Residual stroke risk after left atrial appendage closure in patients with prior oral anticoagulation failure.
Patients with atrial fibrillation (AF) and oral anticoagulation (OAC) failure may benefit from left atrial appendage closure (LAAC), however, the evidence is scarce. We report outcomes of LAAC in patients with OAC failure compared to those with classic indications of OAC contraindications. Prospective registry of LAAC with Amplatzer or WATCHMAN device followed by dual antiplatelet therapy (DAPT) was analyzed (05.2014-11.2019). The study group included patients with OAC failure defined as stroke/TIA/PE/LAA thrombus (n = 39) during OAC, whereas the control group consisted of patients with OAC contraindications (n = 156). Structured follow-up at 3, 6, and 12 months was done. The study group compared to controls was younger [73 (IQR, 62-77) vs 74 (IQR, 68-81) years, P = 0.046], with higher CHA2DS2-VASc [5.0 (IQR, 3.0-6.0) vs 4.0 (IQR, 3.0-5.0), P = 0.001)], lower HAS-BLED [2.0 (IQR, 1.0-3.0) vs 3.0 (IQR, 2.0-3.0), P = 0.006] and similar proportion of WATCHMAN implantations (43.6% vs 44.2%, P = 1.000). The reduction from CHA2DS2-VASc predicted to observed annual stroke/TIA/PE rate was markedly smaller in the study vs control group (14% vs 77%) with 10.3% vs 1.9% stroke/TIA/PE respectively (P = 0.031). The reduction from HAS-BLED predicted to observed annual major nonprocedural bleeding rate was higher (100% vs 7.4%) with 0.0% vs 5.1% major bleedings respectively (P = 0.361). The device-related thrombosis remained similar (13.2% vs 11.3%, P = 0.778). Patients after LAAC for OAC failure and unremarkable prior bleeding history presented with high residual stroke and low bleeding risks. Therefore concomitant long-term OAC or prolonged DAPT should strongly be considered in this population.


Personality trait and quality of life in colorectal cancer survivors
To explore the association between quality of life (QOL) and type D personality, which is characterized by the traits of negative affectivity and social inhibition, and to further identify impacts of these traits after controlling for biophysical and psychological factors in colorectal cancer survivors. Cross-sectional and correlational. Oncology and surgical outpatient clinics of a medical center in Taiwan. 124 patients diagnosed with colorectal cancer who had completed active treatment. Data were collected using a set of structured questionnaires to explore type D personality, biophysical and psychological factors, and QOL. Their associations were verified with Mann-Whitney U test and Spearman's rho correlation. Significant factors associated with QOL were identified with generalized estimating equations. Type D personality and QOL. Patients with type D personality experienced higher physical and psychological distress than those with non-type D personality. Social inhibition remained an important factor leading to impairment in the mental component of QOL after controlling for other associated factors. Negative affectivity was associated with fatigue intensity and interference of fatigue with life activities. Personality trait was found to be an important factor associated with QOL. The trait of social inhibition was a significant factor influencing mental aspects of QOL, whereas negative affectivity was associated with fatigue. Assessing patients' personality, including negative affectivity and social inhibition, could help nurses to develop supportive groups or social networks for these patients and thereby improve QOL for cancer survivors.


Bone mineral changes during pregnancy and lactation.
Significant calcium transfer from the mother to the fetus and infant occurs during pregnancy and lactation, theoretically placing the mother at an increased risk for osteoporosis later in life. During pregnancy, intestinal calcium absorption increases to meet much of the fetal calcium needs. Maternal bone loss also may occur in the last months of pregnancy, a time when the fetal skeleton is rapidly mineralizing. The calcium needed for breast milk production is met through renal calcium conservation and, to a greater extent, by mobilization of calcium from the maternal skeleton. Women experience a transient loss of approx 3-7% of their bone density during lactation, which is rapidly regained after weaning. The rate and extent of recovery are influenced by the duration of lactation and postpartum amenorrhea and differ by skeletal site. Additional calcium intake does not prevent bone loss during lactation or enhance the recovery after weaning. The recovery of bone is complete for most women and occurs even with shortly spaced pregnancies. Epidemiologic studies have found that pregnancy and lactation are not associated with an increased risk of osteoporotic fractures.


A molecular portrait of microsatellite instability across multiple cancers.
Microsatellite instability (MSI) refers to the hypermutability of short repetitive sequences in the genome caused by impaired DNA mismatch repair. Although MSI has been studied for decades, large amounts of sequencing data now available allows us to examine the molecular fingerprints of MSI in greater detail. Here, we analyse ∼8,000 exomes and ∼1,000 whole genomes of cancer patients across 23 cancer types. Our analysis reveals that the frequency of MSI events is highly variable within and across tumour types. We also identify genes in DNA repair and oncogenic pathways recurrently subject to MSI and uncover non-coding loci that frequently display MSI. Finally, we propose a highly accurate exome-based predictive model for the MSI phenotype. These results advance our understanding of the genomic drivers and consequences of MSI, and our comprehensive catalogue of tumour-type-specific MSI loci will enable panel-based MSI testing to identify patients who are likely to benefit from immunotherapy.


Insights on the role of periphytic biofilm in synergism with Iris pseudacorus for removing mixture of pharmaceutical contaminants from wastewater.
The potential of Iris pseudacorus and the associated periphytic biofilm for biodegradation of two common pharmaceutical contaminants (PCs) in urban wastewater was assessed individually and in consortium. An enhanced removal for sulfamethoxazole (SMX) was achieved in consortium (59%) compared to individual sets of I. pseudacorus (50%) and periphytic biofilm (7%) at concentration of 5 mg L-1. Conversely, individual sets of periphytic biofilm (77%) outperformed removal of doxylamine succinate (DOX) compared to individual sets of I. pseudacorus (59%) and consortium (67%) at concentration of 1 mg L-1. Enhanced relative abundance of microflora containing microalgae (Sellaphora, Achnanthidium), rhizobacteria (Acidibacter, Azoarcus, Thioalkalivibrio), and fungi (Serendipita) in periphytic biofilm was observed after treatment. SMX treatment for five days elevated cytochrome P450 enzymes' expressions, including aniline hydroxylase (48%) and aminopyrine N-demethylase (54%) in the periphytic biofilm. Nevertheless, I. pseudacorus showed 175% elevation of aniline hydroxylase along with other biotransformation enzymes, such as peroxidase (629%), glutathione S-transferase (514%), and dichloroindophenol reductase (840%). A floating bed phytoreactor planted with I. pseudacorus and the periphytic biofilm consortium removed 67% SMX and 72% DOX in secondary wastewater effluent. Thus, the implementation of this strategy in constructed wetland-based treatment could be beneficial for managing effluents containing PCs.


4-Hydroperoxycyclophosphamide inhibits proliferation by human granulocyte-macrophage colony-forming cells (GM-CFC) but spares more primitive progenitor cells.
Despite its considerable toxicity to haemopoietic colony-forming cells, 4-hydroperoxycyclophosphamide (4-HC) has successfully been used to purge marrow of leukaemic cells before it is used to rescue patients from high-dose chemoradiotherapy. These conflicting observations indicate that haemopoietic progenitor cells that are not detected by the established colony-forming assays survive exposure to 4-HC and repopulate the marrow. The recent finding that murine spleen colony-forming cells (CFU-S) are resistant to 4-HC [Porcellini A, et al. (1983) Expl Hemat. 11 (suppl 14) 331 (abstract)] [14] also indicates that sensitivity to 4-HC can be used to distinguish primitive progenitor cells from committed progenitor cells. As part of a study on the nature of a population of blast colony-forming cells in human bone marrow, we tested their sensitivity to 4-HC to see whether they also are spared by the drug. We found that 4-HC had much less effect on the blast colony-forming cells than on the granulocyte-macrophage colony-forming cells (GM-CFC). This result suggests that the blast-colony-forming cells may be early human haemopoietic progenitor cells.


A universal route to fabricate bacterial cellulose-based composite membranes for simultaneous removal of multiple pollutants.
A self-standing, robust bacterial cellulose (BC)-based multifunctional composite membrane embedded with desirable nano-adsorbents has been successfully fabricated via a facile versatile strategy. As expected, the developed BC-based composite membrane enables the simultaneous and efficient removal of multiple co-existing pollutants.


Biotransformation and toxicity of acetaminophen in congenic RHA rats with or without a hereditary deficiency in bilirubin UDP-glucuronosyltransferase.
Acetaminophen is eliminated primarily by glucuronidation, thereby avoiding cytochrome P450-catalyzed bioactivation to a toxic reactive intermediate. Previous studies have shown that UDP-glucuronosyltransferase-deficient Gunn rats are more susceptible to acetaminophen toxicity than normal Wistar controls, from which the Gunn strain was derived. However, the Gunn and Wistar strains are not congenic, and differences in toxicologic susceptibility could be due in part to genetic differences other than UDP-glucuronosyltransferase activity. Accordingly, acetaminophen (750 mg/kg, ip) was administered to congenic RHA rats with normal (homozygous, RHA/++), moderately deficient (heterozygous, RHA/j+), and severely deficient (homozygous jaundiced, RHA/jj) activities of bilirubin UDP-glucuronosyltransferase. Acetaminophen metabolites were measured by high-performance liquid chromatography and production of the acetaminophen glucuronide conjugate was quantified by the area under plasma concentration-time curve (AUC) from 0 to 2 hr, standardized by the AUC value for acetaminophen in the same animal (glucuronidation ratio = AUC acetaminophen glucuronide/AUC acetaminophen). The 0- to 2-hr time period for AUC calculations was necessitated by the accumulation at later time points of glucuronide and sulfate conjugates in the plasma of animals experiencing severe nephrotoxicity. Acetaminophen bioactivation was quantified by the 24-hr urinary recovery of glutathione-derived conjugates. Hepatotoxicity and nephrotoxicity were assessed respectively by the peak concentrations of plasma alanine aminotransferase (ALT) and blood urea nitrogen (BUN). Glucuronidation of acetaminophen in RHA/jj rats (0.065 +/- 0.005) (mean +/- SE) was reduced 63% compared to the RHA/++ controls (0.17 +/- 0.01) (p < 0.05). RHA/jj rats demonstrated respective 230- and 7-fold increases in the peak plasma concentrations of ALT (17144 +/- 1014 vs 75 +/- 10) and BUN (128 +/- 23 vs 18.4 +/- 0.2) compared to congenic normal controls (RHA/++) (p < 0.05). Heterozygous animals (RHA/j+) demonstrated intermediary toxicity for both parameters (ALT = 2029 +/- 1581, BUN = 41 +/- 16, p < 0.05). Decreased glucuronide production correlated with elevations in ALT (r = -0.86, p < 0.001), while increased acetaminophen bioactivation correlated directly with both elevated ALT (r = 0.93, p < 0.001) and BUN (r = 0.83, p = 0.001). These results using congenic controls demonstrate that the enhanced susceptibility of UDP-glucuronosyltransferase-deficient rats to acetaminophen toxicity is due to decreased glucuronidation resulting in enhanced bioactivation, rather than to other unappreciated genetic differences.


