern Europe and these series of conferences have become a well-recognized event in the proteomic calendar. Fresher challenges and global healthcare issues such as ageing and chronic diseases are driving clinical and scientific research towards regenerative, reparative and personalized medicine. To this end, proteomics may enable diverse intertwining research fields to reach their end goals. CEEPC will endeavor to facilitate these goals.


Here today ... gone tomorrow.
A 42-year-old woman presented with ptosis of the left upper lid and limitation of elevation and adduction of the left eye. Neuroimaging revealed a left cavernous sinus lesion which on biopsy proved to be a meningioma. She was symptomatically stable for three weeks until she had spontaneous elevation of her left upper lid and resolution of her diplopia over the course of one day. Spontaneous improvement of a neurologic deficit is generally considered evidence against an underlying tumor; however, it should not rule out the possibility that a tumor is present.


Post-warming embryo morphology is associated with live birth: a cohort study of single vitrified-warmed blastocyst transfer cycles.
This study aims to examine whether blastocyst morphology post-warming correlates with live birth. In this cohort study, morphological characteristics post-warming were reviewed in all single vitrified-warmed blastocyst transfer cycles performed between November 2016 and May 2017. Immediately before transfer, the degree of blastocoel re-expansion was graded as A, fully expanded; B, partially expanded ≥ 50%; C, partially expanded < 50%; and D, collapsed. The degree of post-warming cell survival was graded on a scale of 50 to 100% and was then classified into 4 groups: very low 50-70%, low 71-80%, moderate 81-90%, and high 91-100%. Overall, 612 cycles were reviewed, of which 196 included PGT-A tested embryos. The live birth rate (LBR) increased from 11.4% in the collapsed blastocysts group to 38.9% in the post-warming full re-expansion group (p < 0.001) and from 6.5% for blastocysts with a very low cell survival rate to 34.7% for blastocysts with high cell survival rate (p = 0.001). LBR was 6.7% for blastocysts with the worst post-warming morphological characteristics, namely, collapsed with very low cell survival rate. On multivariate analyses, partial blastocyst re-expansion ≥ 50%, full re-expansion, and high cell survival rate remained significantly associated with live birth, after controlling for female age, pre-vitrification morphological grading, and PGT-A. A sub-analysis of cycles using PGT-A tested embryos showed similar results. Post-warming re-expansion and high cell survival rate are associated with higher LBR in euploid and untested blastocysts. However, embryos with poor post-warming morphology still demonstrate a considerable probability of live birth, and they should not be discarded.


Crystal structure of 4-{(E)-[2-(pyridin-4-ylcarbon-yl)hydrazin-1-yl-idene]meth-yl}phenyl acetate monohydrate.
The asymmetric unit of the title compound, C15H13N3O3·H2O, comprises a 4-{(E)-[2-(pyridin-4-ylcarbon-yl)hydrazinyl-idene]meth-yl}phenyl acetate mol-ecule and a solvent water mol-ecule linked by O-H⋯O and O-H⋯N hydrogen bonds from the water mol-ecule and a C-H⋯O contact from the organic mol-ecule. The compound adopts an E conformation with respect to the azomethine bond and the dihedral angle between the pyridine and benzene rings is 21.90 (7)°. The azomethine bond [1.275 (2) Å] distance is very close to the formal C=N bond length, which confirms the azomethine bond formation. An extensive set of O-H⋯O, O-H⋯N, N-H⋯O and C-H⋯O hydrogen bonds builds a two-dimensional network progressing along the c axis.


Resetting the relationship: decolonizing peer review of First Nations' kidney health research.
Kerr et al. interpret the perspectives of First Nations People striving for kidney health within the United States, Canada, Aotearoa (New Zealand), and Australia. The urgency for First Nations Peoples' perspectives and leadership in kidney health care, research, quality reporting, and publishing was confirmed. Advancing this internationally is within scope of high-impact journals, such as Kidney International. Tracking Sovereignty is a proposed framework supporting First Nation Peoples' representation and leadership within journal submission and publication processes.


