NHS recruitment. School daze.
School pupils from ethnic minorities do not see the NHS, and nursing in particular, as offering attractive job opportunities, even in an area of high unemployment. Nursing is perceived as menial, very poorly paid and stressful. Trusts need to improve their literature and send staff into schools to improve recruitment.


Prolonged Altered Mental Status in a Diabetic Hemodialysis Patient.
Osmotic demyelination syndrome (ODS) is a demyelinating disorder of the central nervous system. It usually occurs with rapid correction of severe chronic hyponatremia. ODS is rarely seen as a complication of hyperglycemia. Herein, we report a rare presentation of ODS secondary to hyperosmolar hyperglycemic state. A 28-year-old female with type 1 diabetes, hypertension, seizure disorder, and end-stage renal disease on hemodialysis was brought from a shelter with two days of unresponsiveness and developed ODS after hyperosmolar hyperglycemic state in long-standing uncontrolled diabetes with normal serum electrolyte levels.


Neutrophils and platelets accumulate in the heart, lungs, and kidneys after cardiopulmonary bypass in neonatal pigs.
Cardiac surgery with cardiopulmonary bypass elicits a systemic inflammatory response. An exaggerated response is associated with organ dysfunction and increased morbidity and mortality. The aim of the present study was to investigate whether the cardiopulmonary bypass procedure in itself results in accumulation of isotope-labeled platelets, polymorphonuclear neutrophils, and fibrinogen at organ levels in neonatal pigs and to monitor changes in organ function. Pediatric cardiopulmonary bypass setup with 60 mins of aortic cross-clamp time and 120 mins of hypothermic cardiopulmonary bypass time. Thirty piglets were allocated to sternotomy alone (sham group, n = 15) or to sternotomy and cardiopulmonary bypass (n = 15). Isotope-labeled autologous polymorphonuclear neutrophils, platelets, and commercially available fibrinogen were infused, and the specific accumulation at organ level was measured in a gamma counter 4 hrs after termination of cardiopulmonary bypass. Concomitant changes in oxygenation index and cardiac output were registered. Animals exposed to cardiopulmonary bypass showed a significantly higher technetium-99m-polymorphonuclear neutrophil accumulation in the lungs and kidneys, whereas indium-111-platelets accumulated in the heart and kidneys compared with the sham group. There was a significantly larger increase in oxygenation index and significantly larger decrease in cardiac output between the pre- and postcardiopulmonary bypass period in the cardiopulmonary bypass group compared with the sham group. The cardiopulmonary bypass procedure without cardiac surgery elicits organ dysfunction in terms of impaired respiratory and hemodynamic function. Platelets and polymorphonuclear neutrophils were entrapped in the heart, lungs, and kidneys of cardiopulmonary bypass animals, indicating that cell accumulation may contribute to the developing organ dysfunction.


Transformation system of Beauveria bassiana and Metarhizium anisopliae using nitrate reductase gene of Aspergillus nidulans.
An heterologous transformation system for entomopathogenic fungi B. bassiana and M. anisopliae was developed based on the use of A. nidulans nitrate reductase gene (niaD). B. bassiana and M. anisopliae niaD stable mutants were selected by treatment of protoplast with ethane methane sulphonate (EMS) and regenerated on chlorate medium. The cloned gene was capable of transforming B. bassiana and M. anisopliae at a frequency of 5.8 to 20 transformants per microg of DNA. Most of them were mitotically stable.


Toward Standard Usability Questionnaires for Handheld Augmented Reality.
Usability evaluations are important to improving handheld augmented reality (HAR) systems. However, no standard questionnaire considers perceptual and ergonomic issues found in HAR. The authors performed a systematic literature review to enumerate these issues. Based on these issues, they created a HAR usability scale that consists of comprehensibility and manipulability scales. These scales measure general system usability, ease of understanding the information presented, and ease of handling the device. The questionnaires' validity and reliability were evaluated in four experiments, and the results show that the questionnaires consistently correlate with other subjective and objective measures of usability. The questionnaires also have good reliability based on the Cronbach's alpha. Researchers and professionals can directly use these questionnaires to evaluate their own HAR applications or modify them with the insights presented in this article.


Rapid crystallization of amorphous solid water by porosity induction.
Rapid crystallization of amorphous solid water (ASW) is often associated with crystallization that initiates at random nucleation sites in the bulk and expands in all directions. In this work, by preparing sandwich films of acetonitrile (ACN) and ASW in the form of ACN@ASW and ASW@ACN in an ultrahigh vacuum (UHV), we demonstrate a new method for rapid crystallization of ASW via ACN diffusion-desorption induced porosity in the ASW matrix even in the window of 128-134 K, well below the normal crystallization temperature of 155 K. By placing an HDO (5% D2O in H2O) probe layer in ASW, we found that when ACN diffuses and desorbs through ASW, it induces ASW crystallization where the crystal grows both from the top and from the bottom simultaneously into the bulk. Crystallization kinetics and activation energy (Ea) for the formation of crystalline ice (CI) were evaluated using the Avrami equation and were compared with the previous reports. The evaluated Ea was ∼53 kJ mol-1, close to the Ea of crystal growth (47-56 kJ mol-1) and it suggested the absence of a nucleation process and supported rapid crystallization. Such occurrence of CI due to diffusion of ACN suggests a possible mechanism for the former's existence in many astrophysical environments.


Is total laparoscopic pancreaticoduodenectomy superior to open procedure? A meta-analysis.
Laparoscopy has been widely used in general surgical procedures, but total laparoscopic pancreaticoduodenectomy (TLPD) is still a complex and challenging surgery that is only performed in a small number of patients at a few large academic medical centers. Although the safety and feasibility of TLPD have been established, few studies have compared it with open pancreaticoduodenectomy (OPD) with regard to perioperative and oncological outcomes. Therefore, we carried out a meta-analysis to evaluate whether TLPD is superior to OPD. To compare the treatment outcomes of TLPD and OPD in order to assess the safety and feasibility of TLPD. We conducted a systematic search of studies comparing TLPD with OPD that were published in the PubMed, EMBASE, and Cochrane Library databases through December 31, 2018. The studies comparing TLPD and OPD with at least one of the outcomes we were interested in and with more than 10 cases in each group were included in this analysis. The Newcastle-Ottawa scale was used to assess the quality of the nonrandomized controlled trials and the Jadad scale was used to assess the randomized controlled trials. Intraoperative data, postoperative complications, and oncologic outcomes were evaluated. The meta-analysis was performed using Review Manager Software version 5.3. Random or fixed-effects meta-analyses were undertaken to measure the pooled estimates. A total of 4790 articles were initially identified for our study. After screening, 4762 articles were excluded and 28 studies representing 39771 patients (3543 undergoing TLPD and 36228 undergoing OPD) were eventually included. Patients who underwent TLPD had less intraoperative blood loss [weighted mean difference (WMD) = -260.08 mL, 95% confidence interval (CI): (-336.02, -184.14) mL, P < 0.00001], a lower blood transfusion rate [odds ratio (OR) = 0.51, 95%CI: 0.36-0.72, P = 0.0001], a lower perioperative overall morbidity (OR = 0.82, 95%CI: 0.73-0.92, P = 0.0008), a lower wound infection rate (OR = 0.48, 95%CI: 0.34-0.67, P < 0.0001), a lower pneumonia rate (OR = 0.72, 95%CI: 0.60-0.85, P = 0.0002), a shorter duration of intensive care unit (ICU) stay [WMD = -0.28 d, 95%CI (-2.88, -1.29) d, P < 0.00001] and a shorter length of hospital stay [WMD = -3.05 d, 95%CI (-3.93, -2.17), P < 0.00001], a lower rate of discharge to a new facility (OR = 0.55, 95%CI: 0.39-0.78, P = 0.0008), and a lower 30-d readmission rate (OR = 0.81, 95%CI: 0.68-0.95, P = 0.10) than those who underwent OPD. In addition, the TLPD group had a higher R0 rate (OR = 1.28, 95%CI: 1.13-1.44, P = 0.0001) and more lymph nodes harvested (WMD = 1.32, 95%CI: 0.57-2.06, P = 0.0005) than the OPD group. However, the patients who underwent TLPD experienced a significantly longer operative time (WMD = 77.92 min, 95%CI: 40.89-114.95, P < 0.0001) and had a smaller tumor size than those who underwent OPD [WMD = -0.32 cm, 95%CI: (-0.58, -0.07) cm, P = 0.01]. There were no significant differences between the two groups in the major morbidity, postoperative pancreatic fistula, delayed gastric emptying, postpancreatectomy hemorrhage, bile leak, gastroenteric anastomosis fistula, intra-abdominal abscess, bowel obstruction, fluid collection, reoperation, ICU admission, or 30-d and 90-d mortality rates. For malignant tumors, the 1-, 2-, 3-, 4- and 5-year overall survival rates were not significantly different between the two groups. This meta-analysis indicates that TLPD is safe and feasible, and may be a desirable alternative to OPD, although a longer operative time is needed and only smaller tumors can be treated.


Adolescence: psychopathological discomfort, distress or psychiatric disorder? Clinical experience, description and analysis of a sample.
The aim of this study was to highlight how many psychopathological disorders emerging during adolescence are not easily detectable and interpretable. We investigated the social, emotional and demographic factors related to psychopathological distress, measuring the overall functioning of the child/adolescent and the consequent impact on academic and social functioning, along with its implications on the emergence of feelings of discomfort and anxiety. Many psychopathological disorders are easily detectable and diagnosable in this particular stage of life, and although they are rooted in adolescent distress, they can generate real psychiatric disorders. The data emerging from clinical practice stress the need for a comprehensive in order to identify possible subclinical symptoms for onset of mental illness, so as to be able to implement more targeted and less invasive therapeutic strategies.


Pain, Depression and Inflammation: Are Interconnected Causative Factors Involved?
Co-morbid depression and chronic pain are highly prevalent. The purpose of this review is to examine the role of chronic inflammation as a common mediator of these co-morbidities. Dysfunctional bidirectional pathways between the brain and the immune, endocrine and neurotransmitter systems have been extensively described and implicated in pain and psychiatric disorders. This short review therefore accesses the evidence in favour of the psychoneuroendocrine hypothesis of psychiatric disorders under three main headings: (1) by illustrating how different types of stress play a crucial role in initiating chronic inflammation in major depression, (2) by accessing the evidence that pain is frequently an important component of, and an initiator of, depression, and (3) considering the evidence that chronic inflammation provides an important link between chronic pain and depression, and the possible cellular mechanisms involved in this process. By understanding the critical role that chronic inflammation plays in pain and depression, novel approaches to the development of drugs may emerge that offer improvements in treatment.