Oscillatory ventilation redux: alternative perspectives on ventilator-induced lung injury in the acute respiratory distress syndrome.
For patients with the acute respiratory distress syndrome (ARDS), ventilation strategies that limit end-expiratory derecruitment and end-inspiratory overdistension are the only interventions to have significantly reduced the morbidity and mortality. For this reason, the use of high-frequency oscillatory ventilation (HFOV) was considered to be an ideal protective strategy, given its reliance on very low tidal volumes cycled at very high rates. However, results from clinical trials in adults with ARDS have demonstrated that HFOV does not improve clinical outcomes. Recent experimental and computational studies have shown that oscillation of a mechanically heterogeneous lung with multiple simultaneous frequencies can reduce parenchymal strain, improve gas exchange, and maintain lung recruitment at lower distending pressures compared to traditional 'single-frequency' HFOV. This review will discuss the theoretical rationale for the use of multiple oscillatory frequencies in ARDS, as well as the mechanisms by which it may reduce the risk for ventilator-induced lung injury.


Untying the regulatory roles of miRNAs in CuO-NPs stress response mechanism in maize: A genome-wide sRNA transcriptome analysis.
MicroRNAs (miRNAs), a group of tiny non-coding RNAs play pivotal role in plant responses to environmental stress. The present small RNA transcriptome study aims to untie the role of miRNAs in CuO-NPs stress adaptation in maize seedlings. Restricted seedling growth, enhanced ROS generation and higher membrane damage were recorded under CuO-NPs [<50 nm, 8 mM] treatment. Deep sequencing reveals 7 up- and 36 down-regulated known miRNAs from CuO-NPs challenged leaves. Gene ontology study demonstrates involvement of CuO-NPs responsive miRNAs in a variety of biological processes including plant growth (miR159a, miR159b), redox homeostasis (miR156e, miR395a), detoxification of heavy metals (miR156e, miR827), signal transduction (miR156e, miR156d), and cell signalling (miR167b-3p, miR393a). Enhanced transcriptional abundance of ABC transporter G family member 41 isoform X2 and HM-associated isoprenylated plant protein 45 isoform X1 might be involved in sequestration and detoxification of excess Cu, essential for metal homeostasis in maize. The miR528-5p mediated up-regulation of superoxide dismutase does not give much protection against CuO-NPs induced oxidative stress damages as evident after histochemical staining with NBT. Moreover, CuO-NPs stress mediated down regulation of miR396 could be an underlying cause of the restricted seedling growth. Taken together, our findings provide insights into the miRNA-guided stress regulatory networks involved in plant's adaptive responses to CuO-NPs stress.


Recent Advances in Serum Biomarkers for Risk Stratification and Patient Management in Cardio-Oncology.
Following significant advancements in cancer therapeutics and survival, the risk of cancer therapy-related cardiotoxicity (CTRC) is increasingly recognized. With ongoing efforts to reduce cardiovascular morbidity and mortality in cancer patients and survivors, cardiac biomarkers have been studied for both risk stratification and monitoring during and after therapy to detect subclinical disease. This article will review the utility for biomarker use throughout the cancer care continuum. A recent meta-analysis shows utility for troponin in monitoring patients at risk for CTRC during cancer therapy. The role for natriuretic peptides is less clear but may be useful in patients receiving proteasome inhibitors. Early studies explore use of myeloperoxidase, growth differentiation factor 15, galectin 3, micro-RNA, and others as novel biomarkers in CTRC. Biomarkers have potential to identify subclinical CTRC and may reveal opportunities for early intervention. Further research is needed to elucidate optimal biomarkers and surveillance strategies.


New Concept Air Conditioning System for the Operating Room to Minimize Patient Cooling and Surgeon Heating: A Historical Control Cohort Study.
Intraoperative hypothermia is a common adverse event. For avoiding the complication due to hypothermia, many warming devices and methods have been used in perioperative period. It has been reported that more patients undergoing laparoscopic surgery tend to have hypothermia than with open surgery. To avoid intraoperative hypothermia, many kinds of warming tools have been used. But, it was also reported that some warming methods increased perceptions of distraction and physical demand. To achieve both patients' normothermia and surgeons' comfort, new air conditioning (AC) system was designed with considering the characteristics of laparoscopic surgery. The temperature of the airflows to the patient and to the surgeons can be adjusted independently in this new system. The new system has two parts. One controls the temperature of the central area over the operation table. The air from this part falls on the patients. The other part is the lateral area beside the operating table; the air from this part falls on the surgeons. The subjects of this study were 160 gastric cancer patients and 316 colorectal cancer patients undergoing laparoscopic surgery. The temperature of the central flow was set 23.5 °C, and the temperature of the lateral flow was set 22 °C just after the anesthesia. The number of timepoints the patient spent in hypothermic state, defined as a temperature cooler by 0.5 °C or more than that at the starting point of surgery, was determined in each patient. In the results, the rate of hypothermic state in old operation rooms was 23.8% and that in new operation rooms was 2.7% in male gastric cancer patients (p < 0.01). And those were 37.1% in old operation rooms and 0.9% in new operation rooms in female gastric cancer patients (p < 0.01). The rate of hypothermic state in old operation rooms was 30.0% and that in new operation rooms was 9.5% in male colorectal cancer patients (p < 0.01). And those were 41.6% in old operation rooms and 8.9% in new operation rooms in female colorectal cancer patients (p < 0.01). The similar results were showed in the study, which subjects were limited the patients undergoing surgery in 2015 and 2016; which were the last year the old operation rooms were used and the first year the new operation rooms were used. Thus, the usefulness of the new air conditioning system for achieving both patients' normothermia and comfort of surgeons could be verified in this study.


Diagnostic value of reduced left atrial compliance during ergometry exercise in heart failure with preserved ejection fraction.
Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging in patients presenting with chronic dyspnoea. We sought to determine the diagnostic value of reduced left atrial (LA) compliance during exercise to diagnose HFpEF. Ergometry exercise stress echocardiography was performed in 225 patients with HFpEF and 262 non-heart failure controls (non-cardiac dyspnoea [NCD]) in Protocol 1, where the diagnosis of HFpEF was defined by the HFA-PEFF algorithm. In Protocol 2, the diagnosis of HFpEF was ascertained by exercise right heart catheterization in 67 participants (49 HFpEF and 18 NCD). Speckle-tracking echocardiography was performed at rest and during exercise to determine LA compliance (ratio of LA reservoir strain to E/e'). As compared with NCD, patients with HFpEF demonstrated decreased LA reservoir strain and compliance at rest, and these differences further increased during exercise in Protocol 1. Exercise LA compliance discriminated HFpEF from NCD (area under the curve 0.87, p < 0.0001), with a superior diagnostic ability to exercise E/e' ratio (DeLong p = 0.005). Exercise LA compliance demonstrated incremental diagnostic value over clinical factors (age, systemic hypertension, and atrial fibrillation) and resting LA compliance (χ2 212.4 vs. 166.2, p < 0.0001). These findings were confirmed in Protocol 2. Left atrial compliance during exercise demonstrated superior diagnostic ability to exercise E/e' ratio, with incremental diagnostic value over the resting LA compliance. Exercise LA compliance may enhance the diagnosis of HFpEF among patients with dyspnoea.


A simple approach to the prediction of soil sorption of organophosphorus pesticides.
Organophosphorus pesticides (OP) affect the crops and environments, and the reliable approach to the prediction of soil sorption of pesticides is required. In this respect, we proposed a simple Chemometrics approach, in which the Tchebichef image moment (TM) method was used to extract useful information from the greyscale images of molecular structures and the quantitative model was established by stepwise regression to predict the soil sorption of OPs. Different squared correlation coefficients including the leave-one-out cross-validation (LOO-CV) (Q2) that concerns the training set and the (R2test) which concerns the external independent test set are more than 0.96. This reflects that the established model has considerably high accuracy and reliability. Compared with the literature on the strategies of quantitative structure-property relationship (QSPR), the proposed method is more suitable, in which the established model shows a high predictive ability. Our study provides another effective approach to predict the soil sorption of OPs and also extends the innovative pathway of QSPR modelling.


Spatial location and hyperacuity: the centre/surround localization contribution function has two substrates.
Vernier acuity and jump detection were investigated using a perturbation technique, in which a flanking line is placed to one side of the target line. The size and direction of vernier displacement, or jump, required for no apparent change of location is strongly influenced by the separation between the flanking line and the test line and by its polarity. For flanks within a zone extending approximately 3'-4' to either side of the target line, the target's location is assigned to a weighted centroid of the complete luminance distribution: The target is pulled towards the flank, when the flank has a positive contrast polarity, and repelled when the polarity is negative. The effects of a dark flank on one side and a bright flank on the other are additive. Outside this central zone repulsion effects are obtained independent of the contrast polarity of the flank and flanks on opposite sides of the target line can cancel each other's influence. Varying the duration of the flank produces maximal effects in the surround with shorter duration than that required for maximal effects in the centre. Thus, while the localization contribution function resembles the popular difference of gaussians receptive field profile, it has two components reflecting differing mechanisms. In the centre the earlier centroid hypothesis can be applied with the addition of distance dependent weights. The surround has characteristics resembling the feature interaction seen in figural after-effects.


Down to earth - A new type of hygiene.
In the current issue of the Biomedical Journal a special section introduces the influence earthing (or lack thereof) has on the human body. A variety of enlightening articles elaborate how electromagnetic hygiene involving earthing may lower the occurrence of various diseases, reduce inflammation, improve sleep and help maintain a well-functioning circadian rhythm. Another article has a closer look at the connection between sunspot extrema and pandemics, and the relief grounding may exert on the main complications encountered in COVID-19 infection. This issue furthermore contains articles about the principles and safety of COVID-19 mRNA vaccines, the use of lidocaine against the cytokine storm triggered by SARS-CoV-2, and hypocalcemia as predictive marker in COVID-19. The reader learns about two miRNAs playing a role in colorectal cancer, diffusion characteristics of cerebrospinal fluid, and an approach of rotational radiography leading to a lower radiation exposure. The final articles present the use of dynamic arthroscopy to refine diagnosis of the origin of shoulder pain, the application of traditional Chinese medicine in analysis of chronic kidney disease, and an exchange concerning neuroimaging abnormalities in pediatric COVID-19 cases.