Proposal of cut points for the indication of abdominal obesity among adolescents.
The absence of critical values for the cardiovascular risk identification among Brazilian adolescents represents an important limitation. To prepare critical values for the waist circumference and to analyze its efficiency in indicating increased values of the arterial pressure. Transversal study that evaluated 1,145 adolescents, from 11 to 17 years old (536 of the male sex and 609 of the female), their body weight values, stature, resistance, reactance, tricipital cutaneous fold, waist circumference and arterial pressure (n = 334) were collected. The abdominal obesity was indicated by waist circumference values. The obese adolescents presented higher waist circumference values and, independently of the gender and age group, there was a significant relation between the waist circumference values and all the adiposity indicators adopted in the study. The proposed critical values presented higher sensibility in indicating increased values of the arterial pressure. The critical values proposed for the waist circumference were more sensitive in the indication of increased values of the blood pressure. However, other studies to investigate their efficacy in the indication of other clinical and laboratorial parameters are still needed.


Isolation, purification and functional characterization of alpha-BnIA from Conus bandanus venom.
We report the isolation and characterization by proteomic approach of a native conopeptide, named BnIA, from the crude venom of Conus bandanus, a molluscivorous cone snail species, collected in the South central coast of Vietnam. Its primary sequence was determined by matrix-assisted laser desorption/ionization time-of-flight tandem mass spectrometry using collision-induced dissociation and confirmed by Edman's degradation of the pure native fraction. BnIA was present in high amounts in the crude venom and the complete sequence of the 16 amino acid peptide was the following GCCSHPACSVNNPDIC*, with C-terminal amidation deduced from Edman's degradation and theoretical monoisotopic mass calculation. Sequence alignment revealed that its -C1C2X4C3X7C4- pattern belongs to the A-superfamily of conopeptides. The cysteine connectivity of BnIA was 1-3/2-4 as determined by partial-reduction technique, like other α4/7-conotoxins, reported previously on other Conus species. Additionally, we found that native α-BnIA shared the same sequence alignment as Mr1.1, from the closely related molluscivorous Conus marmoreus venom, in specimens collected in the same coastal region of Vietnam. Functional studies revealed that native α-BnIA inhibited acetylcholine-evoked currents reversibly in oocytes expressing the human α7 nicotinic acetylcholine receptors, and blocked nerve-evoked skeletal muscle contractions in isolated mouse neuromuscular preparations, but with ∼200-times less potency.


Structure-activity studies of rapamycin analogs: evidence that the C-7 methoxy group is part of the effector domain and positioned at the FKBP12-FRAP interface.
Rapamycin is an immunosuppressant natural product, which blocks T-cell mitogenesis and yeast proliferation. In the cytoplasm, rapamycin binds to the immunophilin FKBP12 and the complex of these two molecules binds to a recently discovered protein, FRAP. The rapamycin molecule has two functional domains, defined by their interaction with FKBP12 (binding domain) or with FRAP (effector domain). We previously showed that the allylic methoxy group at C-7 of rapamycin could be replaced by a variety of different substituents. We set out to examine the effects of such substitutions on FKBP12 binding and on biological activity. Rapamycin C-7-modified analogs of both R and S configurations were shown to have high affinities for FKBP12, yet these congeners displayed a wide range of potencies in splenocyte and yeast proliferation assays. The X-ray crystal structures of four rapamycin analogs in complexes with FKBP12 were determined and revealed that protein and ligand backbone conformations were essentially the same as those observed for the parent rapamycin-FKBP12 complex and that the C-7 group remained exposed to solvent. We then prepared a rapamycin analog with a photoreactive functionality as part of the C-7 substituent. This compound specifically labeled, in an FKBP12-dependent manner, a protein of approximately 250 kDa, which comigrates with recombinant FRAP. We conclude that the C-7 methoxy group of rapamycin is part of the effector domain. In the ternary complex, this group is situated in close proximity to FRAP, at the interface between FRAP and FKBP12.