HNF1B expression regulates ECI2 gene expression, potentially serving a role in prostate cancer progression.
Prostate cancer is the most common form of cancer in men, with increased incidence rates observed in older individuals. Prostate cancer is primarily driven via activation of the androgen receptor (AR), the principal transcriptional factor governing prostate cancer cellular programming and its associated metabolism. One of the downstream targets of AR is hepatocyte nuclear factor-1β (HNF1B), an important oncogenic transcription factor in prostate cancer. In the present study, the regulatory role of HNF1B in enoyl-CoA-(Δ) isomerase 2 (ECI2) expression in the transgenic adenocarcinoma of the mouse prostate (TRAMP) mouse model was investigated. Using this model, tumor progression and associated pathological alterations at 12, 18 and 24 weeks were analyzed. Histological sectioning revealed pathological alterations over time, including thickening of glandular epithelial cells (12 weeks), increases in cellular proliferation (18 weeks), and extensive thickening and hardening of the tissue layer (24 weeks). Expression levels of HNF1B and ECI2 proteins were validated by immunohistochemistry and western blotting at different stages of prostate cancer development. HNF1B and ECI2 exhibited minimal differences in protein expression at 12 weeks in TRAMP+ mice. However, by 18 weeks, TRAMP+ mice exhibited multi-fold increases in HNF1B expression levels, along with downregulation of ECI2. These effects were reversed at 24 weeks, indicating an important time-dependent regulation of gene expression. Taken together, these results demonstrated that upon tumor progression, the initial tumor-protective effect of HNF1B is lost along with downregulated expression of HNF1B and increased expression of ECI2.


Oligonucleotide-directed mutagenesis and targeted gene correction: a mechanistic point of view.
Within the last decade, a number of nucleic acid-based gene targeting strategies have been developed with the ultimate goal to cure human genetic disorders caused by mutations. Thus far, site-directed gene targeting is the only procedure that can make predefined alterations in the genome. The advantage of this approach is that expression of the corrected gene is regulated in the same way as a normal gene. In addition, targeted specific mutations can be made in the genome for functional analysis of proteins. Several approaches, including chimeric RNA-DNA oligonucleotides, short single-stranded oligonucleotides, small fragment homologous replacements, and triple-helix-forming oligonucleotides have been used for targeted modification of the genome. Due to the absence of standardized assays and mechanistic studies in the early developmental stages of oligonucleotide-directed gene alteration, it has been difficult to explain the large variations and discrepancies reported. Here, we evaluate the progress in the field, summarize the achievements in understanding the molecular mechanism, and outline the perspective for the future development. This review will emphasize the importance of reliable, sensitive and standardized assays to measure frequencies of gene repair and the use of these assays in mechanistic studies. Such studies have become critical for understanding the gene repair process and setting realistic expectations on the capability of this technology. The conventionally accepted but unproven dogmas of the mechanism of gene repair are challenged and alternative points of view are presented. Another important focus of this review is the development of general selection procedures that are required for practical application of this technology.


Texture-Dependent Adhesion in Polydopamine Nanomembranes.
The conformal nature of in situ polymerization of adhesive dopamine molecules permits the strong underwater adhesion between polydopamine (PDA) nanomembranes and the target substrates. However, the adhesive interaction between the postdeposit PDA nanomembranes and other macrobodies is strongly influenced by the texture of PDA nanomembranes. Here we report the texture-dependent adhesion of PDA nanomembranes both in air and aqueous environments. Despite the nanometer-scale roughness of PDA nanomembranes, interfacial adhesion between PDA nanomembranes and elastomeric bodies are the strong function of the root-mean-square roughness of PDA nanomembranes, root-mean-square gradient of PDA nanomembranes, and the elasticity of the bulk materials. Reduced adhesion due to increased texture is intensified in hydrated conditions, possibly hinting that the conventional explanation of the negative effect of water to adhesion from a molecular level needs to be revisited. These findings can inform the role of adhesive interaction in conformal coatings and provide an explanation for the differential adhesion observed in freestanding PDA nanomembranes.


Prevalence of potential drug-drug interactions among intensive care unit patients receiving linezolid: a cross-sectional study.
Linezolid is commonly used in intensive care units (ICU) but has the potential to interact with other drugs. This study aimed to evaluate the prevalence of potential drug-drug interactions in ICU patients receiving linezolid. Data of ICU patients receiving linezolid were extracted and included in the Hospital Prescription Analysis Program of China, and the risk of potential drug-drug interactions between concomitant drugs and linezolid was evaluated using the Lexicomp database. A total of 3,712 ICU patients from 59 hospitals were included in the analysis, and patients received an average of 17 concomitant drugs. A total of 67.9% of patients had potential drug-drug interactions. Patients receiving concomitant drugs with risk ratings of "X", "D", and "C" categories were 20.8%, 30.4%, and 35.1%, respectively. Opioids were the most frequently prescribed drug class with drug-drug interactions (DDIs) in the "X" category, whereas butorphanol, metoclopramide, and sufentanil were the most contraindicated concomitant drugs. ICU patients receiving linezolid have a high prevalence of potential drug-drug interactions, and efforts should be made to better recognize and manage this risk.


A survey of treatment approaches of malignant ascites in Germany and Austria.
Malignant ascites (MA) is a common manifestation of advanced cancer. Currently, there are no evidence-based guidelines for the management of MA. We conducted a survey with physicians throughout Germany and Austria, to get an overview of current approaches and opinions in the treatment of MA. One hundred and twenty-eight medical oncologists (MO), gastroenterologists (GE), and gynecologists (GYN) completed an electronic questionnaire consisting of 33 questions. Ninety percent of the physicians were from Germany and 10% from Austria; 48% of those were MO, 30% were GYN, and 14% were GE. Most physicians treated an average of 34 patients (pts)/year with MA. Twenty-six percent of these pts suffered from ovarian, 20% from pancreatic, 17% from gastric, and 14% from colorectal cancer. The majority of the physicians associated MA with poor prognosis (92%) and significant reduction in quality of life (87%). One third felt that MA was a contraindication for full dosing of systemic chemotherapy. Paracentesis (PC) was performed in 70% of pts with symptom relieve and quality of life being the main reasons. Almost half of the pts required 3-5 PC, 50% even more than 5 PC during the course of their disease. Only 15% of pts needed multiple PC per week; the majority (79%) needed the procedure either once a week or every 14 days. In 61% of pts, 3-5 L of ascites fluid was drained. Only in 8%, 5 L and more were removed. Volume substitution with IV albumin was performed in 40% of pts. Most pts (55%) had to stay 1-3 h in a healthcare facility for the procedure. However, 21% had to stay ≥1 day. While almost all physicians (89%) performed a PC at some point in the treatment of MA, 75% felt that a systemic chemotherapy and 55% thought a concomitant diuretic therapy were a necessary adjunct. Seven percent of the pts received a targeted treatment with catumaxomab. Repeated PC is the main pillar of treatment of MA; its effect is only temporary and requires significant hospital resources. Further treatment strategies of MA have to be evaluated in prospective studies. Targeted therapies like catumaxomab and VEGF inhibitors should be integrated into these.


[A case of severe falciparum malaria successfully treated with intravenous artesunate and continuous hemodiafiltration].
We report a 54-year-old Japanese man who contracted severe falciparum malaria after visiting West African countries. The patient presented with Plasmodium falciparum parasitemia of 10% on admission and was successfully treated with intravenous artesunate combined with continuous hemodiafiltration. We found that intravenous artesunate had excellent antimalarial activity with rapid parasite clearance and that few adverse effects were observed compared to those reported for intravenous quinine treatment. Supportive therapy was indispensable for saving the life of the patient. Few cases of intravenous artesunate treatment are reported in Japan because the drug has not been legally registered. We wish to emphasize the efficacy of intravenous artesunate with general supportive therapy in the treatment of possible imported severe malaria patients in Japanese medical settings.


Plantar pressure differences among adults with mild flexible flatfoot, severe flexible flatfoot and normal foot when walking on level surface, walking upstairs and downstairs.
[Purpose] This study observed the plantar pressure between flexible flatfoot and normal foot on different walking conditions to find out if flexible flatfoot needs the treatment and how the plantar pressure change while walking upstairs and downstairs. [Subjects and Methods] Fifteen adults with mild flexible flatfoot, fifteen adults with severe flexible flatfoot and fifteen adults with normal foot were examined while walking on a level surface, walking up and down 10 cm and 20 cm stairs. The max force and the arch index were acquired using the RSscan system. The repeated measures ANOVA was performed to analyze the data. [Results] Compared with normal foot, both max force and arch index of severe flatfoot were significantly increased on different walking conditions. When walking down 10 cm and 20 cm stairs, the plantar data of both normal foot and flatfoot were significantly increased. [Conclusion] The plantar pressure of severe flexible flatfoot were significantly larger than that of normal foot on different walking conditions. In addition, the arches of both normal foot and flatfoot were obviously deformed when walking downstairs. It is therefore necessary to be treated for severe flexible flatfoot to prevent further deformation.


Identification and classification of structural soil conservation measures based on very high resolution stereo satellite data.
Land degradation affects large areas of land around the globe, with grave consequences for those living off the land. Major efforts are being made to implement soil and water conservation measures that counteract soil erosion and help secure vital ecosystem services. However, where and to what extent such measures have been implemented is often not well documented. Knowledge about this could help to identify areas where soil and water conservation measures are successfully supporting sustainable land management, as well as areas requiring urgent rehabilitation of conservation structures such as terraces and bunds. This study explores the potential of the latest satellite-based remote sensing technology for use in assessing and monitoring the extent of existing soil and water conservation structures. We used a set of very high resolution stereo Geoeye-1 satellite data, from which we derived a detailed digital surface model as well as a set of other spectral, terrain, texture, and filtered information layers. We developed and applied an object-based classification approach, working on two segmentation levels. On the coarser level, the aim was to delimit certain landscape zones. Information about these landscape zones is useful in distinguishing different types of soil and water conservation structures, as each zone contains certain specific types of structures. On the finer level, the goal was to extract and identify different types of linear soil and water conservation structures. The classification rules were based mainly on spectral, textural, shape, and topographic properties, and included object relationships. This approach enabled us to identify and separate from other classes the majority (78.5%) of terraces and bunds, as well as most hillside terraces (81.25%). Omission and commission errors are similar to those obtained by the few existing studies focusing on the same research objective but using different types of remotely sensed data. Based on our results, we estimate that the construction of the conservation structures in our study area in Eritrea required over 300,000 person-days of work, which underlines the huge efforts involved in soil and water conservation.