Three-dimensional bright-field microscopy with isotropic resolution based on multi-view acquisition and image fusion reconstruction.
Optical Projection Tomography (OPT) is a powerful three-dimensional imaging technique used for the observation of millimeter-scaled biological samples, compatible with bright-field and fluorescence contrast. OPT is affected by spatially variant artifacts caused by the fact that light diffraction is not taken into account by the straight-light propagation models used for reconstruction. These artifacts hinder high-resolution imaging with OPT. In this work we show that, by using a multiview imaging approach, a 3D reconstruction of the bright-field contrast can be obtained without the diffraction artifacts typical of OPT, drastically reducing the amount of acquired data, compared to previously reported approaches. The method, purely based on bright-field contrast of the unstained sample, provides a comprehensive picture of the sample anatomy, as demonstrated in vivo on Arabidopsis thaliana and zebrafish embryos. Furthermore, this bright-field reconstruction can be implemented on practically any multi-view light-sheet fluorescence microscope without complex hardware modifications or calibrations, complementing the fluorescence information with tissue anatomy.


Laparoscopic resection of a non-communicating uterine rudimentary horn using intra-operative indigocarmine injection: A case report.
An unicornuate uterus with a non-communicating rudimentary horn (UUNCRH) is a very rare uterine malformation which is difficult to diagnose and to decide the surgical plan. We aim to describe the case of pediatric UUNCRH patient and our operative technique of laparoscopic intra-uterus indigo carmine injection (LIUICI) to confirm that the rudimentary horn (RH) is non-communicating before the resection and review the relevant literature to ascertain the most appropriate treatment option in these patients. A 11-year-old girl who developed progressive severe abdominal pain and dysmenorrhea was referred to our hospital. Uterine malformation and right hematosalpinx was confirmed with magnetic resonance imaging (MRI). Pre-operative treatment with a gonadotropin-releasing hormone agonist enabled improvement in the symptoms. Laparoscopic exploration was scheduled. The right fallopian tube was resected laparoscopically and a 3Fr tube was inserted into its cut end. Indigo carmine injected in the RH through the tube. No leakage of indigo carmine was found from the vagina, indicating the diagnosis of the uterine malformation is an UUNCRH and we performed the resection of the RH safely. In pediatric patients transvaginal detailed examination is not easy to perform. Therefore, diagnostic and operative laparoscopy is critically important for the safe treatment. In addition, laparoscopic removal of a RH can be used to decrease the incidence of adhesions. We found LIUICI technique before the resection of the RH is safe, technically feasible and minimally invasive approach for pediatric UUNCRH patients.


Mood and Sleep Status and Mental Disorders During Prolonged Winter-Over Residence in Two Korean Antarctic Stations.
Antarctica is a region with extreme climate, characterized by extreme cold and photoperiod. No research has been conducted on the mental health of Korean Antarctic dispatchers. The aim of this study was to investigate the status of mental illness and changes in mood and sleep among Korean crew members staying for a long-term period in the Antarctic station. From 2017 to 2020, crew members who were dispatched from South Korea to two Antarctic stations for a one-year period participated in this study. The crew were evaluated for mood and sleep status and mental illness through psychological tests and interviews by board-certified psychiatrists once before departure and twice during their stay in Antarctica. The incidence of mental illness was confirmed and changes in sleep and depression were analyzed. A total of 88 participants were included in the final analysis, and 7 of them (8.0%) were diagnosed with mental disorders such as insomnia in early winter. The total Beck Depression Inventory (BDI) score increased significantly in the early winter period, and the total Insomnia Severity Index (ISI) and Pittsburgh Sleep Quality Inventory (PSQI) scores increased in both early and late winter. The difference in changes in mood and sleep symptoms before, during, and after dispatch between the two stations was not significant. This is the first study to investigate the mental illness and mood and sleep status of Korean crews dispatched to Antarctica. In early winter, there were significant increases in mental illness and depressive symptoms, and a worsening of sleep status.


Ca2+ signalling in cardiogenesis.
A variety of InsP3-dependent Ca2+ signals coded in time, amplitude and space occur during the process of cardiac cell differentiation and heart development. Studies performed in both embryos and embryonic stem cell differentiating in cardiomyocytes have uncovered that Ca2+ regulates multiple steps of these biological processes in vertebrates. These include secretion of cardiogenic factors, cardiac transcriptional cascades and in turn gene expression, myofibrillogenesis and initiation of embryonic pacemaker activity. Evidence is accumulating to foresee Ca2+ as a major second messenger in directing the fate of stem cells and patterning the heart in the embryo.


Trends in depression incidence in China, 1990-2019.
Depression is one of the most widespread health burdens for the general population in China. This study aims to assess the long-term trends of depression incidence in China between 1990 and 2019. The incidence data were drawn from the Global Burden of Disease Study 2019, and an age-period-cohort model was used in the analysis. The net drift was -0.66% (95% CI: -0.79% to -0.53%) per year for both genders. For males, the local drift was lower than 0 (P<0.05) in those aged 10-54 years, and higher than 0 (P<0.05) in those aged 60-69 years. For females, the local drift was lower than 0 (P<0.05) in those aged 10-49 years and higher than 0 (P<0.05) in those aged 55-84 years. Females had a higher risk of depression incidence than males. Compared with the 1990-1994 period, the relative risk (RR) of depression incidence in 2015-2019 decreased by 12.2% in males and 12.3% in females, and compared to the 1903-1907 birth cohort, the cohort RRs in the 2008-2012 birth cohort decreased by 42.1% in males and 34.5% in females. Period and cohort RRs all showed an increased tendency in recent periods and birth cohorts. These data are macrolevel estimates at the national level, may have ecological fallacies. Although the age-standard incidence of depression has declined in China as a whole in the last three decades, the incidence of depression among older individuals has increased. More efforts are needed to promote the mental health of elderly individuals in China.


"It's a horrible assignment": A qualitative study of labor and delivery nurses' experience caring for patients undergoing labor induction for fetal anomalies or fetal demise.
This study sought to explore labor and delivery (L&D) nurses' experiences caring for women undergoing induction for intrauterine fetal demise (IUFD) or termination for fetal anomalies, and to characterize reluctance towards participation in abortion care or - conversely - the commitment to provide services. Researchers conducted a qualitative study that consisted of open-ended, semistructured interviews with 15 registered nurses who care for women on L&D at a large metropolitan hospital. We analyzed these data for content and themes. Labor and delivery nurses struggle emotionally, logistically, and morally with bereavement care, whether their patients are experiencing an IUFD or termination for fetal anomalies. The analysis generated the following themes: the emotionally intense work of perinatal loss, feelings of incompetence in bereavement care, ethical conflicts, and judgment of both termination and IUFD patients. In addition, nurses who chose to provide care for patients undergoing induction termination for fetal anomalies described a duty to care for all patients despite the increased logistic and emotional burden. Much of the discomfort L&D nurses reported caring for patients undergoing induction termination stems from the emotional toll, lack of skills, and bureaucratic burden of bereavement care rather than a moral objection to abortion. Instituting interventions to improve staffing, simplify paperwork, augment bereavement training, and improve support for the emotional burden of caring for these patients may therefore increase access to competent and compassionate abortion care. Labor and delivery nurses struggle with bereavement care whether their patients are experiencing an IUFD or termination for fetal anomalies. Instituting interventions - like interdisciplinary simulation - to support nurses in bereavement care may increase the number willing to participate in abortion care, thereby improving patient access.


Induction of anti-pepsin antibodies after immunization with pepsin-extracted collagen.
Immunization with pepsin-extracted human type II collagen purified by different precipitation steps, although not showing any contamination with the enzyme on SDS-polyacrylamide gel electrophoresis, resulted in the generation of antibodies to the enzyme in addition to an immune response to collagen. These antibodies could be removed by immune absorption on a pepsin affinity column, leaving reactivity to type II collagen unaltered. High performance liquid chromatography on hydroxylapatite columns indicated that pepsin remained associated with the collagen molecules even after repeated precipitation and coeluted with a fraction of the collagen preparation. These results demonstrate that pepsin-extracted collagens may contain minimal amounts of the enzyme. On immunization, these impurities may induce the formation of unwanted antibodies, which might simulate a false specificity of the antibody preparation.


Acquired basal encephalocele.
The radiodiagnostic signs of congenital basal encephalocele are well known. The case history described here shows that a long existing, acquired, traumatic transethmoidal encephalocele can cause the same roentgen appearance. The differences between the congenital and recent posttraumatic forms are indicated.


Renal Implications of Left Renal Vein Ligation for Portal Flow Augmentation in Liver Transplantation.
Spontaneous lienorenal shunts (SLS) siphon blood away from the portal circulation and may compromise portal inflow in liver transplantation (LT). Performing a left renal vein ligation (LRVL) is a relatively easy and efficacious method of overcoming this portal 'steal'. However, given the delicate state of renal function in these patients, its short and long term effects remain undefined. The aim of this study was to evaluate the efficacy of LRVL in augmenting portal flow and safety with regards to renal function. A prospectively collected database of 1638 consecutive LT recipients between January 2010 and August 2020 was reviewed. Twenty-eight patients who underwent LRVL were identified. There were six paediatric recipients, who were analysed separately. Data with regards to imaging, renal function, intraoperative portal hemodynamics, and renal morbidity were analysed. Of the 22 adults, 21 underwent live donor LT. 22.5% had a pre-transplant history of acute kidney injury (AKI). Pre-operative CT demonstrated portal vein thrombosis and SLS in 63.6% and 92.9% of patients respectively. LRVL resulted in a significant augmentation of portal hemodynamics in both the adult and paediatric recipients. Postoperatively, 14.3% and 35.7% of patients developed chylous drain output and AKI respectively. Of 13 patients who underwent CT at various timeframes, 5 patients had a partial re-canalisation of LRV at 6 months. From renal and portal standpoints, LRVL is a safe and effective technique of augmenting portal inflow. Further large-scale multicentre studies and consensus will help define an objective algorithmic approach to LT recipients with SLS.


Sensory, spectrometric (PTR-ToF-MS) and chemometric analyses to distinguish extra virgin from virgin olive oils.
Olive oil samples were obtained from six cultivars grown in different environments, and graded by chemical analyses as extra virgin (EVOOs). These were evaluated for flavors and off-flavors, and relative VOCs spectrum as determined by PTR-ToF-MS. A hierarchical clustering of Panel test data separated olive oil in three groups, one including the samples with perceived off-flavor (VOOs), regardless of cultivar and environment. The Pearson's correlation coefficients between the mass data from PTR-ToF-MS and the sensory characteristics perceived by the Panel test were determined. A mass-to-sensory attributes correlation index was calculated. A color-coded card was built up based on the intensities (ncps) of five selected protonated mass data that was able to distinguish EVOOs from VOOs olive oil samples.