Red cell distribution width, anemia and their associations with white matter integrity among middle-aged urban adults.
Anemia (blood hemoglobin [Hb] <13 g/dL among males; <12 g/dL among females) and elevated red cell distribution width (RDW) are potential risk factors for reduced brain white matter integrity (WMI), reflected by lower fractional anisotropy or increased mean diffusivity. Cross-sectional data with exposure-outcome lag time was used, whereby hematological exposures (RDW and Hb) and covariates were compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study with available visit 1 (v1; 2004-2009) and/or v2 (2009-2013) data; while diffusion tensor magnetic resonance imaging (dMRI) outcome data were collected at HANDLS SCAN visit (vscan: 2011-2015, n = 214, mean follow-up from v1 ±SD: 5.6 ± 1.8 year). Multivariable-adjusted linear regression analyses were conducted, overall, stratifying by sex, and further restricting to the nonanemic for RDW exposures in part of the analyses. Among males, RDW(v1) was linked with lower global mean fractional anisotropy (standardized effect size b = -0.30, p= 0.003, q < 0.05; basic model), an association only slightly attenuated with further covariate adjustment. Anemia was not a risk factor for poor WMI, independently of RDW. Ultimately, pending further longitudinal evidence, initial RDW appears to be associated with poorer WMI among males.


Opioid Prescriptions Following Otologic Surgery: A Population-Based Study.
To examine postoperative opioid-prescribing patterns following otologic surgery. Retrospective population-based descriptive study. All hospitals in the Canadian province of Ontario. Of all patients with advanced ear surgery between July 1, 2012, and March 31, 2019, 7 cohorts were constructed: tympanoplasty with or without ossiculoplasty (n = 7812), atticotomy/limited mastoidectomy (n = 1371), mastoidectomy (n = 3717), semicircular canal occlusion (SCO; n = 179), stapedectomy (n = 2735), bone-implanted hearing aid insertion (n = 280), and cochlear implant (n = 2169). Prescriptions filled for narcotics postoperatively were calculated per morphine milligram equivalent (MME) opioid dose. Multivariable regression was used to determine predictors of higher opioid doses. The mean ± SD MMEs prescribed were as follows: tympanoplasty with or without ossiculoplasty, 246.77 ± 1380.78; atticotomy/limited mastoidectomy, 283.32 ± 956.10; mastoidectomy, 280.56 ± 1018.50; SCO, 328.61 ± 1090.86; stapedectomy, 164.64 ± 657.18; bone-implanted hearing aid insertion, 326.11 ± 1054.66; and cochlear implant, 200.87 ± 639.93. SCO (odds ratio [OR], 1.69 [95% CI, 1.16-2.48]) and mastoidectomy (OR, 1.50 [95% CI, 1.36-1.66]) were associated with higher opioid doses than tympanoplasty-ossiculoplasty. Asthma (OR, 1.24 [95% CI, 1.12-1.38]), chronic obstructive pulmonary disease (OR, 1.29 [95% CI, 1.12-1.47]), myocardial infarction (OR, 1.33 [95% CI, 1.05-1.68]), diabetes (OR, 1.22 [95% CI, 1.08-1.39]), and substance-related and addictive disorders (OR, 2.59 [95% CI, 1.67-4.00]) were associated with higher opioid doses prescribed. Overall MME prescribed by year demonstrates a sharp drop from 2017-2018 to 2018-2019. This large comprehensive population study provides insight into the prescribing patterns following otologic surgery. The large amounts prescribed and substantial variation require further study to determine barriers that limit good opioid-prescribing stewardship in the postoperative period.