MiR-30a Inhibits the Epithelial--Mesenchymal Transition of Podocytes through Downregulation of NFATc3.
MicroRNAs (miRNAs) possess an important regulating effect among numerous renal diseases, while their functions in the process of epithelial-to-mesenchymal transition (EMT) after podocyte injury remain unclear. The purpose of our study is to identify the potential functions of miR-30a in EMT of podocytes and explore the underlying mechanisms of miR-30a in the impaired podocytes. The results revealed that downregulation of miR-30a in podocyte injury animal models and patients, highly induced the mesenchymal markers of EMT including Collagen I, Fibronectin and Snail. Furthermore, overexpression of miR-30a enhances epithelial markers (E-cadherin) but diminished mesenchymal markers (Collagen I, Fibronectin and Snail) in podocytes. In addition, we established miR-30a target NFATc3, an important transcription factor of Non-canonical Wnt signaling pathway. More importantly, our findings demonstrated that the augmentation of miR-30a level in podocytes inhibits the nuclear translocation of NFATc3 to protect cytoskeleton disorder or rearrangement. In summary, we uncovered the protective function of miR30a targeting NFATc3 in the regulation of podocyte injury response to EMT.


LC-ion trap electrospray MS-MS for the determination of cyclopiazonic acid in milk samples.
An LC-ESI-MS (negative ions) method was developed for the determination of cyclopiazonic acid (CPA), a mycotoxin produced by many Aspergillus and Penicillium genuses, in milk samples. First, the acquisition parameters of the ESI mass spectrometer were optimised for deprotonated CPA and MS-MS measurements were performed, giving a fragmentation pattern. After this stage, LC separation was applied to milk extracts (with or without CPA spikes) by means of an aminic column, using the selective reaction monitoring (SRM) acquisition mode for MS detection. The CPA response was linear over three decades of concentration and an LOD of 5 ng mL(-1) was estimated; moreover, the extraction procedure produced almost quantitative recoveries of CPA from milk. Twenty different milk samples were analysed and three of them were found to be contaminated with CPA to various extents.


Influences of climate on aflatoxin producing fungi and aflatoxin contamination.
Aflatoxins are potent mycotoxins that cause developmental and immune system suppression, cancer, and death. As a result of regulations intended to reduce human exposure, crop contamination with aflatoxins causes significant economic loss for producers, marketers, and processors of diverse susceptible crops. Aflatoxin contamination occurs when specific fungi in the genus Aspergillus infect crops. Many industries frequently affected by aflatoxin contamination know from experience and anecdote that fluctuations in climate impact the extent of contamination. Climate influences contamination, in part, by direct effects on the causative fungi. As climate shifts, so do the complex communities of aflatoxin-producing fungi. This includes changes in the quantity of aflatoxin-producers in the environment and alterations to fungal community structure. Fluctuations in climate also influence predisposition of hosts to contamination by altering crop development and by affecting insects that create wounds on which aflatoxin-producers proliferate. Aflatoxin contamination is prevalent both in warm humid climates and in irrigated hot deserts. In temperate regions, contamination may be severe during drought. The contamination process is frequently broken down into two phases with the first phase occurring on the developing crop and the second phase affecting the crop after maturation. Rain and temperature influence the phases differently with dry, hot conditions favoring the first and warm, wet conditions favoring the second. Contamination varies with climate both temporally and spatially. Geostatistics and multiple regression analyses have shed light on influences of weather on contamination. Geostatistical analyses have been used to identify recurrent contamination patterns and to match these with environmental variables. In the process environmental conditions with the greatest impact on contamination are identified. Likewise, multiple regression analyses allow ranking of environmental variables based on relative influence on contamination. Understanding the impact of climate may allow development of improved management procedures, better allocation of monitoring efforts, and adjustment of agronomic practices in anticipation of global climate change.


[D-penicillamine--a current review of areas of use and dosage guidelines].
The present paper reviews the different therapeutic uses of D-penicillamine and outlines the dosage regimen of D-penicillamine for treatment of rheumatoid arthritis. While many open clinical trials are published, only a few controlled, double-blind studies investigate the "optimal" dosing of D-penicillamine. From these findings, a uniform regimen cannot be named but the heterogenous appearance of chronic polyarthritis requires an individual therapy. In order to minimize the risk of side effects, however, it is necessary to follow the guideline "go low--go slow" as postulated by Jaffe.


[Bladder inverted papilloma. Report of a new case].
Herein we describe an additional case of inverted papilloma of the bladder that had been incidentally discovered. Cystoscopy was required to make the diagnosis, which was confirmed anatomo-pathologically. The clinical and histological features of this disease entity are briefly discussed.


Hormone-like activity of human thrombin.
Recently, we have shown that thrombin is a chemotaxin and growth-promoting agent for cells of the mononuclear phagocytic lineage. These activities are independent of thrombin's enzymatic activity. Unlike other chemotactic factors, thrombin is specific for monocytes and does not attract granulocytes. To further explore the cellular specificity we have used a human leukemia cell line HL-60 that is capable of in vitro differentiation toward either monocytes (HL-60/mono) following incubation with 1,25(OH)2D3, or granulocytes (HL-60/gran) following incubation with DMSO. In contrast to undifferentiated HL-60 cells or HL-60/gran, we find that HL-60/mono respond chemotactically to intact human alpha-thrombin, esterolytically inactive iPR2P-alpha-thrombin, and the thrombin-derived peptide CB67-129, previously shown to contain the thrombin chemotactic exosite. In addition, thrombin induces in HL-60/mono association of actin with the cytoskeleton and causes an increase in levels of free cytosolic Ca2+. These phenomena are well characterized as early events occurring concomitant with directed cell movement associated with exposure to chemotactic agents such as FMLP. Furthermore, in contrast to fibroblasts, both iPR2P-alpha-thrombin and the thrombin chemotactic peptide CB67-129 evoke dose-dependent [3H]TdR incorporation, protein synthesis, and cell replication in growth-arrested J-744 cells, a murine macrophage-like cell line. Limited tryptic digests of CB67-129 lose chemotactic activity but retain full mitogenic activity, demonstrating that as with PDGF, the sites on CB67-129 required for chemotaxis and mitogenesis are clearly dissociable. The mitogenic effects of the CB67-129 digest can be mimicked by a synthetic tetradecapeptide analogue of CB67-129 (residues 367-380) that includes the loop B insertion sequence, previously shown to be critical for thrombin's chemotactic effects. From these data, it is apparent that the loop B insertion is critical for thrombin's nonenzymic biological effects on cells, but additional sites are required for stimulation of cell movement.


Inhibition of endocytic transport by aluminum fluoride implicates GTPases as regulators of endocytosis.
It is now well established that GTP-binding proteins are important regulators of vesicular transport. Recent work has shown that multiple GTPases (both monomeric and heterotrimeric) are required for trafficking. In the present study we have used aluminum fluoride (AIF), a reagent that activates trimeric G proteins, as a tool to study the involvement of this family of GTPases in the regulation of endocytosis in intact cells. Our results indicate that AIF inhibits fusion of early endosomes with an intracellular proteolytic compartment. Using the mixing of sequentially internalized ligands as a measure of endocytosis, we found that AIF inhibited endocytic transport as assessed by both biochemical and morphological methods. Taken together these results suggest that AIF affects membrane fusion, a common step in vesicular transport. To further examine the effects of AIF we tested this compound in a cell-free assay that reconstitutes fusion among endosomes. AIF affected endosomal fusion in a different way than did GTP gamma S, an agent that activates both trimeric and small GTPases. Our results suggest that the coordinated activation of both classes of GTPases are required for efficient endocytic transport.


MicroRNA 155-deficiency leads to decreased autoantibody levels and reduced severity of nephritis and pneumonitis in pristane-induced lupus.
We herein examine the role of endogenous miR155 in the development of systemic manifestations in pristane induced lupus. Systemic lupus in miR155-deficient and wild type mice was induced upon injection of pristane and analyzed after 8 months, PBS-injected mice served as controls. Glomerulonephritis and pneumonitis were quantified using the kidney biopsy score and a newly adapted histomorphometric image analysis system; lung tissue was further analyzed by tissue cytometry. Serum levels of anti-dsDNA, anti-histone and anti-chromatin antibodies were measured by ELISA. Frequencies of B cells, activated and regulatory CD4+ T cells as well as Th1, Th2, Th17 cells were measured by flow cytometry. RT-qPCR was used to measure expression levels of interferon-signature and T-cell subset related as well as miR155-associated genes. After induction of lupus, miR155-deficient mice had significant less pulmonary involvement (perivascular inflammatory area in mm2/mm2 lung area 0.00092±0.00015 vs. 0.0027±0.00075, p = 0.0347) and renal disease (glomerular activity score 1.95±0.19 vs 3±0.26, p = 0.0029) compared to wild types. MiR155-deficient mice had significantly lower serum levels of disease-associated auto-antibodies and decreased frequencies of activated CD4+CD25+ (Foxp3-) cells. Upon restimulation, CD4+ cells showed a less pronounced Th2 and Th17 and a slightly decreased Th1 response in mir155-deficient mice. Pristane-treated wild types showed significantly up-regulated expression of genes related to the INF-signature (MX1, IP10, IRF7, ISG15). MiR155-deficient mice had less severe organ involvement, lower serum auto-antibody levels, a less prominent T cell response and lower expressions of genes jointly responsible for disease development. Thus, antagonizing miR155 might be a future approach in treating SLE.


Genetic enhancement of visual learning by activation of protein kinase C pathways in small groups of rat cortical neurons.
Although learning and memory theories hypothesize that memories are encoded by specific circuits, it has proven difficult to localize learning within a cortical area. Neural network theories predict that activation of a small fraction of the neurons in a circuit can activate that circuit. Consequently, altering the physiology of a small group of neurons might potentiate a specific circuit and enhance learning, thereby localizing learning to that circuit. In this study, we activated protein kinase C (PKC) pathways in small groups of neurons in rat postrhinal (POR) cortex. We microinjected helper virus-free herpes simplex virus vectors that expressed a constitutively active PKC into POR cortex. This PKC was expressed predominantly in glutamatergic and GABAergic neurons in POR cortex. This intervention increased phosphorylation of five PKC substrates that play critical roles in neurotransmitter release (GAP-43 and dynamin) or glutamatergic neurotransmission (specific subunits of AMPA or NMDA receptors and myristoylated alanine-rich C kinase substrate). Additionally, activation of PKC pathways in cultured cortical neurons supported activation-dependent increases in release of glutamate and GABA. This intervention enhanced the learning rate and accuracy of visual object discriminations. In individual rats, the numbers of transfected neurons positively correlated with this learning. During learning, neuronal activity was increased in neurons proximal to the transfected neurons. These results demonstrate that potentiating small groups of glutamatergic and GABAergic neurons in POR cortex enhances visual object learning. More generally, these results suggest that learning can be mediated by specific cortical circuits.