3D endoscopy shows enhanced anatomical details and depth perception vs 2D: a multicentre study.
The current standard endoscopic technique is a high resolution visualisation up to Full HD and even 4 K. A recent development are 3D endoscopes providing a 3-dimensional picture, which supposedly gives additional information of depth, anatomical details and orientation in the surgical field. Since the 3D-endoscopic technique is new, little scientific evidence is known whether the new technique provides advantages for the surgeon compared to the 2D-endoscopic standard technique in FESS. This study compares the standard 2D-endoscopic surgical technique with the new commercially available 3D-endoscopic technique. The prospective randomized interventional multicenter study included a total of 80 referred patients with chronic rhinosinusitis with and without polyps without prior surgery. A bilateral FESS procedure was performed, one side with the 2D-endoscopic technique, the other side with the 3D-endoscopic technique. The time of duration was measured. Additionally, a questionnaire containing 20 items was completed by 4 different surgeons judging subjective impression of visualisation and handling. 2D imaging was superior to 3D apart from "recognition of details", "depth perception" and "3D effect". For usability properties 2D was superior to 3D apart from "weight of endoscopes". Mean duration for surgery was 26.1 min for 2D and 27.4 min. for 3D without statistical significance (P = 0.219). Three-dimensional endoscopy features improved depth perception and recognition of anatomic details but worse overall picture quality. It is useful for teaching purposes, yet 2D techniques provide a better outcome in terms of feasibility for routine endoscopic approaches.


Effect of positive end-expiratory pressure on lung mechanics during anaesthesia in dogs.
We studied supine anaesthetized dogs to determine whether the use of positive end-expiratory pressure to increase functional residual capacity (FRC) could thereby prevent the small lung compliance values frequently reported during anaesthesia. We first made control measurements of FRC and of both static (CSTAT) and dynamic (CDYN) lung compliance. Continuous positive pressure ventilation (CPPV) with 5 cm H2O positive end-expiratory pressure was then commenced, and FRC and compliance measurements were repeated at 15-minute intervals during one hour of CPPV. We found that the positive end-expiratory pressure served to increase FRC to a level expected for unanaesthetized normally breathing dogs in the same posture (J. Appl. Physiol. 36: 93, 1974), and this FRC was well maintained during the one-hour observation period. Despite the volume preservation, we found a marked decline in lung compliance, equal in both CSTAT and CDYN; however, these changes were completely reversed to control values following hyperinflation of lung (artificial sighting). We conclude that diminution in lung compliance in our anaesthetized dogs was not dependent on low lung volume breathing but must have been due to another mechanism such as suppression of sighing or possibly regional hypoventilation. It might well be important to recognize that reversible reduction of compliance may occur despite increase of FRC in patients managed with positive end-expiratory pressure.


Management of base of tongue squamous cell carcinoma: experience with 85 patients in Taipei Veterans General Hospital.
The optimal treatment of base of tongue squamous cell carcinoma (BOTSCC) remains controversial. To optimize treatment planning, this study analyzed the outcomes of patients with BOTSCC treated in Taipei Veterans General Hospital. Retrospective chart reviews were performed for 107 patients with BOTSCC from January 1990 to December 2004, and 85 patients were included, with a mean follow-up interval of 38 months. Patients were divided into surgical and radiotherapy/chemoradiation therapy (RT/CRT) groups. Potentially significant variables for survival were analyzed. The 3-year overall survival (OS) and disease-free survival rates were 40% and 37.1%, respectively. No significant differences in the patient and disease characteristics between the surgical (n = 39) and RT/CRT groups (n = 46) were found. Advanced overall stage (p = 0.034), cervical lymph node metastasis (p = 0.007), and regional recurrence (p = 0.024) were poor prognostic factors for OS. In early-stage disease (Stages I and II), the 3-year OS was higher in the surgical group (68.6%) than in the RT/CRT group (37.5%), but the significance was only borderline (p = 0.071). There was no significant difference in the 3-year OS between the patients in the surgical and CT/CRT groups with advanced-stage disease. In the surgical group, lymphovascular permeation (p = 0.015) and soft-tissue involvement (p = 0.01), determined by pathologic examination, were poor prognostic factors for OS. Recurrence occurred in 35 patients (41.2%), with no significant difference in local, regional, or distant control between the surgical and RT/CRT groups. These findings emphasize the importance of neck disease control in the treatment of BOTSCC. Although currently, RT/CRT is used more frequently, surgery may still have a role in the treatment of early-stage disease. Both surgery with adjuvant therapy and RT/CRT produced equivalent survival rates in the treatment of advanced-stage disease, but the recurrence rate was unsatisfactory. A more effective treatment modality with less early and late toxicity is needed.


CD147 and glioma: a meta-analysis.
Gliomas are the most common primary brain tumors. This meta-analysis aimed to systematically evaluate the relationship between CD147 expression in tissues and the clinicopathological features of patients with glioma. We searched PubMed (1966-2016), EMBASE (1980-2016), Cochrane Library (1996-2016), Web of Science (1945-2016), China National Knowledge Infrastructure (1982-2016), and Wan Fang databases (1988-2016). Quality assessment of the literature was performed using the Newcastle-Ottawa Scale, with Revman 5.3 and Stata 14.0 for analysis. In total, 1806 glioma patients from 19 studies were included, and patients with CD147 overexpression had poorer overall survival [hazard ratio (HR) = 2.211, P < 0.0001], a higher risk of recurrence (HR = 2.20, P = 0.0025), and a lower 5-year survival rate [odds ratio (OR) 0.12; 95% CI 0.08-0.19; P < 0.00001]. We observed significant differences in CD147 expression when comparing glioma tissues versus non-cancerous brain tissues (OR 20.42; 95% CI 13.94-29.91; P < 0.00001), tumor grades III-IV versus grades I-II (OR 5.88, 95% CI 4.15-8.34; P < 0.00001), and large versus small tumors (OR 1.58, 95% CI 1.04-2.40; P = 0.03). We also observed a significant correlation with matrix metalloproteinase (MMP) 2 (OR 39.11, 95% CI 11.47-133.34; P < 0.00001) and MMP9 (OR 13.35, 95% CI 4.67-38.18; P < 0.00001). CD147 expression did not differ based on patient's age (young vs. old, P = 0.89) or gender (female vs. male, P = 0.57). CD147 expression may be a potential prognostic biomarker for poorer overall and relapse-free survival, and may affect the 5-year survival rate in glioma patients. CD147 expression is also closely correlated with poor clinical characteristics in glioma patients.


Experimental evaluation of rigor mortis. V. Effect of various temperatures on the evolution of rigor mortis.
Objective measurements were carried out to study the evolution of rigor mortis on rats at various temperatures. Our experiments showed that: (1) at 6 degrees C rigor mortis reaches full development between 48 and 60 hours post mortem, and is resolved at 168 hours post mortem; (2) at 24 degrees C rigor mortis reaches full development at 5 hours post mortem, and is resolved at 16 hours post mortem; (3) at 37 degrees C rigor mortis reaches full development at 3 hours post mortem, and is resolved at 6 hours post mortem; (4) the intensity of rigor mortis grows with increase in temperature (difference between values obtained at 24 degrees C and 37 degrees C); and (5) and 6 degrees C a "cold rigidity" was found, in addition to and independent of rigor mortis.


Considerations with Fractures of the Posterior Malleolus in Ankle Fractures.
Foot and ankle surgeons are commonly confronted with the surgical dilemma on when and how to best surgically address trimalleolar ankle fractures with a posterior malleolar component. This may involve either direct fixation of the posterior malleolus or indirect stabilization with the fixation of the medial and lateral malleoli and trans-syndesmotic fixation. Recently there has been a paradigm shift in the management of these injuries with a more thorough understanding of anatomy, stability, and long-term sequela of these injuries. This article aims to evaluate the current literature on posterior malleolar ankle fractures, approaches to fixing the posterior malleolus, and outcomes and complications of these procedures.


Double-valence photoionization of SUVA134a molecule (CFH2 CF3 ).
In this work we investigate the single-photon double ionization of the SUVA 134a (1,1,1,2-tetrafluoroethane) molecule in the energy range from 21.21 to 320 eV. Our experimental data are supported by Thomas' and Samson's models. It is shown that the double photoionization of the SUVA 134a can be expressed as a sum of the so-called shake-off (SO) and the knockout (KO) processes. The experiments were executed at the TGM beamline at Laboratório Nacional de Luz Síncrotron in Campinas, Brazil. The source of EUV and X-ray radiation was a bending magnet that enabled us to work in the photon energy range of 21.21 to 320 eV. The spectrometer was devised to collect 100% of the ions with kinetic energies up to 30 eV. The photoelectron-photoion (PEPICO) and photoelectron-photoion-photoion (PE2PICO) coincidence techniques were used in the present work. The ratio of double-to-total photoionization as a function of the photon energy for the SUVA molecule exhibits remarkably similar behavior with other atomic and molecular systems. SO depends on large excess energy above the ionization threshold, enabling the photoelectron to leave the interaction region rather speedily to yield a sudden change in the Coulomb field that the shaken electron feels. The measured asymptotic SO probability is PSO (∞) = 0.09. The present analysis shows that the separation of SO and KO processes relies on the experimental evidence that there is no significant interference between SO and KO. The analysis also shows that the separate formulation of KO and SO presents a factual portrayal of double photoionization. Despite having 50 electrons, SUVA has lower double-to-total photoionization fraction (9%) in comparison, for instance, to argon atoms (~20%), which has 18 electrons. This lower e-e correlation could be attributed to its larger volume, that is, lower electron density.


QM/MM analysis, synthesis and biological evaluation of epalrestat based mutual-prodrugs for diabetic neuropathy and nephropathy.
Herein, a quantum mechanics/molecular mechanics (QM/MM) based biotransformation study was performed on synthetically feasible mutual-prodrugs of epalrestat which have been identified from an in-house database developed by us. These prodrugs were submitted to quantum polarized ligand docking (QPLD) with the CES1 enzyme followed by MM-GBSA calculation. Electronic aspects of transition state of these prodrugs were also considered to study the catalytic process through density functional theory (DFT). ADMET analysis of prodrugs was then carried out to assess the drug-likeness. On the basis of in-silico results, the best five prodrugs were synthesized and further evaluated for their neuroprotective and nephroprotective potential in high-fat diet-streptozotocin (HFD-STZ) induced diabetes in rat model. Clinically relevant molecular manifestations of diabetic complications (DC) including aldose reductase (ALR2) activity and oxidative stress markers such as reduced glutathione (GSH), catalase (CAT), and thiobarbituric acid reactive substances (TBARS) were determined in blood plasma as well as tissues of the brain and kidneys. The histopathological examination of these organs was also carried out to see the improvement in structural deformities caused due to neuropathy and nephropathy. Finally, in-vivo pharmacokinetic study was performed for the best two prodrugs to assess the improvement in biopharmaceutical attributes of parent drugs. Overall, EP-G-MFA and EP-MFA have significantly reduced the hyperglycemia-induced ALR2 activity, levels of oxidative stress markers, and manifested about a two-fold increase in the biological half-life (T1/2) of parent drugs. The overall findings of this study suggest that methyl ferulate conjugated prodrugs of epalrestat may be considered as potential protective agents in diabetic neuropathy and nephropathy.