Influence of antilymphocyte and antipolymorphonuclear sera on the pyrogenic effect of scarlet fever toxin.
The role played by lymphocytes in the pyretic response to scarlet fever toxin (ET) was studied in vivo using antilymphocyte serum (ALS). Two i.v. injections of ALS inhibited the pyretic response to a subsequent ET injection in rabbits. The course of endotoxin fever remained uninfluenced by ALS. Antipolymorphonuclear serum had no effect on the pyretic response to either of the toxins. Pretreatment with ALS also inhibited the skin reaction after i.d. injection of ET. These findings are further evidence a mediating role of lymphocytes in the biological effects of ET, among other things in the release of endogenous pyrogen.


Correction: Scaffold Functions of 14-3-3 Adaptors in B Cell Immunoglobulin Class Switch DNA Recombination.
[This corrects the article DOI: 10.1371/journal.pone.0080414.].


Molecular interaction fields (MIFs) to predict lipophilicity and ADME profile of antitumor Pt(II) complexes.
To describe a computational tool to calculate molecular descriptors of potential application in ADME virtual screening of antitumor Pt(II) drug candidates. The multistep computational procedure consists in (a) building and optimization (PM3) of the 3D structures of the investigated complexes, (b) parametrization of Pt(II) and its implementation in GRID, (c) GRID calculations and extraction of the information content with VolSurf and BIOCUBE4mf, and (d) PLS analysis to look for the correlation between experimental data and the molecular descriptors. The following results were obtained: (a) the calibration of the GRID force field to take into account the platinum di-cation, (b) solid PLS models between log k30 and log kw with VolSurf descriptors which highlight the main structural differences between the two chromatographic parameters, (c) the prediction of virtual (of each conformer) log k30 and log kw, and (d) the identification of the main descriptors governing VD(ss) of drugs in clinical use. The study suggests a strategy to identify good Pt(II) complexes prior to their synthesis to eliminate as soon as possible drug candidates with unfavorable PK profile.


Optimizing ultrathin Ag films for high performance oxide-metal-oxide flexible transparent electrodes through surface energy modulation and template-stripping procedures.
Among new flexible transparent conductive electrode (TCE) candidates, ultrathin Ag film (UTAF) is attractive for its extremely low resistance and relatively high transparency. However, the performances of UTAF based TCEs critically depend on the threshold thickness for growth of continuous Ag films and the film morphologies. Here, we demonstrate that these two parameters could be strongly altered through the modulation of substrate surface energy. By minimizing the surface energy difference between the Ag film and substrate, a 9 nm UTAF with a sheet resistance down to 6.9 Ω sq-1 can be obtained using an electron-beam evaporation process. The resultant UTAF is completely continuous and exhibits smoother morphologies and smaller optical absorbances in comparison to the counterpart of granular-type Ag film at the same thickness without surface modulation. Template-stripping procedure is further developed to transfer the UTAFs to flexible polymer matrixes and construct Al2O3/Ag/MoOx (AAM) electrodes with excellent surface morphology as well as optical and electronic characteristics, including a root-mean-square roughness below 0.21 nm, a transparency up to 93.85% at 550 nm and a sheet resistance as low as 7.39 Ω sq-1. These AAM based electrodes also show superiority in mechanical robustness, thermal oxidation stability and shape memory property.


Possible abscopal effect in urothelial carcinoma of the upper urinary tract after treatment with immune checkpoint inhibitors.
Regression of non-irradiated metastatic lesions after radiation therapy is known as the abscopal effect. We report a case of urothelial carcinoma in which the abscopal effect was possibly observed after immune checkpoint inhibitor administration. A 68-year-old woman diagnosed with left renal pelvic cancer underwent total nephroureterectomy and regional lymph node dissection. Eight months later, imaging studies detected local recurrence and paraaortic lymph node metastasis. The tumor progressed despite cisplatin + gemcitabine, pembrolizumab, and gemcitabine + docetaxel therapy. Radiation therapy was administered to a painful back lesion, which resulted in dramatic symptom relief. Computed tomography 2 months after radiation therapy indicated reduced size of the irradiated lesion and some non-irradiated lymph nodes. Combined radiation therapy and immune checkpoint inhibitors can provide additional benefits for certain cancers, possibly due to negative immunomodulatory response blockade. Thus, this combined therapy may be a new metastatic urothelial carcinoma treatment strategy.