How resilience works.
Why do some people bounce back from life's hardships while others despair? HBR senior editor Diane Coutu looks at the nature of individual and organizational resilience, issues that have gained special urgency in light of the recent terrorist attacks, war, and recession. In the business arena, resilience has found its way onto the list of qualities sought in employees. As one of Coutu's interviewees puts it, "More than education, more than experience, more than training, a person's level of resilience will determine who succeeds and who fails." Theories abound about what produces resilience, but three fundamental characteristics seem to set resilient people and companies apart from others. One or two of these qualities make it possible to bounce back from hardship, but true resilience requires all three. The first characteristic is the capacity to accept and face down reality. In looking hard at reality, we prepare ourselves to act in ways that allow us to endure and survive hardships: We train ourselves how to survive before we ever have to do so. Second, resilient people and organizations possess an ability to find meaning in some aspects of life. And values are just as important as meaning; value systems at resilient companies change very little over the long haul and are used as scaffolding in times of trouble. The third building block of resilience is the ability to improvise. Within an arena of personal capabilities or company rules, the ability to solve problems without the usual or obvious tools is a great strength.


[The estimated glomerular filtration rate in outpatients].
The glomerular filtration rate (GFR) calculated by the MDRD formula was estimated in a population of outpatients aged over 18 years. Serum creatinine concentrations were measured, by using 5 analytical systems: Abbott Architect (n = 9054), Roche Modular (n = 22947), Roche Integra 400 (n = 2748), Roche Integra 700 (n = 8350), and Roche Hitachi (n = 20196). For 4 systems, the distribution of GFR differed little. The exception was the Roche Hitachi analytical system where TE and bias were higher than the acceptable requirements. Therefore, with this system, the proportion of outpatients with a GFR of < 60 ml/min per 1.73 m2 was twice higher than that with the use other analytical systems. Such publications should contain data on the analytical quality of measurement of serum creatinine concentrations in the range of 88 to 140 micromol/l. The estimated GFR may be clinically used provided that the performance of this test will be better than the acceptable analytical quality requirements established by the working NKDEP group.


Fine needle aspiration cytology of primary cutaneous mucinous carcinoma of axilla-report of a rare case.
Primary mucinous eccrine carcinoma is a rare malignant adnexal tumor of older patients. The histopathological features of this tumor are well-established but the cytomorphology of this neoplasm has only been documented in a few cases. The cytology and histology of this tumor may mimic metastatic mucinous carcinoma and may cause a diagnostic dilemma, especially when the tumor is located at axilla. A correct diagnosis is important because the prognosis is better than that of a metastatic mucinous carcinoma. Here we report the cytological and histological features of a case of primary cutaneous mucinous carcinoma of axilla in an elderly male patient.


Nonlinear diffusion in multicomponent liquid solutions.
Mutual diffusion in multicomponent liquids is studied. It is taken into consideration that the influence of complex formation on the diffusion process may be substantial. The theory is applied to analyze mass transfer in an acetone-chloroform solution. The molecular complex concentration was obtained from the analysis of Fourier transform infrared spectra of this solution. Taking into account molecular complex formation allows one to explain the experimental dependence of diffusion coefficients on the composition (components concentration). The accuracy of experimental and theoretical data descriptions in the frame of our model is compared to the accuracy for some other approaches.


Effectiveness of imatinib mesylate over etoposide in the treatment of sensitive and resistant chronic myeloid leukaemia cells in vitro.
Chronic myeloid leukaemia (CML) is a form of leukaemia derived from the myeloid cell lineage. Imatinib mesylate, the breakpoint cluster region-abelson murine leukeamia kinase inhibitor, is a specific reagent used in the clinical treatment of CML. The DNA topoisomerase II inhibitor, etoposide, is also employed as a therapeutic, though it is used to a lesser extent. The present study aims to evaluate the effects of CML-targeted therapy, utilising imatinib mesylate and etoposide in the in vitro treatment of parental sensitive and adriamycin-resistant CML in the K562 and K562/ADM cell lines, respectively. Preliminary work involved the screening of multidrug resistant (MDR) gene expression, including MDR1, MRP1 and B-cell lymphoma 2 (BCL-2) at the mRNA levels. The sensitive and resistant CML cell lines expressed the MRP1 gene, though the sensitive K562 cells expressed low, almost undetectable levels of MDR1 and BCL-2 genes relative to the K562/ADM cells. Following treatment with imatinib mesylate or etoposide, the IC50 for imatinib mesylate did not differ between the sensitive and resistant cell lines (0.492±0.024 and 0.378±0.029, respectively), indicating that imatinib mesylate is effective in the treatment of CML regardless of cell chemosensitivity. However, the IC50 for etoposide in sensitive K562 cells was markedly lower than that of K562/ADM cells (50.6±16.5 and 194±8.46 µM, respectively), suggesting that the higher expression levels of MDR1 and/or BCL-2 mRNA in resistant cells may be partially responsible for this effect. This is supported by terminal deoxynucleotidyl transferase dUTP nick-end labeling data, whereby a higher percentage of apoptotic cells were found in the sensitive and resistant K562 cells treated with imatinib mesylate (29.3±0.2 and 31.9±16.7%, respectively), whereas etoposide caused significant apoptosis of sensitive K562 cells (18.3±8.35%) relative to K562/ADM cells (5.17±3.3%). In addition, the MDR genes in K562/ADM cells were knocked down by short interfering RNAs. The percentage knockdowns were 15.4% for MRP1, 17.8% for MDR and 30.7% for BCL-2, which resulted in a non-significant difference in the half maximal inhibitory concentration value of K562/ADM cells relative to K562 cells upon treatment with etoposide.


Pyogenic bacterial pneumonia in human immunodeficiency virus-infected inpatients: a clinical, radiological, microbiological, and epidemiological study.
We prospectively studied features of pyogenic bacterial pneumonia in 263 consecutive human immunodeficiency virus-infected inpatients over a 6-month study period. Risk factors for bacterial pneumonia were examined by a case-control study that included 33 cases who presented with at least one episode of bacterial pneumonia and 80 controls without bacterial pneumonia. The estimated cumulative incidence of bacterial pneumonia per year was 12.5 cases per 100 inpatients (95% confidence interval [CI], 8.8-17.2). The 38 episodes of bacterial pneumonia that occurred in the 33 inpatients were mainly unilateral, but 32 episodes were patchy lobar or diffuse infiltrates. Microbiological etiologies were obtained in 33 of the 38 episodes of bacterial pneumonia. Thirty-seven pathogens were identified, including Streptococcus pneumoniae (16, of which 12 had a decreased susceptibility to penicillin), Haemophilus influenzae (6), and Pseudomonas aeruginosa (6). The risk factors for bacterial pneumonia that were identified after logistic regression included prior sinusitis within 1 month before admission (odds ratio [OR], 3.2; 95% CI, 1.1-9.1) and prior bacterial infection of the lower respiratory tract within 6 months before admission (OR, 3.1; 95% CI, 1.1-8.3).


Influence of endothelium and surgical preparation on responses of human saphenous vein and internal thoracic artery to angiotensin II.
1. The saphenous vein (SV) and internal thoracic artery (ITA) are the most commonly used conduits for coronary artery bypass surgery (CABS). The ITA shows better long term patency than the SV, at least in part due to their different responses to agonists, as well as physical differences between the ITA and SV at the time of grafting. 2. Angiotensin II (A II), a potent endogenous vasoconstrictor circulates at augmented levels during and after CABS, but little is known about the effects of A II on the SV and ITA. 3. We studied the contractile effects of A II on SV and ITA as intact rings from a heterogeneous group of patients undergoing CABS. Two groups of SV samples were studied; freshly excised SV (FSV) with no further manipulation and SV that had been surgically prepared for use as a bypass conduit (PSV). We also assessed the function of the endothelium in FSV, PSV and ITA, by measuring the relaxation of preconstricted rings to bradykinin. In some tissues endothelial presence was examined histologically. 4. Surgical preparation of SV affected the contractile ability of the smooth muscle, as PSV contracted less than FSV to potassium chloride (KCl, 90 mM) (P < 0.0001). Loss of endothelial function was seen in 25% of FSV, 50% of PSV and 33% of ITA. 5. A II caused concentration dependent contractions in all rings, over the same concentration range (1 nM-100 nM). In rings of FSV the presence of functional endothelium attenuated the response, median values with endothelium being less than half that without endothelium (P < 0.0007, at 100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)


A Case of Facial Partial Unilateral Lentiginosis Treated with Low-Fluence 1,064 nm Q-Switched Neodymium-Doped Yttrium Aluminum Garnet Laser.
Partial unilateral lentiginosis (PUL) is an unusual pigmentary disorder characterized by numerous lentigines grouped within an area of normal skin. Although treatment is not necessary, many patients with facial PUL seek medical help for cosmetic reasons. There is no established standard treatment for PUL. Conventional lasers may cause postinflammatory hyperpigmentation because keratinocytes are injured during the process. Also, scarring, long downtime, and pain are important issues. A 19-year-old patient with facial PUL was successfully treated with low-fluence 1,064-nm Q-switched neodymium-doped yttrium aluminum garnet (QS Nd:YAG) laser. Although the exact mechanism by which low-fluence 1,064-nm QS Nd:YAG laser improves pigmentary lesions is unclear, the terms "subcellular selective photothermolysis" and "melanocyte apoptosis and replacement" have been proposed. If appropriate measures are taken to monitor patient response during and after the procedure, low-fluence 1,064-nm QS Nd:YAG laser may achieve good cosmetic results in the treatment of PUL with a very safe and effective profile.