Multi-parametric MRI in the diagnosis and scoring of gastrointestinal acute graft-versus-host disease.
Acute gastrointestinal graft-versus-host disease (GI-aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation (HSCT). Diagnosis relies on clinical, endoscopic, and pathological investigations. Our purpose is to assess the value of magnetic resonance imaging (MRI) in the diagnosis, staging, and prediction of GI-aGVHD-related mortality. Twenty-one hematological patients who underwent MRI for clinical suspicion of acute GI-GVHD were retrospectively selected. Three independent radiologists, blinded to the clinical findings, reanalyzed MRI images. The GI tract was evaluated from stomach to rectum by analyzing fifteen MRI signs suggestive of intestinal and peritoneal inflammation. All selected patients underwent colonoscopy with biopsies. Disease severity was determined on the basis of clinical criteria, identifying 4 stages of increasing severity. Disease-related mortality was also assessed. The diagnosis of GI-aGVHD was histologically confirmed with biopsy in 13 patients (61.9%). Using 6 major signs (diagnostic score), MRI showed 84.6% sensitivity and 100% specificity in identifying GI-aGVHD (AUC = 0.962; 95% confidence interval 0.891-1). The proximal, middle, and distal ileum were the segments most frequently affected by the disease (84.6%). Using all 15 signs of inflammation (severity score), MRI showed 100% sensitivity and 90% specificity for 1-month related mortality. No correlation with the clinical score was found. MRI has proved to be an effective tool for diagnosing and scoring GI-aGVHD, with a high prognostic value. If larger studies will confirm these results, MRI could partly replace endoscopy, thus becoming the primary diagnostic tool for GI-aGVHD, being more complete, less invasive, and more easily repeatable. • We have developed a new promising MRI diagnostic score for GI-aGVHD with a sensitivity of 84.6% and specificity of 100%; results are to be confirmed by larger multicentric studies. • This MRI diagnostic score is based on the six MRI signs most frequently associated with GI-aGVHD: small-bowel inflammatory involvement, bowel wall stratification on T2-w images, wall stratification on post-contrast T1-w images, ascites, and edema of retroperitoneal fat and declivous soft tissues. • A broader MRI severity score based on 15 MRI signs showed no correlation with clinical staging but high prognostic value (100% sensitivity, 90% specificity for 1-month related mortality); these results also need to be confirmed by larger studies.


Influence of cypermethrin and fenvalerate on natural soil algal populations.
Two synthetic pyrethroids, cypermethrin and fenvalerate, were assessed for their effects on soil algae. Single or two repeated applications of cypermethrin or a single application of fenvalerate to soil at 0.5 to 1.0 kg ha-1 had no inhibitory effect on algal flora. Two applications of fenvalerate, at concentrations of 0.75 to 5 kg ha-1, resulted in a significant increase in populations of algae. No change in the population size was observed even when either monocrotophos or quinalphos was added between two applications of a pyrethroid, all at the 1.0 kg ha-1 level.


[Intermittent disturbances of perception during fasting in a 46-year-old female patient].
We report the case of a 46-year-old female patient who presented in the emergency department with intermittent disturbances of perception when fasting. In the diagnostic fasting test, a hyperinsulinemic hypoglycemia already occurred after 7h. A sonographic examination was inconspicuous, therefore, a Ga 68-HA-DOTATATE positron emission tomography computed tomography (PET-CT) was carried out. The results were indicative of a neuroendocrine neoplasm, which gave rise to the suspicion of an insulinoma. For surgical treatment the patient was transferred to an external hospital. Following surgery, the patient was free of symptoms. If multiple symptoms of hypoglycemia are present, an insulinoma as the cause must be considered in the differential diagnostics.


[Use of triphthazine in the treatment of mentae disorders].
Clinical experience gained in the Soviet Union shows that Triphthazine (Trifluoperazine) is among the most useful drugs for mass treatment of psychoses. This drug is being widely used in psychiatric practice.


Interferon-alpha-induced morphological changes of megakaryocytes: a histomorphometrical study on bone marrow biopsies in chronic myeloproliferative disorders with excessive thrombocytosis.
Interferon(rIFN)-alpha, a successful therapeutic agent in the control of thrombocytosis, has been shown to suppress human megakaryopoiesis. We investigated bone marrow biopsies from 12 patients with thrombocytosis due to chronic myeloproliferative disorders. Prior to treatment as well as during rIFN-alpha-2c therapy, several morphometric parameters of megakaryopoiesis were evaluated. Megakaryocyte density decreased significantly in all patients, megakaryocyte size decreased in polycythaemia vera, agnogenic myeloid metaplasia, and essential thrombocythaemia, but increased in chronic myeloid leukaemia. The various changes observed during therapy indicate an inhibitory effect of rIFN-alpha-2c on megakaryopoiesis and suggest a selective influence on megakaryocytes at various stages of maturation. Increased numbers of pyknotic (bare) nuclei may reflect a shortening of megakaryocyte life-span. No remarkable changes were found in the fibre content of the bone marrow.


Fungal colonization in patients with cancer of the upper respiratory tract.
Fungal opportunistic infections are a danger for immunocompromised hosts, such as patients with malignancies, especially in a hospital environment. We studied a group of patients with solid tumors of the respiratory tract on admission and after twenty days of hospitalization. Colonization by moulds and/or yeasts was frequently found. Preventive measures should be applied to avoid colonization inside the hospital. The importance of overcrowding, sanitation and diet is pointed out.


Prevalence of FANCM germline variants in BRCA1/2 negative breast and/or ovarian cancer patients from Pakistan.
The Fanconi anemia complementation group M (FANCM) gene is a potential candidate for breast/ovarian cancer susceptibility in European populations. Here, we examined the contribution of FANCM germline variants to hereditary breast and/or ovarian cancer in Pakistan. Comprehensive FANCM variant screening was performed in 201 BRCA1 and BRCA2 (BRCA1/2) negative Pakistani patients with and without triple-negative breast cancer (TNBC) and/or ovarian cancer, using denaturing high-performance liquid chromatography analysis (DHPLC) followed by DNA sequencing. Novel variants were tested for their potential effect on protein function using in silico tools. Reverse transcription (RT)-PCR analysis of RNA extracted from one deletion/insertion (delins) variant (p.K1780delinsNGIT) carrier and three non-carriers was performed to evaluate the impact of this variant on splicing. Furthermore, potentially functional variants were evaluated in 200 healthy female controls. A missense variant (p.V1857M) was identified in a 50-year-old TNBC patient with a family history of breast cancer. It was also identified in the index patient´s daughter, who was diagnosed with osteosarcoma at 15 years of age. Further, one delins variant (p.K1780delinsNGIT) was identified in a 45-year-old non-TNBC patient, but not detected in her brother, who was diagnosed with Hodgkin's lymphoma at 38 years of age. Based on in silico and RNA analyses, p.V1857M and p.K1780delinsNGIT were predicted as variants of uncertain significance (VUS), respectively. Both variants were absent in 200 healthy controls. Our findings suggest a marginal contribution of FANCM variants to hereditary breast/ovarian cancer in Pakistan, which need to be confirmed in larger studies.


Controlled release of a poorly water-soluble drug from hot-melt extrudates containing acrylic polymers.
Controlled release tablets containing a poorly water-soluble drug, indomethacin (IDM), acrylic polymers (Eudragit RD 100, Eudragit L 100, or Eudragit S 100), and triethyl citrate (TEC) were prepared by hot-melt extrusion. The physicochemical and IDM release properties of the controlled release hot-melt extrudates were investigated. Indomethacin (IDM) was found to be both thermally and chemically stable following hot-melt extrusion processing and displayed a plasticizing effect on Eudragit RL PO as demonstrated by a decrease in the glass transition temperatures of the polymer. The inclusion of either Pluronic F68, Eudragit L 100, or Eudragit S 100 in the powder blend containing Eudragit RD 100 prior to processing increased the rate of release of the IDM from the extrudates. An increase in the media pH and a decrease in the granule particle size also increased the rate of release of IDM. The inclusion of TEC up to 8% in the granule formulation or compressing the granules into tablets had no significant effect on the drug release rate. Indomethacin (IDM) was transformed from a crystalline Form I into an amorphous form in the Eudragit RD 100 granules following hot-melt extrusion. The thermal processing facilitated the formation of a solid solution with a continuous matrix structure that was shown to control drug diffusion from the extrudates.


Primary high-grade myoepithelial carcinoma of the lung: A study of three cases illustrating frequent SMARCB1-deficiency and review of the literature.
Primary myoepithelial carcinoma of the lung is exceptionally rare and, hence, remained poorly characterized. We present 3 tumors affecting 2 males and 1 female aged 60 to 84 years. Tumor size ranged from 4 to 10 cm. All presented as well circumscribed non-encapsulated peripheral solitary masses. One patient died postoperatively. The other two were lost to follow-up. Histologically, all tumors were high-grade with predominance of myxoid/chordoid (2) and rhabdoid (1) pattern. Immunohistochemistry (IHC) showed reactivity with vimentin, pankeratin, EMA and smooth muscle actin. Two tumors were SMARCB1-deficient (one with additional loss of SMARCA2 and PBRM1). RNA sequencing revealed no gene fusions. Review of reported cases (total: 16) showed that pulmonary myoepithelial carcinoma affects both sexes equally at a median age of 60 years (24-84), presents predominantly as peripheral masses (69%) in the lower lobes (66%) of smokers (70%) with a median size of 6 cm (1.5-13), and originates as high-grade de novo carcinoma. Forty percent of patients died of disease at a median of 12.5 months (0 to 62). Only 40% of patients were disease free at last follow-up (median, 9.5 months). Prominent lobulation and myxoid stroma were frequent histological features. Most tumors displayed variable combinations of epithelioid, spindle, plasmacytoid, clear, ovoid or round cells. Three of 6 tumors subjected to different RNA panels showed EWSR1 rearrangements (fused to PBX1, ZNF444 or to unknown partner). Two of 3 tumors lacking gene fusions were SMARCB1-deficient (both showed secondary EWSR1 FISH abnormalities due to 22q deletion). Primary pulmonary myoepithelial carcinoma is a rare aggressive malignancy that recapitulates its soft tissue and salivary counterpart. Exclusion of metastasis from other primaries is mandatory and can only be achieved by detailed clinical history and imaging.