Many birds with one stone: targeting the (p)ppGpp signaling pathway of bacteria to improve antimicrobial therapy.
Winning the war against resistant bacteria will require a change of paradigm in antibiotic discovery. A promising new direction is the targeting of non-essential pathways required for successful infection, such as quorum-sensing, virulence, and biofilm formation. Similarly important will be strategies to prevent or revert antibiotic resistance. Here, we argue that the (p)ppGpp signaling pathway should be a prime target of this effort, since its inactivation could potentially achieve all these goals simultaneously. The hyperphosphorylated guanine nucleotide (p)ppGpp is an ancient and universal second messenger of bacteria that has pleotropic effects on the physiology of these organisms. Initially described as a stress signal-an alarmone-it is now clear that (p)ppGpp plays a more general and fundamental role in bacterial adaptation, by integrating multiple internal and environmental signals to establish the optimal balance between growth and maintenance functions at any given time. Given such centrality, perturbation of the (p)ppGpp pathway will affect bacteria in multiple ways, from the ability to adjust metabolism to the available nutrients to the capacity to differentiate into developmental forms adapted to colonize different niches. Here, we provide an overview of the (p)ppGpp pathway, how it affects bacterial growth, survival and virulence, and its connection with antibiotic tolerance and persistence. We will emphasize the dysfunctions of cells living without (p)ppGpp and finalize by reviewing the efforts and prospects of developing inhibitors of this pathway, and how these could be employed to improve current antibiotic therapy.


Bias in observational studies on the effectiveness of in hospital use of hydroxychloroquine in COVID-19.
During the first waves of the coronavirus pandemic, evidence on potential effective treatments was urgently needed. Results from observational studies on the effectiveness of hydroxychloroquine (HCQ) were conflicting, potentially due to biases. We aimed to assess the quality of observational studies on HCQ and its relation to effect sizes. PubMed was searched on 15 March 2021 for observational studies on the effectiveness of in-hospital use of HCQ in COVID-19 patients, published between 01/01/2020 and 01/03/2021 on. Study quality was assessed using the ROBINS-I tool. Association between study quality and study characteristics (journal ranking, publication date, and time between submission and publication) and differences between effects sizes found in observational studies compared to those found in RCTs, were assessed using Spearman's correlation. Eighteen of the 33 (55%) included observational studies were scored as critical risk of bias, eleven (33%) as serious risk and only four (12%) as moderate risk of bias. Biases were most often scored as critical in the domains related to selection of participants (n = 13, 39%) and bias due to confounding (n = 8, 24%). There were no significant associations found between the study quality and the characteristics nor between the study quality and the effect estimates. Overall, the quality of observational HCQ studies was heterogeneous. Synthesis of evidence of effectiveness of HCQ in COVID-19 should focus on RCTs and carefully consider the added value and quality of observational evidence.