Maternal exposure to airborne polychlorinated biphenyls (PCBs) and risk of adverse birth outcomes.
Human health effects of airborne lower-chlorinated polychlorinated biphenyls (LC-PCBs) are largely unexplored. Since PCBs may cross the placenta, maternal exposure could potentially have negative consequences for fetal development. We aimed to determine if exposure to airborne PCB during pregnancy was associated with adverse birth outcomes. In this cohort study, exposed women had lived in PCB contaminated apartments at least one year during the 3.6 years before conception or the entire first trimester of pregnancy. The women and their children were followed for birth outcomes in Danish health registers. Logistic regression was performed to estimate odds ratios (OR) for changes in secondary sex ratio, preterm birth, major congenital malformations, cryptorchidism, and being born small for gestational age. We performed linear regression to estimate difference in birth weight among children of exposed and unexposed mothers. All models were adjusted for maternal age, educational level, ethnicity, and calendar time. We identified 885 exposed pregnancies and 3327 unexposed pregnancies. Relative to unexposed women, exposed women had OR 0.97 (95% CI 0.82, 1.15) for secondary sex ratio, OR 1.13 (95% CI 0.76, 1.67) for preterm birth, OR 1.28 (95% CI 0.81, 2.01) for having a child with major malformations, OR 1.73 (95% CI 1.01, 2.95) for cryptorchidism and OR 1.23 (95% CI 0.88, 1.72) for giving birth to a child born small for gestational age. The difference in birth weight for children of exposed compared to unexposed women was - 32 g (95% CI-79, 14). We observed an increased risk of cryptorchidism among boys after maternal airborne LC-PCB exposure, but due to the proxy measure of exposure, inability to perform dose-response analyses, and the lack of comparable literature, larger cohort studies with direct measures of exposure are needed to investigate the safety of airborne LC-PCB exposure during pregnancy.


Studies of aquatic fungi. XX. Seasonal changes of mycoflora in the pool in the palace park.
Studies of aquatic fungi were carried out in the annual cycle in the years 1987-1989 against a background of hydrochemical relations in the pool in the park of the Medical Academy in Białystok. 59 species of aquatic fungi were found, of which a prevailing number were reported many times in various water reservoirs of Poland. Such species, however, as Diplophlyctis complicata, Nowakowskiella atkinsii, Allomyces moniliformis, Pythium pulchrum, Zoophage phanera, Lemonniera filiforme and Tricladium patulum are new to Polish hydromycoflora. In summer months (July-August) the mycoflora of the pool was poor; the occurrence of various species of aquatic fungi increased in autumn and spring, and less so in winter.


Clinical significance of B7-H4 expression in matched non-small cell lung cancer brain metastases and primary tumors.
B7-H4, a member of the inhibitory B7 family, is shown to have a profound inhibitory effect on the proliferation, activation, cytokine secretion, and development of cytotoxicity of T cells and may be involved in immune evasion in cancer patients. Although B7-H4 expression has been detected in non-small cell lung cancer (NSCLC), there are no published reports on the expression of B7-H4 in brain metastases from NSCLC. We examined the expression of B7-H4 by immunohistochemistry in 49 cases of brain metastatic NSCLC, 18 cases of matched primary NSCLC, and 20 cases of NSCLC patients who had neither brain metastases nor other distant metastases. B7-H4 was highly expressed in 20 (40.8%) out of 49 brain metastases and two (11.1%) out of 18 matched primary tumors. The expression of B7-H4 in brain metastases appeared to be significantly higher than their matched primary tumors (P = 0.016). We also found that patients with high B7-H4 expression in their primary NSCLC have a higher risk of developing brain metastases (P = 0.022). Univariate analyses showed that median overall survival was significantly shorter in patients with high B7-H4 expression in brain metastases (P = 0.002). Multivariate analyses showed that B7-H4 was a significant independent prognostic indicator (P = 0.003). NSCLC patients with high B7-H4 expression may benefit from aggressive treatment and close surveillance. Furthermore, our study suggests that B7-H4 may play an important role in the metastatic process of NSCLC and is promising to be a new immune checkpoint molecule for future antitumoral immunotherapy.


Regulation of the mRNA expression for tumor necrosis factor-alpha in rat liver macrophages.
Kupffer cells are known to produce tumor necrosis factor-alpha upon stimulation with endotoxin or viruses. This tumor necrosis factor-alpha synthesis is suppressed by prostaglandin E2 or dexamethasone. Using Northern blotting and reverse transcriptase-polymerase chain reaction, it is demonstrated that endotoxin-induced tumor necrosis factor-alpha synthesis is blocked by prostaglandin E2 or dibutyryl 3':5'-cyclic adenosine monophosphate on the transcriptional level. Tumor necrosis factor-alpha itself suppressed endotoxin-evoked tumor necrosis factor-alpha mRNA expression when given in a narrow time interval with lipopolysaccharide. Interleukin-10 of human or mouse origin also inhibited the synthesis of tumor necrosis factor-alpha mRNA and protein when given more than 2 h prior to the endotoxin challenge. The suppressive effect of prostaglandin E2 lasted for more than 36 h while IL-10 blocked tumor necrosis factor-alpha production for barely 24 h. Dexamethasone reduced the endotoxin-induced tumor necrosis factor-alpha mRNA formation by approximately 50% only, although it led to nearly complete inhibition of the synthesis of the mature protein. Taken together with reverse transcriptase-polymerase chain reaction data revealing significant amounts of tumor necrosis factor-alpha mRNA in resting Kupffer cells, an additional posttranscriptional regulation of tumor necrosis factor-alpha synthesis has to be assumed. Tumor necrosis factor-alpha mRNA was not induced by interferon-gamma, interleukin-1 beta or interleukin-6 (the latter two cytokines are also synthesized by Kupffer cells), but a 24-h prestimulation of liver macrophages with interferon-gamma or phorbol ester had a modest priming effect.(ABSTRACT TRUNCATED AT 250 WORDS)


Primary Health Care and Disasters: Applying a "Whole-of-Health System" Approach through Reverse Triage in Mass-Casualty Management.
In 2019, the World Health Organization (WHO) published the Health Emergency and Disaster Risk Management (H-EDRM) framework detailing how effective management of disasters, including mass-casualty incidents (MCIs), can be achieved through a whole-of-health system approach where each level of the health care system is involved in all phases of the disaster cycle. In light of this, a primary health care (PHC) approach can contribute to reducing negative health outcomes of disasters, since it encompasses the critical roles that primary care services can play during crises. Hospitals can divert non-severe MCI victims to primary care services by applying reverse triage (RT), thereby preventing hospital overloading and ensuring continuity of care for those who do not require hospital services during the incident. This study explores the topic by reviewing the literature published on early discharge of MCI victims through RT criteria and existing referral pathways to primary care services. A scoping literature review was performed and a total of ten studies were analyzed. The results showed that integrating primary care facilities into disaster management (DM) through the use of RT may be an effective strategy to create surge during MCIs, provided that clear referral protocols exist between hospitals and primary care services to ensure continuity of care. Furthermore, adequate training should be provided to primary care professionals to be prepared and be able to provide quality care to MCI victims. The results of this current review can serve as groundwork upon which to design further research studies or to help devise strategies and policies for the integration of PHC in MCI management.


Eye history and examination in general practice.
Time spent in carrying out a careful history taking and examination allows for accurate detail in making a diagnosis. If doubt occurs, reference to an ophthalmologist--even if only a telephone call--is wise.


Novel Human FCGR1A Variants Affect CD64 Functions and Are Risk Factors for Sarcoidosis.
CD64 (or FcγRIA) is the sole functional high affinity IgG Fc receptor coded by FCGR1A gene in humans. The FCGR1A genetics has not been comprehensively investigated and effects of human FCGR1A variants on immune functions remain unknown. In the current study, we identified three novel FCGR1A variants including the single nucleotide variant (SNV) rs1848781 (c.-131) in the proximal FCGR1A gene promoter region, the rs587598788 indel variant within the FCGR1A intron 5, and the non-synonymous SNV rs1050204 (c.970G>A or FcγRIA-p.D324N) in the FCGR1A coding region. Genotype-phenotype analyses revealed that SNV rs1848781 genotypes were significantly associated with CD64 expression levels. Promoter reporter assays show that rs1848781G allele had significantly higher promoter activity than the rs1848781C, confirming that the rs1848781 is a functional FCGR1A SNV affecting promoter activity and gene expression. The rs587598788 indel genotypes were also significantly associated with levels of CD64 expression. Moreover, the non-synonymous SNV rs1050204 (FcγRIA-p.D324N) alleles significantly affected CD64-mediated phagocytosis, degranulation, and pro-inflammatory cytokine productions. Genetic analyses revealed that FCGR1A genotypes were significantly associated with sarcoidosis susceptibility and severity. Our data suggest that FCGR1A genetic variants may affect immune responses and play a role in sarcoidosis.


Parallels between tooth development and repair: conserved molecular mechanisms following carious and dental injury.
The reparative mechanisms that operate following carious and traumatic dental injury are critical for pulp survival and involve a series of highly conserved processes. It appears that these processes share genetic programs-linked to cytoskeletal organization, cell movement, and differentiation-that occur throughout embryogenesis. Reactionary dentin is secreted by surviving odontoblasts in response to moderate stimuli, leading to an increase in metabolic activity. In severe injury, necrotic odontoblasts are replaced by other pulp cells, which are able to differentiate into odontoblast-like cells and produce a reparative dentin. This complex process requires the collaborative efforts of cells of different lineage. The behavior of each of the contributing cell types during the phases of proliferation, migration, and matrix synthesis as well as details of how growth factors control wound cell activities are beginning to emerge. In this review, we discuss what is known about the molecular mechanisms involved in dental repair.


Ataxia-telangiectasia: a clinical and laboratory review study of 14 cases.
Fourteen patients with ataxia-telangiectasia and 10 relatives were studied. Besides neurological examination, laboratorial investigations as to their immunological condition were carried out. In this study, our attention was attracted to the most frequent and relevant laboratorial data being decreased serum and salivary levels of IgA, decreased rate of blastic transformation of lymphocytes and increased serum levels of alpha-fetoprotein (AFP). On the other hand, no patient showed increased levels of carcinoembryonic antigen (CEA). Our population reported a consanguinity rate of 28.5%.


A review of astigmatism and its possible genesis.
Astigmatism is a refractive condition encountered commonly in clinical practice. This review presents an overview of research that has been carried out examining various aspects of this refractive error. We examine the components of astigmatism and the research into the prevalence and natural course of astigmatic refractive errors throughout life. The prevalence of astigmatism in various ethnic groups and diseases and syndromes is also discussed. We highlight the extensive investigations that have been conducted into the possible aetiology of astigmatism, however, no single model or theory of the development of astigmatism has been proven conclusively. Theories of the development of astigmatism based on genetics, extraocular muscle tension, visual feedback and eyelid pressure are considered. Observations and evidence from the literature supporting and contradicting these hypotheses are presented. Recent advances in technology such as wavefront sensors and videokeratoscopes have led to an increased understanding of ocular astigmatism and with continued improvements in technology, our knowledge of astigmatism and its genesis should continue to grow.