Correlated responses in growth hormone to selection for weight gain in mice.
Correlated responses in pituitary gland weight and growth hormone (GH) concentration in the serum and pituitary were studied in lines of mice selected for growth rate, and in controls. The selection criteria were weight gain between 28 and 38 days on an ad libitum feed intake (EPA line), or on intake restricted to 80% of the control mice (EPR line), and weight gain between 48 and 58 days under the above two feeding regimes (LPA and LPR lines). The control line was maintained by random breeding. In generation 13, pituitary weight and growth hormone levels were determined at 38 days in lines EPA, EPR and the control and at 58 days in lines LPA, LPR and the control. Pituitary weight, corrected for body weight gain, was smaller in the EPA line than in the control line at 38 days and was greater in the LPR line than in the control line at 58 days. There were large differences in serum GH concentrations between the selected lines and the control; the differences were statistically significant at 38 days, with the EPA and EPR lines having lower levels than the controls. ZUSAMMENFASSUNG: Veränderung von Wachstumshormonspiegel bei Selektion für Zuwachs bei Mäusen Veränderungen im Hypophysengewicht und Wachstumshormon-(GH)-Konzentrationen im Serum und in der Hypophyse wurden bei Wachstumsselektionslinien und bei Kontrollmäusen untersucht. Selektionskriterien waren Zuwachs zwischen 28 und 38 Tagen bei ad libitum Futteraufnahme (EPA Linie) oder bei Linien, wo Futteraufnahme auf 80% derjenigen der Kontrollmäuse (EPR Linie) begrenzt wurde und Zuwachs zwischen 48 und 58 Tagen unter beiden Futterweisen (LPA und LPR Linie). Die Kontrollinie wurde durch Zufallspaarung fortgepflanzt. In Generation 13 wurden Hypophysengewicht und Wachstumshormonspiegel im Alter von 38 Tagen in Linien EPA, EPR und in Kontrollen und bei 58 Tagen in Linien LPA und LPR und Kontrollen bestimmt. Hypophysengewicht, korrigiert für Zuwachs, war geringer in der LPA Linie als in der Kontrolle bei 38 Tagen Alter und größer in der LPR Linie als in der Kontrolle bei 58 Tagen. Zwischen GH Konzentrationen selektierter und Kontrollinien waren erhebliche Differenzen, die bei 38 Tagen signifikant waren, wobei EPA und EPR Linien geringere Werte als die Kontrollen aufwiesen.


Choice of artificial tear formulation for patients with dry eye: where do we start?
Dry eye is prevalent in many parts of the world. As a result, ophthalmologists and other health care professionals, such as optometrists and general practitioners, often help these patients manage their symptoms. The most common form of treatment for management of dry eye is over-the-counter tear lubricants. A number of tear lubricant formulations are available that vary by their mechanism of action. This article suggests simple guidelines on how lubricants can be selected for patients with mild to moderate dry eye. Side effects of lubricants, such as burning on instillation because of mismatches of eye drop with tear acidity, are also discussed.


SAR by interligand nuclear overhauser effects (ILOEs) based discovery of acylsulfonamide compounds active against Bcl-x(L) and Mcl-1.
Overexpression of antiapoptotic members of the Bcl-2 family proteins, such as Bcl-x(L) and Mfl-1, has been shown to be involved in resistance to chemotherapeutic drugs in many forms of cancers. Recent efforts from the Abbott Laboratories resulted in the development of the acylsulfonamide compound and clinical candidate that targets selectively Bcl-2, Bcl-x(L), and Bcl-w while it is not active against Mcl-1 and Bfl-1. However, early clinical and preclinical studies suggest that pan-Bcl-2 antagonists, targeting simultaneously Mcl-1, Bcl-xL, and possibly all other four antiapoptotic Bcl-2 proteins, may result in more efficacious drugs. Here, following an NMR fragment-based approach, SAR by ILOEs, we report on compounds that exhibit nanomolar affinities for both Bcl-x(L) and Mcl-1 in vitro. We believe that these molecules can be used as useful starting point for the development of novel Bcl-2 antagonists, in particular targeting Mcl-1.


Affect-Related Brain Activity and Adolescent Substance Use: A Systematic Review.
This review aims to summarize the research on brain activity during affective processing (i.e., reward, negative emotional stimuli, loss) and adolescent substance use (SU). Most research revealed links between altered neural activity in midcingulo-insular, frontoparietal and other network regions and adolescent SU. Increased recruitment of midcingulo-insular regions-particularly the striatum-to positive affective stimuli (e.g., monetary reward) was most often associated with initiation and low-level use of substances, whereas decreased recruitment of these regions was most often associated with SUD and higher risk SU. In regards to negative affective stimuli, most research demonstrated increased recruitment of midcingulo-insular network regions. There is also evidence that these associations may be sex-specific. Future research should employ longitudinal designs that assess affect-related brain activity prior to and following SU initiation and escalation. Moreover, examining sex as as moderating variable may help clarify if affective neural risk factors are sex-specific.


Current Status and Future Direction of Nanomedicine: Focus on Advanced Biological and Medical Applications.
Nanotechnology is the engineering and manipulation of materials and devices with sizes in the nanometer range. Colloidal gold, iron oxide nanoparticles and quantum dot semiconductor nanocrystals are examples of nanoparticles, with sizes generally ranging from 1 to 20 nm. These nanotechnologies have been researched tremendously in the last decade and this has led to a new area of "nanomedicine" which is the application of nanotechnology to human health-care for diagnosis, monitoring, treatment, prediction and prevention of diseases. Recently progress has been made in overcoming some of the difficulties in the human use of nanomedicines. In the mid-1990s, Doxil was approved by the FDA, and now various nanoconstructs are on the market and in clinical trials. However, there are many obstacles in the human application of nanomaterials. For translation to clinical use, a detailed understanding is needed of the chemical and physical properties of particles and their pharmacokinetic behavior in the body, including their biodistribution, toxicity, and biocompatibility. In this review, we provide a broad introduction to nanomedicines and discuss the preclinical and clinical trials in which they have been evaluated.


Synergistic efficacy of Bisbenzimidazole and Carbonyl Cyanide 3-Chlorophenylhydrazone combination against MDR bacterial strains.
Activation of efflux systems and the formation of biofilm are majorly adapted by microbes to resist antimicrobial agents. PPEF (bisbenzimidazole) targeting topoisomerase IA is observed to be an effective bactericidal agent against both Gram-positive and Gram-negative bacterial strains and thus can be developed as potent broad-spectrum antibiotic against MDR strains. PPEF treatment did not cause target specific mutation instead it leads to up-regulation of efflux gene in E. coli K12 as a mechanism of resistance. Microscopy, fluorescence spectroscopy and flow cytometry result demonstrate higher accumulation of PPEF in efflux gene deleted E. coli K12 mutants, and also suggest that Carbonyl Cyanide 3-Chlorophenylhydrazone (CCCP), resist the efflux of PPEF, and thus increases efficacy of PPEF. Herein, we report, PPEF and CCCP synergistically killed the persistent bacterial cells, which are not killed by PPEF alone. The above two compounds together inhibited biofilm formation, eradicate preformed biofilms and kills the biofilm cells of P. aeruginosa. PPEF and CCCP together reduced bacterial load of E. coli ATCC25922 by 6 log10 in neutropenic thigh infection model of balb/c mice. Present study suggests that combination therapy could be a promising antimicrobial strategy to handle MDR pathogenic strains.


Evaluating the evidence for assessing BNP and NT-proBNP levels.
To provide an overview of 5 systematic reviews in this issue of Clinical Biochemistry addressing the diagnostic and prognostic power of natriuretic peptides. Editorial. Limited quality of the primary studies and the large variability in their results limit the inferences that can be drawn from reviews in this series. The current data justify neither enthusiastic use, nor confident rejection, of BNP and NT-proBNP levels to inform the prognosis or diagnosis of heart failure.


High density lipoproteins and oxidative stress in breast cancer.
Breast cancer is one of the main leading causes of women death. In recent years, attention has been focused on the role of lipoproteins, alterations of cholesterol metabolism and oxidative stress in the molecular mechanism of breast cancer. A role for high density lipoproteins (HDL) has been proposed, in fact, in addition to the role of reverse cholesterol transport (RCT), HDL exert antioxidant and anti-inflammatory properties, modulate intracellular cholesterol homeostasis, signal transduction and proliferation. Low levels of HDL-Cholesterol (HDL-C) have been demonstrated in patients affected by breast cancer and it has been suggested that low levels of HDL-C could represent a risk factor of breast cancer. Contrasting results have been observed by other authors. Recent studies have demonstrated alterations of the activity of some enzymes associated to HDL surface such as Paraoxonase (PON1), Lecithin-Cholesterol Acyltransferase (LCAT) and Phospholipase A2 (PLA2). Higher levels of markers of lipid peroxidation in plasma or serum of patients have also been observed and suggest dysfunctional HDL in breast cancer patients. The review summarizes results on levels of markers of oxidative stress of plasma lipids and on alterations of enzymes associated to HDL in patients affected by breast cancer. The effects of normal and dysfunctional HDL on human breast cancer cells and molecular mechanisms potentially involved will be also reviewed.


Structural analysis and expression profile of a novel gene on chromosome 5q23 encoding a Golgi-associated protein with six splice variants, and involved within the 5q deletion of a Ph(-) CML patient.
We have identified a novel gene, upstream of the cytokine gene cluster region in 5q23-31, residing within one of the most common deleted segments associated with MDS. The novel gene exhibits significant alternative splicing generating at least six splice variants encoding four putative proline-rich protein isoforms, one of which is Golgi-associated. The gene is ubiquitously expressed and conserved among species with the C. elegans homologue being the most interesting, since it resides within an operon with two other genes, phospholipase D and dishevelled, a member of the Wnt pathway, suggesting a functional association. In addition, the novel gene and other key regulatory genes of the region, such IL3, Ril, AF5q31 and TCF-1, were found to be deleted in an atypical CML case, thus underscoring the significance of this subregion in the leukemogenesis process.


Monodispersed and size-controlled multibranched gold nanoparticles with nanoscale tuning of surface morphology.
A novel seed-mediated synthetic route to produce multibranched gold nanoparticles is reported, in which it is possible to precisely tune both their size and nanostructuration, while maintaining an accurate level of monodispersion. The nanoscale control of surface nanoroughness/branching, ranging from small bud-like features to elongated spikes, allows to obtain fine tuning of the nanoparticle optical properties, up to the red and near-IR region of the spectrum. Such anisotropic nanostructures were demonstrated to be excellent candidates for SERS applications, showing significantly higher signals with respect to the standard spherical nanoparticles.


[Traumatic posterior dislocation of the sternoclavicular joint. A case report of joint stabilization with gracilis tendon graft].
Dislocation of the sternoclavicular joint is an uncommon injury. Especially posterior dislocations with potentially life-threatening complications present a challenging situation for the treating surgeon regarding diagnosis and therapy. Reduction and fixation of the joint is the treatment of choice. We present the case of such an injury in an adolescent judoka who was treated by open reduction and reconstructive surgery using the gracilis tendon graft technique.