Association of pre-stroke frailty and health-related factors with post-stroke functional independence among community-dwelling Chinese older adults.
Frailty is associated with a range of poor post-stroke outcomes. There is still a lack of comprehensive understanding of the temporal relationship between pre-stroke frailty status and other related factors with functional recovery after stroke. This study aims to evaluate pre-stroke frailty status and health-related factors associated with functional independence among community-dwelling Chinese older adults. The dataset based on the China Health and Retirement Longitudinal Study (CHARLS) conducted in 28 provinces across China was used. The pre-stroke frailty status was assessed using the Physical Frailty Phenotype (PFP) scale with the 2015 wave data. The PFP scale consisted of five criteria with a total score of 5, and categorized into non-frail (0 point), prefrail (1 and 2 points), and frail (3 or more points). Covariates included demographic factors (age, sex, marital status, residence, and education level) and health-related variables (comorbidities, self-reported health status and cognition). Activities of daily living (ADL) and instrumental activities of daily living (IADL) were assessed as the functional outcomes, with difficulties in at least one of the 6 ADL items and 5 IADL items defined as ADL/IADL limitation respectively. A logistic regression model was used to estimate the associations. A total of 666 participants who were newly diagnosed with stroke during the 2018 wave were included. 234 (35.1%) participants were classified as non-frail, 380 (57.1%) participants were classified as prefrail, and 52 (7.8%) participants were classified as frail. Pre-stroke frailty was significantly associated with ADL and IADL limitations post stroke. Additional significant variables with ADL limitation were age, female and more comorbidities. Additional significant variables with IADL limitation were age, female, married or cohabitating, more comorbidities and pre-stroke lower global cognitive score. Frailty status was associated with ADL and IADL limitations after stroke. A more comprehensive assessment of frailty in older people may help to identify those with most significant risk for declining functional capacities after stroke and to develop appropriate intervention strategies.


Salinomyces polonicus: A moderately halophilic kin of the most extremely halotolerant fungus Hortaea werneckii.
A clade where the most halotolerant fungus in the world - Hortaea werneckii, belongs (hereafter referred to as Hortaea werneckii lineage) includes five species: Hortaea werneckii, H. thailandica, Stenella araguata, Eupenidiella venezuelensis, and Magnuscella marina, of which the first species attracts increasing attention of mycologists. The species diversity and phylogenetic relationships within this lineage are weakly known. In this study two moderately halophilic black yeast strains were isolated from brine of graduation tower in Poland. Molecular phylogenetic analyses based on the rDNA ITS1-5.8S-ITS2 (=ITS), rDNA 28S D1-D2 (=LSU), and RNA polymerase II (rpb2) sequences showed that the two strains belong to Hortaea werneckii lineage but cannot be assigned to any described taxa. Accordingly, a new genus and species, Salinomyces and Salinomyces polonicus, are described for this fungus. Furthermore, molecular phylogenetic analyses have revealed that Hortaea thailandica is more closely related to S. polonicus than to H. werneckii. A new combination Salinomyces thailandicus is proposed for this fungus.


A neural network model for coordination of hand gesture during reach to grasp.
In this paper a neural network model for spatio-temporal coordination of hand gesture during prehension is proposed. The model includes a simplified control strategy for whole hand shaping during grasping tasks, that provides a realistic coordination among fingers. This strategy uses the increasing evidence that supports the view of a synergistic control of whole fingers during prehension. In this control scheme, only two parameters are needed to define the evolution of hand shape during the task performance. The proposal involves the design and development of a Library of Hand Gestures consisting of motor primitives for finger pre-shaping of an anthropomorphic dextrous hand. Through computer simulations, we show how neural dynamics of the model leads to simulated grasping movements with human-like kinematic features. The model can provide clear-cut predictions for experimental evaluation at both the behavioural and neural levels as well as a neural control system for a dextrous robotic hand.


Effects of cisplatin on cell cycle kinetics, morphological change, and cleavage pattern of DNA in two human ovarian carcinoma cell lines.
We evaluated the effects of cisplatin on the cell kinetics, cytomorphological changes, and cleavage patterns of DNA in two lines of human ovarian carcinoma cells. KF-1 cells displayed a cell cycle arrest in the G2M phase, while HMG cells displayed a transient cell accumulation in the S phase, without obvious G2M arrest. Morphological changes characterized by condensation and fragmentation of chromatin, and DNA cleavage by oligonucleosome-sized DNA fragments were observed in the HMG cells but not in the KF-1 cells. The pattern of cell death in HMG cells was considered to be apoptosis, but that of KF-1 cells necrosis. These findings showed the different mechanisms of anti-tumor effect of cisplatin on human ovarian carcinoma cell lines, including cell kinetics and pattern of cell death.