Effects of prenatal music stimulation on state/trait anxiety in full-term pregnancy and its influence on childbirth: a randomized controlled trial.
Many researchers have pointed out the strong relationship between maternal psychological well-being and fetal welfare during pregnancy. The impact of music interventions during pregnancy should be examined in depth, as they could have an impact on stress reduction, not only during pregnancy but also during the course of delivery, and furthermore induce fetal awareness. This study aimed to investigate the effect of music on maternal anxiety, before and after a non-stress test (NST), and the effect of music on the birthing process. The four hundred and nine pregnant women coming for routine prenatal care were randomized in the third trimester to receive either music (n = 204) or no music (n = 205) stimulation during an NST. The primary outcome was considered as the maternal state anxiety score before and after the NST, and the secondary outcome was the birthing process. Before their NST, full-term pregnant women who had received music intervention were found to have a similar state-trait anxiety score to those from the control group, with 38.10 ± 8.8 and 38.08 ± 8.2, respectively (p = .97). After the NST, the mean state-trait anxiety score of each group was recorded, with results of 30.58 ± 13.2 for those with music intervention, and 43.11 ± 15.0 for those without music intervention (p < .001). In the control group, the NST was followed by a statistically significant increase in the state-trait anxiety score (38.08 ± 8.2 versus 43.11 ± 15.0, p < .001). However, listening to music during the NST resulted in a statistically significant decrease in the state-trait anxiety score of the study group (38.10 ± 8.8 versus 30.58 ± 13.2, OR = 0.87, p < .001). Furthermore, the first stage of labor was shorter in women who received music stimulation (OR = 0.92, p < .004). They also presented a more natural delivery beginning (spontaneous) and less medication (stimulated and induced) than those who were not stimulated musically, with statistically significant differences (p < .01). Prenatal music intervention could be a useful and effective tool to reduce anxiety in full-term pregnant women during an NST and improve the delivery process by reducing the first stage of labor in nulliparous women.


Towards the routine use of in silico screenings for drug discovery using metabolic modelling.
Currently, the development of new effective drugs for cancer therapy is not only hindered by development costs, drug efficacy, and drug safety but also by the rapid occurrence of drug resistance in cancer. Hence, new tools are needed to study the underlying mechanisms in cancer. Here, we discuss the current use of metabolic modelling approaches to identify cancer-specific metabolism and find possible new drug targets and drugs for repurposing. Furthermore, we list valuable resources that are needed for the reconstruction of cancer-specific models by integrating various available datasets with genome-scale metabolic reconstructions using model-building algorithms. We also discuss how new drug targets can be determined by using gene essentiality analysis, an in silico method to predict essential genes in a given condition such as cancer and how synthetic lethality studies could greatly benefit cancer patients by suggesting drug combinations with reduced side effects.


[Feasibility of using artificial intelligence for screening COVID-19 patients in ParaguayViabilidade do uso de inteligência artificial na triagem de pacientes com COVID-19 no Paraguai].
Study the feasibility of using artificial intelligence as a sensitive and specific method for COVID-19 screening in patients with respiratory conditions, using chest CT scan images and a telemedicine platform. From March 2020 to June 2021, the authors conducted an observational descriptive multicenter feasibility study based on artificial intelligence (AI) for COVID-19 screening using chest images of patients with respiratory conditions who presented at public hospitals. The AI platform was used to diagnose chest CT scan images; this was then compared with molecular diagnosis (RT-PCR) to determine whether they matched and to analyze the feasibility of AI for screening patients with suspected COVID-19. A telemedicine platform was used to send images and diagnostic results. Screening of 3 514 patients with a suspected COVID-19 diagnosis was performed in 14 hospitals around the country. Most patients were aged 27 to 59 years, followed by those over 60. The average age was 48.6 years; 52.8% were male. The most frequent findings were severe pneumonia, bilateral pneumonia with pleural effusion, bilateral pulmonary emphysema, and diffuse ground glass opacity, among others. There was an average of 93% matching and 7% mismatching between images analyzed by AI and RT-PCR. Sensitivity and specificity of the AI system, obtained by comparing AI and RT-PCR screening results, were 93% and 80% respectively. The use of sensitive and specific AI for stratified rapid detection of COVID-19 in patients with respiratory conditions by using chest CT scan images and a telemedicine platform in public hospitals in Paraguay is feasible.


High-contrast spectroscopic photoacoustic characterization of thermal tissue ablation in the visible spectrum.
High-contrast tissue characterization of thermal ablation has been desired to evaluate therapeutic outcomes accurately. This paper presents a photoacoustic (PA) characterization of thermal tissue ablation in the visible spectrum, in which higher light absorbance can produce spectral contrast starker than in the near-infrared range. Ex vivo experiments were performed to measure visible PA spectra (480-700 nm) from fresh porcine liver tissues that received a thermal dose in a range of cumulative equivalent minutes at 43°C (CEM43). The local hemoglobin lobe area between 510-600 nm and wholespectral area under the curve were evaluated to represent the transition of hemoglobin into methemoglobin (MetHb) in the target tissue. The thermal process below an estimated therapeutic CEM43 threshold (80-340 minutes) presented a progressive elevation of the PA spectrum and an eventual loss of local hemoglobin peaks in the visible spectrum, closer to the MetHb spectrum. Interestingly, an excessive CEM43 produced a substantial drop in the PA spectrum. In the spectral analysis, the visible spectrum yielded 13.9-34.1 times higher PA sensitivity and 1.42 times higher contrast change than at a near-infrared wavelength. This novel method of PA tissue characterization in the visible spectrum could be a potential modality to evaluate various thermal therapeutic modalities at high-contrast resolution.


Immunomagnetic enrichment of interstitial cells of Cajal.
Disruptions of networks of interstitial cells of Cajal (ICC), gastrointestinal pacemakers and mediators of neurotransmission, can lead to disordered phasic contractions and peristalsis by reducing and uncoupling electrical slow waves. However, detailed analysis of the ICC network behavior has been hampered by their scarcity, limited accessibility in intact tissues, and contamination with other cell types in culture. Our goal was to develop a simple technique to purify ICC from murine gastrointestinal muscles for functional studies. We identified ICC in live small intestinal muscles or primary cell cultures by Kit immunoreactivity using fluorescent antibodies. Because this technique also labels resident macrophages nonspecifically, parallel studies were performed in which nonfluorescent Kit antibodies and macrophages labeled with fluorescent dextran were used for subtractive analysis of ICC. In both groups, Kit-positive cells were tagged with superparamagnetic antibodies and sorted on magnetic columns. Efficacy was assessed by flow cytometry. ICC enrichment from primary cultures and freshly dissociated tissues was approximately 63-fold and approximately 8-fold, respectively. Unlike the cells derived directly from tissues, cells sorted from cultures frequently yielded extensive, nearly homogenous ICC networks on reseeding. Monitoring oscillations in mitochondrial Ca(2+) or membrane potential by imaging revealed spontaneous rhythmicity in these networks. Cells that did not bind to the columns yielded cultures that were depleted of ICC and dominated by smooth muscle cells. In conclusion, immunomagnetic sorting of primary cultures of ICC results in relatively homogenous, functional ICC networks. This technique is less suitable for obtaining ICC from freshly dispersed cells.


The clinicopathological characteristics and prognosis of patients with node-positive gastric cancer after curative surgery.
Lymph node (LN) metastasis is one of the independent prognostic factors of gastric cancer (GC). The difference in survival rates and initial recurrence patterns in patients with node-positive GC with retrieved LN numbers greater than or less than 16 is worthy of further study. A total of 1314 patients with node-positive GC were enrolled. The clinicopathological characteristics, retrieved LN numbers, adjuvant chemotherapy, initial recurrence patterns, and survival differences between serosa-negative and serosa-positive GC were investigated. For serosa-negative GC, patients with retrieved LN numbers ≥16 were associated with fewer tumor recurrences, locoregional recurrences, distant metastases, and better 5-year overall survival (OS) rates and disease-free survival (DFS) rates. For serosa-positive GC, patients with retrieved LN numbers ≥16 were associated with similar locoregional and distant metastasis and similar 5-year OS and DFS rates compared with those with retrieved LN numbers <16. Retrieved LN numbers fewer than 16 can cause stage migration compared with retrieved LN numbers ≥16. Multivariate analysis showed that both the retrieved LN numbers (≥ or <16) and adjuvant chemotherapy were independent prognostic factors affecting OS in serosa-negative GC, while adjuvant chemotherapy but not the retrieved LN numbers was an independent prognostic factor of OS in serosa-positive GC. For serosa-negative GC, retrieved LN numbers fewer than 16 can cause stage migration, a higher tumor recurrence rate and worse OS and DFS rates compared with patients with retrieved LN numbers ≥16. Due to a high tumor recurrence rate in serosa-positive GC, adjuvant chemotherapy rather than retrieved LN numbers played an important role in improving patient prognosis.


Membrane filter method to study the effects of Lactobacillus acidophilus and Bifidobacterium longum on fecal microbiota.
A large number of commensal bacteria inhabit the intestinal tract, and interbacterial communication among gut microbiota is thought to occur. In order to analyze symbiotic relationships between probiotic strains and the gut microbiota, a ring with a membrane filter fitted to the bottom was used for in vitro investigations. Test strains comprising probiotic nitto strains (Lactobacillus acidophilus NT and Bifidobacterium longum NT) and type strains (L. acidophilus JCM1132(T) and B. longum JCM1217(T) ) were obtained from diluted fecal samples using the membrane filter to simulate interbacterial communication. Bifidobacterium spp., Streptococcus pasteurianus, Collinsella aerofaciens, and Clostridium spp. were the most abundant gut bacteria detected before coculture with the test strains. Results of the coculture experiments indicated that the test strains significantly promote the growth of Ruminococcus gnavus, Ruminococcus torques, and Veillonella spp. and inhibit the growth of Sutterella wadsworthensis. Differences in the relative abundances of gut bacterial strains were furthermore observed after coculture of the fecal samples with each test strain. Bifidobacterium spp., which was detected as the dominant strain in the fecal samples, was found to be unaffected by coculture with the test strains. In the present study, interbacterial communication using bacterial metabolites between the test strains and the gut microbiota was demonstrated by the coculture technique. The detailed mechanisms and effects of the complex interbacterial communications that occur among the gut microbiota are, however, still unclear. Further investigation of these relationships by coculture of several fecal samples with probiotic strains is urgently required.