[Use of a rotation flap from tissues of the preauricular region and lateral surface of the neck for closing a penetrating defect of the cheek].
The authors use the rotational flap tranfered from the lateral surface of the neck, with one-stage epithelization of the wound surface from the side of the mouth cavity with a split skin graft, to correct the postoperative penetrating defect of the cheek. The necessity of a thorough fixation of the skin graft on the wound surface emphasized.


A genomewide linkage analysis for prostate cancer susceptibility genes in families from Germany.
Prostate cancer is a complex disease with a substantial genetic contribution involved in the disease risk. Several genomewide linkage studies conducted so far have demonstrated a strong heterogeneity of susceptibility. In order to assess candidate regions that are particularly relevant for the German population, we performed a genomewide linkage search on 139 prostate cancer families. A nonparametric method (Zlr scores), using GENEHUNTERPLUS, was applied at 500 markers (panel P1400, deCODE), with an average spacing of 7.25 cM. In the entire family collection, linkage was most evident at 8p22 (Zlr=2.47, P=0.0068), close to the previously identified susceptibility gene MSR1. Further local maxima with Zlr>2 (P<0.025) were observed at 1q, 5q and 15q. In a subgroup of 47 families, which matched the Johns Hopkins criteria of hereditary prostate cancer, suggestive linkage was found on 1p31 (Zlr=3.37, P=0.00038), a previously not described candidate region. The remaining 92 pedigrees, with no strong disease history, revealed a maximum Zlr=3.15 (P=0.00082) at 8q13, possibly indicating a gene with reduced penetrance or recessive inheritance. Our results suggest pronounced locus heterogeneity of prostate cancer susceptibility in Germany. In the present study population, the MSR1 gene could play a significant role. Other conspicuous loci, like 1p31 and 8q13, need further investigation in order to verify their relevance and to identify candidate genes.


Changes in night sky brightness after a countywide LED retrofit.
The US National Park Service (NPS) Night Skies Program measured changes in sky brightness resulting from a countywide lighting retrofit project. The retrofit took place in Chelan County, a gateway community to North Cascades National Park and Lake Chelan National Recreation Area in Washington State. The county retrofitted all 3693 county-owned high pressure sodium (HPS) street lamps to full cutoff LEDs. This number is about 60% of the County's total outdoor street and area lights. About 80% of the newly installed lights were 3000 K in color temperature and 20% were 4000 K. The 4000 K LEDs were used to meet Washington State Department of Transportation guidelines. To measure sky brightness, we used the NPS night sky camera system before the retrofit started in 2018 and after its completion in 2019. These images were photometrically calibrated and mosaicked together to provide hemispherical images in V band. For comparison with our ground-based measurement, we obtained the satellite imagery taken by Visible Infrared Imaging Radiometer Suite (VIIRS) onboard the Suomi National Polar-orbiting Partnership satellite. Our measurements show that the post-retrofit skyglow became brighter and extended higher in the sky, but upward radiance, as measured by the day-night band radiometer, decreased. These divergent results are likely explained by a substantial increase in light emitted at wavelengths shorter than 500 nm, and a relative decrease in upward light emission due to better shielded luminaires. These results also demonstrate that earlier models relating VIIRS day-night band data to skyglow will - at a minimum - require substantial revision to account for the different characteristics of solid state luminaires.


Phase 1/1b Studies of UCB0599, an Oral Inhibitor of α-Synuclein Misfolding, Including a Randomized Study in Parkinson's Disease.
Parkinson's disease (PD) and its progression are thought to be caused and driven by misfolding of α-synuclein (ASYN). UCB0599 is an oral, small-molecule inhibitor of ASYN misfolding, aimed at slowing disease progression. The aim was to investigate safety/tolerability and pharmacokinetics (PK) of single and multiple doses of UCB0599. Safety/tolerability and PK of single and multiple doses of UCB0599 and its metabolites were investigated in two phase 1 studies in healthy participants (HPs), where food effect and possible interaction with itraconazole (ITZ) were assessed (UP0030 [randomized, placebo-controlled, dose-escalation, crossover study, N = 65] and UP0078 [open-label study, N = 22]). Safety/tolerability and multi-dose PK of UCB0599 were subsequently investigated in a phase 1b randomized, double-blind, placebo-controlled study of participants with PD (UP0077 [NCT04875962], N = 31). Across all studies, UCB0599 displayed rapid absorption with linear, time-independent PK properties; PK of multiple doses of UCB0599 were predictable from single-dose exposures. No notable food-effect was observed; co-administration with ITZ affected UCB0599 disposition (maximum plasma concentration and area under the curve increased ~1.3- and ~2 to 3-fold, respectively) however, this did not impact the safety profile. Hypersensitivity reactions were reported in UP0030 (n = 2) and UP0077 (n = 2). Treatment-related adverse events occurred in 43% (UCB0599), and 30% (placebo) of participants with PD were predominantly mild-to-moderate in intensity and were not dose related. Seventy-three HPs and 21 participants with PD received UCB0599 doses; an acceptable safety/tolerability profile and predictable PK support continued development of UCB0599 for the slowing of PD progression. A phase 2 study in early-stage PD is underway (NCT04658186). © 2022 UCB Pharma. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Coarsening of extracellularly biosynthesized cadmium crystal particles induced by thioacetamide in solution.
A novel coarsening route for extracellularly biosynthesized cadmium nanocrystals was investigated for the first time. In this process, the white rot fungus Coriolus versicolor was employed to take up cadmium ions and synthesize extracellular cadmium crystal particles. The coarsening of the particles was induced by thioacetamide under certain conditions. Scanning electron microscopy showed that the formed cadmium crystal particles were coarsened from about 100nm to 2-3μm. The corresponding energy-dispersive X-ray spectra confirmed the presence of proteins in the particles. The maximum removal efficiency of Cd(II) increased from 17% to 87%, and the corresponding sorption capacity of biomass increased from 4 to 24mgg(-1) with the completion of the coarsening process. The properties of the coarsened particles were also examined using X-ray diffraction (XRD) and transmission electron microscopy (TEM). XRD analysis of fungal mycelial pellets embedded with the coarsened particles confirmed the formation of cubic crystalline cadmium sulfide particles. The TEM results suggest that the coarsened particles were composed of clusters of several smaller particles. The changes in the functional groups on the biomass surface were studied through Fourier transform infrared spectroscopy. Based on the results above, a possible mechanism for the formation and coarsening of cadmium crystal particle is also discussed.


Lives or livelihood: Insights from locked-down India due to COVID19.
India is the second most populous country of the world, counted among the most rapidly growing economies of the world. Realizing that a fast spread of COVID19 in India would wipe-out a huge part of the world population, the government of India found itself in a dilemma of whether to save lives or livelihoods. Prioritizing lives for livelihood, the government announced to lockdown the country. This measure is supposed to leave a lasting impact on the economy of the country, which is evident from a cut in the GDP growth forecast by Moody's (from 5.3 per cent to 2.5 per cent for calendar year 2020) within ten days of the earlier projection. This article suggests measures to the government of India to balance between saving lives and sustaining the economy.


Generation and characterization of functional phosphoserine-incorporated neuronal nitric oxide synthase holoenzyme.
Phosphorylation is an important pathway for the regulation of nitric oxide synthase (NOS) at the posttranslational level. However, the molecular underpinnings of NOS regulation by phosphorylations remain unclear to date, mainly because of the problems in making a good amount of active phospho-NOS proteins. Herein, we have established a system in which recombinant rat nNOS holoprotein can be produced with site-specific incorporation of phosphoserine (pSer) at residue 1412, using a specialized bacterial host strain for pSer incorporation. The pSer1412 nNOS protein demonstrates UV-Vis, far-UV CD and fluorescence spectral properties that are identical to those of nNOS overexpressed in other bacterial strains. The protein is also functional, possessing normal NO production and NADPH oxidation activities in the presence of abundant substrate L-Arg. Conversely, the rate of FMN-heme interdomain electron transfer (IET) in pSer1412 nNOS is considerably lower than that of wild-type (wt) nNOS, while the phosphomimetic S1142E mutant possesses similar electron transfer kinetics to that of wt. The successful incorporation and high yield of pSer1412 into rat nNOS and the significant change in the IET kinetics upon the phosphorylation demonstrate a highly useful method for incorporating native phosphorylation sites as a substantial improvement to commonly used phosphomimetics.


[Drugs employed during pregnancy and contraceptive methods in rheumatic disease. New evidence].
Voluntary birth control, the ability to identify the best moment for becoming pregnant depending on disease activity, and the need to avoid conception during the administration of teratogenic drugs are the main reasons for the use of contraceptive methods among women with rheumatic diseases. This article reviews the risks that antirheumatic drugs represent during conception, pregnancy and lactation and the contraceptive methods that are currently available to patients. Hormonal therapy has developed considerably and can further our understanding of safety aspects, especially for systemic lupus erythematosus patients. Recently the methods of administration have evolved, and now include transdermal and intravaginal routes, a progesterone-releasing intrauterine device, and an extended-cycle oral contraceptive. Rheumatologists work increasingly in conjunction with patients to assist in choices regarding contraceptive methods and pregnancy planning. Each decision should be individualized according to the personal preference and the stage of reproductive life.


Effects of fatty acids on Na/Ca exchange in cardiac sarcolemmal membranes.
Three structurally distinct amphiphiles palmitic acid, oleic acid, and palmityl carnitine were studied to determine their effects on sodium dependent calcium uptake by purified cardiac sarcolemmal vesicles (PSL). Sodium dependent calcium uptake by PSL when studied over a 20 min reaction period was composed of an initial rapid uptake (20.9 +/- 0.93 nmol/mg X 30 s, mean +/- S.E. n = 20) a plateau in calcium content (42.4 +/- 3.2 nmol/mg, mean +/- S.E. n = 20) and a slow spontaneous release characterized by a first order rate constant of 0.68 +/- 0.08/h (mean +/- S.E. n = 18). Both palmityl carnitine and palmitic acid inhibited, whereas oleic acid stimulated initial calcium uptake. All three amphiphiles shortened the time to peak calcium content, inhibited peak calcium content and increased the rate constant for calcium release. All these effects were observed at fatty acid: membrane phospholipid mole ratios of 0.67 : 1 to 1.67 : 1 for oleic acid and palmityl carnitine and 0.02 : 1 to 0.42 : 1 for palmitic acid. These effects do not reflect disruption of membrane vesicle structure and may be explained, at least in part, by amphiphile induced increases in sarcolemmal membrane ion permeability. Although amphiphile accumulation has been implicated in the pathogenesis of cellular abnormalities in the ischemic myocardium, this study has shown that large amounts of amphiphile relative to membrane lipid are required to alter sarcolemmal membrane function in vitro.