Systematic review of cases of acute myelitis in individuals with COVID-19.
An incremental number of cases of acute transverse myelitis (ATM) in individuals with ongoing or recent coronavirus disease 2019 (COVID-19) have been reported. A systematic review was performed of cases of ATM described in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by screening both articles published and in preprint. Twenty cases were identified. There was a slight male predominance (60.0%) and the median age was 56 years. Neurological symptoms first manifested after a mean of 10.3 days from the first onset of classical, mostly respiratory symptoms of COVID-19. Overall, COVID-19 severity was relatively mild. Polymerase chain reaction of cerebrospinal fluid for SARS-CoV-2 was negative in all 14 cases examined. Cerebrospinal fluid findings reflected an inflammatory process in most instances (77.8%). Aquaporin-4 and myelin oligodendrocyte protein antibodies in serum (tested in 10 and nine cases, respectively) were negative. On magnetic resonance imaging, the spinal cord lesions spanned a mean of 9.8 vertebral segments, necrotic-hemorrhagic transformation was present in three cases and two individuals had additional acute motor axonal neuropathy. More than half of the patients received a second immunotherapy regimen. Over a limited follow-up period of several weeks, 90% of individuals recovered either partially or near fully. Although causality cannot readily be inferred, it is possible that cases of ATM occur para- or post-infectiously in COVID-19. All identified reports are anecdotal and case descriptions are heterogeneous. Whether the condition and the observed radiological characteristics are specific to SARS-CoV-2 infection needs to be clarified.


Epstein-Barr Virus-Positive Mucocutaneous Ulcers Complicate Colitis Caused by Immune Checkpoint Regulator Therapy and Associate With Colon Perforation.
Cancer therapy with immune checkpoint inhibitors can cause colitis and colon perforation. We investigated whether infection with Epstein Barr virus (EBV) associates with development and severity of colitis in patients receiving immune checkpoint inhibitor therapies. We performed a retrospective analysis of fixed colon tissues from 16 patients (12 men, 4 women, median age, 69.5 y) with colitis after immune checkpoint inhibitor therapy (9 patients treated with anti-CTLA4, 3 patients treated with anti-PD1, and 4 patients received a combination). Ten tissue samples were biopsies and 6 were collected during resection (4 surgeries for colon perforation). Patients were treated between 2010 and 2018 in the United Kingdom. The tissues were analyzed by pathology, in situ hybridization (to detect EBV-encoded small RNAs [EBERs]), and immunohistochemistry. Clinical data were also collected. Colon tissues from 4 of the 13 patients who received anti-CTLA4 (alone or in combination, 4 with colon perforation) had EBV-positive lymphoproliferations that manifested as florid ulcers associated with polymorphous infiltrates containing EBV-positive blasts (CD30+ or CD30-negative, CD20+, CD3-negative, and EBER+), plasma cells (CD138+, CD20-negative, and EBER+ or EBER-negative), and small B cells (CD20+, CD3-negative, and EBER+ or EBER-negative), consistent with EBV-positive mucocutaneous ulcers (EBVMCUs). In analyses of biopsies collected from 2 patients with EBVMCUs over multiple time points, we found that earlier biopsies had no or only a few EBV-positive cells, whereas 1 later biopsy had EBVMCU and co-infection with cytomegalovirus. EBVMCUs were associated with steroid-refractory colitis (100% of EBV-positive patients vs 12.5% of EBV-negative patients; P = .008) and colon perforation (100% of EBV-positive patients vs no EBV-negative patients; P = .001). We found that colon tissues from 4/13 patients with colitis after anti-CTLA4 therapy (4/6 patients who underwent resection and 4/4 patients with colon perforation) contained EBVMCUs. EBVMCUs seem to arise secondarily in areas of inflamed colon due to immunosuppressive treatment for colitis. EBVMCUs are associated with steroid-refractory colitis and colon perforation.