[Characteristics of erectile dysfunction in old males with lacunar infarction].
To investigate the characteristics of erectile dysfunction (ED) in old males with lacunar infarction. A total of 38 old patients ages from 60 to 70 years were involved. The questionnaire of international index of erectile function 5 (IIEF -5) was used to determine the status and severity of ED. According to the focus of infarction on MRI, the patients were divided into two groups, Group I with lacunar infarction and minor neurological deficits, and Group II with none. The total IIEF-5 scores were compared between the two groups and repeatedly evaluated six months after discharge. According to the total scores of IIEF-5, the prevalence of ED in Group II (95%) was higher, and the incidence of severe ED was significantly increased (60.0% vs. 44.4%, P < 0.05) as compared with Group II. In both the two groups, severe ED was more often seen in diabetic patients. At six months after discharge, the total scores of IIEF-5 were significantly increased (11.2 +/- 3.2 vs. 15.6 +/- 2.2, P < 0.05). ED is significantly increased in old males with lacunar infarction, and it is more severe in diabetic patients. Post-stroke rehabilitation care helps to improve ED.


Metatranscriptomic Analysis of Virus Diversity in Urban Wild Birds with Paretic Disease.
Wild birds are major natural reservoirs and potential dispersers of a variety of infectious diseases. As such, it is important to determine the diversity of viruses they carry and use this information to help understand the potential risks of spillover to humans, domestic animals, and other wildlife. We investigated the potential viral causes of paresis in long-standing, but undiagnosed, disease syndromes in wild Australian birds. RNA from diseased birds was extracted and pooled based on tissue type, host species, and clinical manifestation for metagenomic sequencing. Using a bulk and unbiased metatranscriptomic approach, combined with clinical investigation and histopathology, we identified a number of novel viruses from the families Astroviridae, Adenoviridae, Picornaviridae, Polyomaviridae, Paramyxoviridae, Parvoviridae, and Circoviridae in common urban wild birds, including Australian magpies, magpie larks, pied currawongs, Australian ravens, and rainbow lorikeets. In each case, the presence of the virus was confirmed by reverse transcription (RT)-PCR. These data revealed a number of candidate viral pathogens that may contribute to coronary, skeletal muscle, vascular, and neuropathology in birds of the Corvidae and Artamidae families and neuropathology in members of the Psittaculidae The existence of such a diverse virome in urban avian species highlights the importance and challenges in elucidating the etiology and ecology of wildlife pathogens in urban environments. This information will be increasingly important for managing disease risks and conducting surveillance for potential viral threats to wildlife, livestock, and human health.IMPORTANCE Wildlife naturally harbor a diverse array of infectious microorganisms and can be a source of novel diseases in domestic animals and human populations. Using unbiased RNA sequencing, we identified highly diverse viruses in native birds from Australian urban environments presenting with paresis. This research included the clinical investigation and description of poorly understood recurring syndromes of unknown etiology: clenched claw syndrome and black and white bird disease. As well as identifying a range of potentially disease-causing viral pathogens, this study describes methods that can effectively and efficiently characterize emergent disease syndromes in free-ranging wildlife and promotes further surveillance for specific pathogens of potential conservation and zoonotic concern.


Diagnostic Evaluations of Autism Spectrum Disorder during the COVID-19 Pandemic.
A global pandemic has significantly impacted the ability to conduct diagnostic evaluations for autism spectrum disorder (ASD). In the wake of the coronavirus, autism centers and providers quickly needed to implement innovative diagnostic processes to adapt in order to continue serve patient needs while minimizing the spread of the virus. The International Collaborative for Diagnostic Evaluation of Autism (IDEA) is a grassroots organization that came together to discuss standards of care during the pandemic and to provide a forum wherein providers communicated decisions. This white paper is intended to provide examples of how different centers adjusted their standard approaches to conduct diagnostic evaluations for ASD during the pandemic and to provide insight to other centers as they go through similar challenges.


Increased Risk of Migraine among Students with Asthma: Results of Headache and Asthma Study among University Students.
Several studies in developed countries have investigated the relationship between migraine and asthma. To examine the relationship between asthma and migraine among university students in a low middle-income country. We conducted a cross-sectional study across three universities in the middle belt region of Nigeria. A self-administered questionnaire developed from the International Classification of Headache Disorders was used to screen for migraine. The European Community Respiratory Health Survey (ECRHS) survey tool screened for asthma and its related conditions. Migraine was diagnosed in subjects with recurrent, moderate to severe unilateral throbbing headaches associated with nausea, vomiting, or visual disturbances. Asthma was defined as reporting a previous asthma attack or currently taking asthma medication within the preceding 12 months. The frequency of asthma was significantly higher among those with migraine than those without migraine (28.6% vs. 9.0%). Conversely, migraine was significantly prevalent in participants with asthma (7.1%vs. 1.9%). On multivariate analysis, there were significant associations between migraine and asthma [aOR = 2.56 (95% CI 1.15-5.77)]. Other factors associated with migraine were female gender [aOR = 2.22 (95% CI 1.06-4.65)] and family history of recurrent headache in firstdegree relatives [aOR = 4.03 (95% CI 1.15-5.77)]. Our study shows an increased frequency and risk of migraine in participants diagnosed with asthma and vice versa. These results support the bidirectional association between migraine and asthma. Physicians, therefore, should be aware of the possibility of migraine in patients with asthma who complain of headaches.


Adverse events of erythropoietin in long-term and in acute/short-term treatment.
Erythropoietin has been shown to be effective both in the reversal of anaemia in patients with end-stage renal failure and to increase the volume of autologous red blood cells donated preoperatively as well as to decrease the units of homologous blood transfused. This review analyzes the side effects of erythropoietin reported in the literature for long-term administration (mainly in patients with end-stage renal failure) as well as for acute/short-term administration (in patients participating in an autologous predeposit programme). The most important adverse events reported for long-term administration are as follows: (a) arterial hypertension; (b) cerebral convulsion/hypertensive encephalopathy; (c) thrombo-embolism; (d) iron deficiency; (e) influenza-like syndrome. The numbers given for these side effects are mainly taken from the first and dose-finding studies in patients with renal failure. These figures differ very much from the data given in controlled studies analyzing adverse events as well. Summarizing the results from controlled, multi-center trials in patients with end-stage renal failure or in AIDS patients, no significant differences have been observed between the control group and the patients treated with erythropoietin. The overall-incidence of side effects occurring in either group of these two studies was of approximately 83% and 95%, respectively. In contrast to these results the data published for the dose finding/treatment studies is approximately 30% for development of arterial hypertension, approximately 5% for occurrence of cerebral convulsion/hypertensive encephalopathy, approximately 10% for thrombo-embolic complications/clotting of vascular access, approximately 50% for development of iron deficiency, and approximately 10% for symptoms summarized as influenza-like syndrome.(ABSTRACT TRUNCATED AT 250 WORDS)


An autopsied case of corticobasal degeneration presenting with frontotemporal dementia followed by myoclonus.
A Japanese woman developed frontotemporal dementia (FTD)-like symptoms of abnormal behavior, such as stereotyped behavior and disinhibition. The patient developed these symptoms at the age of 59 years, although aphasia symptoms were not apparent at early disease stages. Progressive parkinsonism was dominant on the left side, and conspicuous myoclonus was recognized in the late disease stage. MRI indicated severe, right side-dominant frontotemporal lobe atrophy with white matter degeneration. Brainstem and cerebellar atrophy were also observed. The patient underwent gastrostomy 7 years after the onset of her symptoms and died at the age of 70 years. Neuropathological examination showed diffuse neuron loss with gliosis and tissue rarefaction in the frontotemporal lobe, particularly in the right anterior portion of the frontal lobe. Spongiform changes and ballooned neurons were also observed in the frontotemporal cortex, particularly in the superficial layer and deeper layers, respectively. Gallyas-Braak silver staining and anti-phosphorylated tau immunostaining indicated numerous argyrophilic and tau-positive structures, including pretangles, astrocytic plaques, coiled bodies and neuropil threads. We speculate that the myoclonus observed in the present case was at least partly caused by or related to the spongiform change and ballooned neurons in the cerebral cortex. The clinical phenotypes of corticobasal degeneration (CBD) vary considerably, and the clinical presentation of the present patient was compatible with frontal behavioral-spatial syndrome in the early disease stage. However, in the later disease stages, her symptoms were reflective of corticobasal syndrome. Because it is not rare for the clinical phenotype to change along with disease progression in cases of CBD, we should consider CBD in cases presenting with FTD at symptom onset.


[Urodynamic and roentgenologic changes following ventral levatorplasty].
Our first 23 patients treated by this method were followed up by urodynamic assessment and urethrocystovaginography 13 months after the operation. Urodynamic assessment was performed according to the criteria of the International Continence Society. There was no statistically significant difference in the resting urethral closure pressure (UCP), neither at maximum point nor at 30% or 70% of the urethral functional length (UFL). The postoperative reduction of UFL was statistically significant but did not exercise any significant influence on continence. The maximum bladder volume was not affected. For assessing the urethral stress profile we calculated the depression quotient which was significantly unfavourable at 30% of UFL but not affected at 70%. The lateral urethrocystovaginogram was interpreted according to Green. Most of the parameters were significantly improved. At the time of reexamination 70% of the patients were subjectively continent, whereas in 21.7% the incontinence remained unchanged and deteriorated in 8.6%. In our opinion, this modified anterior repair is not recommended as a method to encourage a wider range of indications for the vaginal repair of incontinence. Hence, this operation method should be performed only in case of an evident insufficiency of the vesicourethrovaginal septum.


Unraveling the Critical Role of Site Occupancy of Lithium Codopants in Lu2SiO5:Ce3+ Single-Crystalline Scintillators.
Lithium codoping has emerged as an effective strategy to enhance the light yield of oxide scintillators for radiation detection applications, but the understanding of the actual role played by Li+ remains unclear. In this work, we comprehensively study the effects of Li codoping on optical and scintillation properties of Lu2SiO5:Ce (LSO:Ce) single crystals and reveal the critical role of site occupancy of Li. High-quality LSO:Ce single crystals codoped with 0.05, 0.1, and 0.3 at. % Li ions were grown by the Czochralski method. The optical absorption spectra confirm nonconversion of stable Ce3+ to Ce4+ in Li-codoped LSO:Ce regardless of the Li codoping concentration. The photoluminescence decay kinetics suggest an enhanced ionization of the excited 5d1 state of Ce3+ centers in highly codoped samples. A simultaneous improvement of scintillation light yield, decay time, and afterglow is achieved in LSO:Ce codoped with low concentrations of Li. The preferential occupation of Li at interstitial spaces and lutetium sites is proven to rely on its codoping concentration by using the 7Li nuclear magnetic resonance technique. The concentration-dependent site occupancy of Li alters the defect structures of LSO:Ce, in particular resulting in a distinct change in the number of cerium spatially correlated oxygen vacancies confirmed by thermoluminescence and afterglow measurements.