A QSAR analysis of toxicity of Aconitum alkaloids.
Biological activity of Aconitum alkaloids may be related to their toxicity rather than to a specific pharmacological action. A Quantitative structure-activity relationships (QSAR) analysis was performed on the following two groups of alkaloids: compounds with an aroyl/aroyloxy group at R(14) position (yunaconitine, bulleyaconitine, aconitine, beiwutine, nagarine, 3-acetyl aconitine, and penduline), and compounds with the aroyloxy group at R(4) position (N-deacetyllappaconitine, lappaconitine, ranaconitine, N-deacetylfinaconitine, N-deacetylranaconitine). The LD(50) (micromol/kg) of the 12 alkaloids were obtained from the literature. LD(50) was significantly lower in group 1 than in group 2. The steric and core-core repulsion energies were significantly higher in group 1. The total energy and heat of formation and electronic energies were significantly lower in group 1. The reactivity index of N, C1', C4' and C6' were similar between groups. The reactivity index of C2' was significantly higher and the reactivity index of C3' and C5' were significantly lower in group 1. Log P and pKa were similar between groups. Molecular weight was significantly higher in group 1. A significant linear relationship was observed between log LD(50) and either analgesic log ED(50) or local anesthetic log ED(50). The LD(50)/analgesic ED(50) obtained from average values was 5.9 for group 1 and 5.0 for group 2. However, the LD(50)/local anesthetic ED(50) was 40.4 and 318, respectively. The study supports that the analgesic effects of these alkaloids are secondary to their toxic effects whereas alkaloids from group 2 are susceptible to be further studied as local anesthetic agents.


Studies on thyroid hormone-binding proteins. II. Binding of thyroid hormones, retinol-binding protein, and fluorescent probes to prealbumin and effects of thyroxine on prealbumin subunit self association.
Vitamin A in human plasma is transported by its specific carrier protein, the retinol-binding protein. Under physiological conditions the protein forms a stable protein-protein complex with the tetrameric plasma protein, the thyroxine-binding prealbumin. Human prealbumin was shown to interact with the fluorescent probes 1,8-anilinonaphthalene sulfonate (ANS) and 2-p-toluidinylnaphthalene-6-sulfonate (TNS). ANS bound to the protein at two independent sites with the apparent association constant 3 X 10(5) M-1, whereas TNS interacted with a single site with the binding constant 5 X 10(k) M-1. The fluorescent yield of protein-bound ANS was 0.95, a more than 200-fold enhancement compared with that of ANS in aqueous solutions. TNS enhanced its quantum yield nearly 500-fold to 0.37. On addition of thyroid hormones the fluorescent probes could be quantitatively displaced from the protein. This finding suggested that triiodthyronine, thyroxine, and the probes bound to a common site in prealbumin, which is likely to have a strongly hydrophobic character. The association constants for the interaction between prealbumin and the thyroid hormones could be calculated by using the hormones as competitive inhibitors in the TNS-prealbumin titrations. The data from the competition experiments together with those obtained from equilibrium dialysis revealed one major hormone binding site on the protein. The calculated association constant were 9 X 10(6) M-1 and 1 X 10(8) M-1 for triiodothyronine and thyroxine, respectively. Prealbumin monomers were bound to Sepharose by covalent attachment, and their properties were examined. Evidence was obtained demonstrating that the retinol-binding protein could interact with a single subunit of prealbumin. The estimated apparent association constant for the interaction of the protein and the matrix-bound monomeric prealbumin was 3 X 10(4) M-1, approximately 250-fold lower than that measured for protein and matrix-bound tetrameric prealbumin. The data, however, strongly suggest that there are four retinol-binding protein sites per prealbumin molecule. Using the technique of sedimentation equilibrium ultracentrifugation the prealbumin subunit self-association has been studied. The energy of the interaction for the prealbumin subunits is very high, and various concentrations of guanidine hydrochloride has to be used to perturb the equilibrium. All experiments indicated that prealbumin dissociates directly into monomers without the presence of intermediate forms. Thyroxine perturbed the chemical equilibrium of the prealbumin monomer-tetramer system by strengthening the interaction between the subunits.


Metals in water, sediments, and biota of an offshore oil exploration area in the Potiguar Basin, Northeastern Brazil.
Metal concentrations were evaluated in water, bottom sediments, and biota in four field campaigns from 2002 to 2004 in the Potiguar Basin, northeastern Brazil, where offshore oil exploration occurs. Analyses were performed by inductively coupled plasma mass spectrometry and inductively coupled plasma optical emission spectrometry. Total metal concentrations in water (dissolved + particulate) and sediments were in the range expected for coastal and oceanic areas. Abnormally high concentrations in waters were only found for Ba (80 μg l(-1)) and Mn (12 μg l(-1)) at the releasing point of one of the outfalls, and for the other metals, concentrations in water were found in stations closer to shore, suggesting continental inputs. In bottom sediments, only Fe and Mn showed abnormal concentrations closer to the effluent releasing point. Metal spatial distribution in shelf sediments showed the influence of the silt-clay fraction distribution, with deeper stations at the edge of the continental shelf, which are much richer in silt-clay fraction showing higher concentrations than shallower sediments typically dominated by carbonates. Metal concentrations in estuarine (mollusks and crustaceans) and marine (fish) organisms showed highest concentrations in oysters (Crassostrea rhizophorae). Fish tissues metal concentrations were similar between the continental shelf influenced by the oil exploration area and a control site. The results were within the range of concentrations reported for pristine environments without metals contamination. The global results suggest small, if any, alteration in metal concentrations due to the oil exploration activity in the Potiguar Basin. For monitoring purposes, the continental inputs and the distribution of the clay-silt fraction need to be taken into consideration for interpreting environmental monitoring results.


Sex Differences in Internalizing Symptoms and Amygdala Functional Connectivity in Neurotypical Youth.
Amygdala resting-state functional connectivity (rsFC) is altered in adolescents with internalizing disorders, though the relationship between rsFC and subclinical symptomatology in neurotypical youth remains unclear. Here we examined whether amygdala rsFC varied across a continuum of internalizing symptoms in 110 typically-developing (TD) youths 8 to 17 years old using functional magnetic resonance imaging (fMRI). We assessed overall internalizing symptoms, as well as anxious-depressed, withdrawn-depressed, and somatic complaints. Given known sex differences in the prevalence of internalizing disorders, we compared connectivity between males and females. As compared to males, females with greater internalizing, anxious-depressed, and somatic symptoms displayed greater connectivity with the cingulate gyrus, insula, and somatosensory cortices. In contrast, males with greater anxious-depressed symptoms demonstrated weaker connectivity with the subcallosal prefrontal cortex. Sex differences in rsFC in relation to symptom severity were evident for the whole amygdala and for two of its subnuclei (centromedial and superficial amygdala). Overall, results suggest that, for females, higher internalizing symptoms are associated with greater rsFC between the amygdala and regions implicated in emotional and somatosensory processing, salience detection, and action selection. Future longitudinal investigations are needed to determine whether this hyperconnectivity may confer resilience to, or pose risk for, the development of internalizing disorders.


Lead poisoning from a gunshot wound. Report of a case and review of the literature.
A man was hospitalized on three occasions for symptoms of lead intoxication 20 to 25 years after a gunshot wound that resulted in retention of a lead bullet in his hip joint. The potential for lead toxicity as a complication of a lead missile injury appears to be related to (1) the surface area of lead exposed for dissolution, (2) the location of the lead projectile, and (3) the length of time during which body tissues are exposed to absorbable lead. Cases of lead poisoning of immediate onset resulting from lead shot have been reported in Europe, but all documented cases of ammunition-related plumbism reported in the United States have involved synovial fluid dissolution of a single lead bullet over many years. The solvent characteristics of synovial fluid and associated local arthritis are apparently important factors in the dissolution and absorption of lead from projectiles located in joints. Awareness that lead intoxication can be a complication of retained lead projectiles should allow rapid institution of appropriate diagnostic and therapeutic modalities when such a clinical situation arises.


Molecular cloning and expression profiles of IGFBP-1a in common carp (Cyprinus carpio) and its expression regulation by growth hormone in hepatocytes.
In this study, we cloned and determined IGFBP-1a cDNA from common carp (Cyprinus carpio) liver. The 1655 bp full-length cDNA consisted of a 96 bp 5-untranslated region (UTR), a 789 bp open reading frame encoding 262 amino acid residues and a 770 bp 3-UTR containing seven mRNA instability motifs. Northern blot revealed a 1.8 kb IGFBP-1a transcript. IGFBP-1a mRNA was widely distributed in all tissues examined and predominantly expressed in the liver. During embryogenesis, IGFBP-1a mRNA was firstly observed in blastula stage, and significant increases were observed in body segment stage, lens formation stage and blood cycling stage. After hatching, its expression increased more than twenty times. Furthermore, hypoxia could significantly up-regulate IGFBP-1a expression in the liver and brain. IGFBP-1a expression increased with ovarian maturation and decreased at regressed stage. In testis, IGFBP-1a mRNA maintained relatively higher levels at recrudescing and matured stages, while it sharply declined at regressed stage. In primary cultured hepatocytes, IGFBP-1a gene was greatly down-regulated by growth hormone via the MAPK and PI3 kinase signaling pathways. These results suggest that IGFBP-1a may be involved in the IGF system regulating growth, development and reproduction in common carp.


RTOG quality assurance guidelines for clinical trials using hyperthermia administered by ultrasound.
Clinical quality assurance guidelines are established for RTOG hyperthermia protocols in which unfocused planar ultrasound may be used to administer hyperthermia. Measurement of temperature at a few fixed points is no longer considered to be adequate. Thermal mapping is required to obtain profiles of the temperature across the tumor dimensions, including margins of normal tissue. The thermometry strategies established for microwaves are to be adhered to with oblique insertion of the probes recommended. Two types of errors arise which are generally not present with microwaves. A measurement error, commonly referred to as a temperature artifact, arises because of absorption and/or viscous heating of the probe. Another error arises when thermocouples are used due to the conduction of heat along the wire leads, especially the copper wire. Several thermometry systems are evaluated with regard to the expected artifact and conduction errors. Acceptable systems include: a) indexing a polyurethane sheathed single sensor thermocouple in a polyurethane catheter, b) indexing a fiberoptic probe in a steel needle, c) indexing a single sensor thermocouple in a steel needle, and d) use of manganin-constantan multisensor thermocouples. Unacceptable systems include: a) fixed or static probes that do not provide profiles of the temperature across the tumor dimensions, b) copper-constantan multisensor thermocouples, and c) teflon sheathed thermocouples inserted into a teflon catheter.