The Flatstent versus the conventional umbrella devices in the percutaneous closure of patent foramen ovale.
Patent foramen ovale (PFO) has been associated with paradoxical embolism leading to stroke/transient ischemic attack, migraine, and neurological decompression sickness. In search for the optimal device that would achieve effective clinical closure with minimal complications, a better device selection based on PFO anatomy and improvements in device design is needed. The Flatstent is a new device designed to treat the highly prevalent long-tunnel PFOs from within, minimizing the amount of material left behind in an attempt to reduce device-related complications. The objective is to compare the safety and efficacy of the novel Flatstent versus the conventional umbrella devices in the transcatheter closure of PFO in a nonrandomized, retrospective, single-center study. Between March 2010 and March 2013, 88 patients underwent PFO closure at The Heart Hospital, London with either the novel Flatstent or one of the four conventionally used umbrella devices (GORE Helex Septal Occluder, Occlutech Figulla Flex, Biostar Septal Occluder, and Amplatzer PFO Occluder) depending on their PFO anatomy. Patients were then evaluated with contrast transthoracic echocardiography (TTE) and/or transoesophageal echocardiography (TOE) at 6 weeks and 1 year after the procedure. The residual shunt and complication rates between the Flatstent and umbrella devices were compared. The Flatstent was used in 27 patients (30.7%), whereas 61 patients (69.3%) received one of the four umbrella devices. Primary efficacy point of clinical closure defined as grade 0 or grade 1; residual shunt was achieved in 81.3% in the Flatstent cohort and 80.3% in the umbrella device group at 6 weeks follow-up. At 1 year, the clinical closure rates reached 92.6 and 91.8%. There were two device embolizations, one in each cohort during the immediate postoperative period (<24 hrs), with successful retrieval. One patient in the umbrella device group developed transient atrial fibrillation, which was controlled medically. Event recurrence rate was 0% at 1 year. No difference was found in closure or complication rates between the Flatstent and the umbrella devices. With appropriate preassessment of the PFO anatomy, the Flatstent works as a safe and effective method of treating the PFO from within the tunnel, especially in those with long-tunnel PFOs. Longer follow-up is needed to establish superiority.


Gallium Triggers Ferroptosis through a Synergistic Mechanism.
The gallium ion (Ga3+ ) has long been believed to disrupt ferric homeostasis in the body by competing with iron cofactors in metalloproteins, ultimately leading to cell death. This study revealed that through an indirect pathway, gallium can trigger ferroptosis, a type of non-apoptotic cell death regulated by iron. This is exemplified by the gallium complex of the salen ligand (Ga-1); we found that Ga-1 acts as an effective anion transporter that can affect the pH gradient and change membrane permeability, leading to mitochondrial dysfunction and the release of ferrous iron from the electron transfer chain (ETC). In addition, Ga-1 also targeted protein disulfide isomerases (PDIs) located in the endoplasmic reticulum (ER) membrane, preventing the repair of the antioxidant glutathione (GSH) system and thus enforcing ferroptosis. Finally, a combination treatment of Ga-1 and dietary polyunsaturated fatty acids (PUFAs), which enhances lipid peroxidation during ferroptosis, showed a synergistic therapeutic effect both in vitro and in vivo. This study provided us with a strategy to synergistically induce Ferroptosis in tumor cells, thereby enhancing the anti-neoplastic effect.


Histopathologic review of pineal parenchymal tumors identifies novel morphologic subtypes and prognostic factors for outcome.
Pineal parenchymal tumors (PPTs) are rare neoplasms of the central nervous system, and data concerning clinical outcomes are limited. The purpose of this study was to define the clinical behavior of PPT according to current histopathologic criteria and identify prognostic factors to guide therapeutic decisions. Seventy-five patients treated for PPT at a single institution between 1992 and 2015 were retrospectively identified. Forty-five resection specimens were available and re-reviewed. Freedom from progression (FFP) and overall survival (OS) were estimated using the Kaplan-Meier method and compared using log-rank tests. Median follow-up was 4.1 years. All patients initially underwent surgery; 78% of patients with PPT of intermediate differentiation (PPTID) and all patients with pineoblastoma received adjuvant therapy. Pathologic re-review refined classification in 27% of cases, with the majority of these being adult patients with pineal tumors originally classified as pineoblastomas that more accurately resembled PPTID based on the 2007 WHO classification. Our histologic review also identified that PPTIDs can be classified into small-cell and large-cell morphologic subtypes, which have distinct clinical outcomes. Tumor grade, extent of resection, and neuraxis spread were prognostic for FFP. PPTID subtype, extent of resection, and neuraxis spread were prognostic for OS. Genetic analysis of a pineoblastoma case identified somatic mutations of DICER1, ARID1A, and KDM5C genes. PPTIDs can be classified into 1 of 2 novel morphologic subtypes that are associated with distinct clinical outcomes. Tumor grade, neuraxis spread, and extent of resection also influence outcome for patients with PPT.


Programming the cochlear implant based on electrical acoustic reflex thresholds: patient performance.
The electrical acoustic reflex threshold (EART) has been shown to be a reliable estimate of behavioral comfort levels in both child and adult cochlear implant patients. The purpose of this study was to investigate the potential for using EARTs for programming the Nucleus cochlear implant. EARTs and behavioral comfort levels were obtained from 7 adult implant patients. Two programs or "maps" were made for each patient, one based on behavioral comfort levels and one based on EARTs. Performance on open set tests of speech recognition was measured with each map. Mean data suggest that speech perception is similar with both maps. Analysis of individual data revealed that, whereas 2 subjects performed better with the C-level maps, the remaining 5 subjects tended to perform either better with the EART map or equally well with both maps. These results suggest that EARTs may be an adequate substitute for comfort levels when programming the implant for patients who are unable to make reliable psychophysical judgments.


Neck ligament strength is decreased following whiplash trauma.
Previous clinical studies have documented successful neck pain relief in whiplash patients using nerve block and radiofrequency ablation of facet joint afferents, including capsular ligament nerves. No previous study has documented injuries to the neck ligaments as determined by altered dynamic mechanical properties due to whiplash. The goal of the present study was to determine the dynamic mechanical properties of whiplash-exposed human cervical spine ligaments. Additionally, the present data were compared to previously reported control data. The ligaments included the anterior and posterior longitudinal, capsular, and interspinous and supraspinous ligaments, middle-third disc, and ligamentum flavum. A total of 98 bone-ligament-bone specimens (C2-C3 to C7-T1) were prepared from six cervical spines following 3.5, 5, 6.5, and 8 g rear impacts and pre- and post-impact flexibility testing. The specimens were elongated to failure at a peak rate of 725 (SD 95) mm/s. Failure force, elongation, and energy absorbed, as well as stiffness were determined. The mechanical properties were statistically compared among ligaments, and to the control data (significance level: P < 0.05; trend: P < 0.1). The average physiological ligament elongation was determined using a mathematical model. For all whiplash-exposed ligaments, the average failure elongation exceeded the average physiological elongation. The highest average failure force of 204.6 N was observed in the ligamentum flavum, significantly greater than in middle-third disc and interspinous and supraspinous ligaments. The highest average failure elongation of 4.9 mm was observed in the interspinous and supraspinous ligaments, significantly greater than in the anterior longitudinal ligament, middle-third disc, and ligamentum flavum. The average energy absorbed ranged from 0.04 J by the middle-third disc to 0.44 J by the capsular ligament. The ligamentum flavum was the stiffest ligament, while the interspinous and supraspinous ligaments were most flexible. The whiplash-exposed ligaments had significantly lower (P = 0.036) failure force, 149.4 vs. 186.0 N, and a trend (P = 0.078) towards less energy absorption capacity, 308.6 vs. 397.0 J, as compared to the control data. The present decreases in neck ligament strength due to whiplash provide support for the ligament-injury hypothesis of whiplash syndrome.


Effects of raloxifene on fracture risk in postmenopausal women: the Raloxifene Use for the Heart Trial.
Using data from a randomized placebo-controlled trial of 10,101 postmenopausal women not selected on the basis of osteoporosis, we examined whether the effect of raloxifene treatment on fractures was consistent across categories of fracture risk. Treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of the presence or absence of risk factors for fracture. In The Raloxifene Use for The Heart (RUTH) trial, women assigned to raloxifene had a lower risk of clinical vertebral fractures but not nonvertebral fractures. However, it is uncertain whether the effect of raloxifene on fractures in this population not selected for low BMD differs according to risk factors for fractures. We randomly assigned 10,101 postmenopausal women >or=55 yr of age with documented coronary heart disease or at high risk for coronary events to 60 mg raloxifene daily or placebo and followed them for a median of 5.6 yr. Fractures (nonvertebral and clinical vertebral) were prespecified secondary endpoints that were reported at semiannual visits. Fractures were adjudicated and confirmed using X-ray reports or medical records. There was no difference between raloxifene and placebo groups in risk of nonvertebral fractures (428 versus 438 events; hazard ratio [HR], 0.96; 95% CI, 0.84-1.10), including hip/femur (89 versus 103 events; HR, 0.85; 95% CI, 0.64-1.13) and wrist (107 versus 111 events; HR, 0.95; 95% CI, 0.73-1.24) fractures. Women treated with raloxifene had a lower risk of clinical vertebral fractures (64 versus 97 events; HR, 0.65; 95% CI, 0.47-0.89). The effect of treatment with raloxifene on risk of nonvertebral and clinical vertebral fractures was consistent across fracture risk categories defined at baseline by age, smoking status, physical activity level, prior history of fracture, family history of hip fracture, diabetes mellitus, previous use of hormone therapy, thyroid hormone use, statin use, weight loss, body mass index, or fracture specific summary risk score. In older women with or at high risk of coronary heart disease not selected on the basis of osteoporosis or increased fracture risk, treatment with raloxifene for 5 yr reduced the risk of clinical vertebral fractures, but not nonvertebral fractures, irrespective of presence or absence of risk factors for fracture.