Plasma viscosity and fibrinogen in relation to haemodynamic findings in chronic congestive heart failure.
The aim of this study was to investigate an inflammatory response indicated by fibrinogen and plasma viscosity in relation to haemodynamic and clinical findings of patients with stable CHF due to coronary heart disease (CHD).


Autologous bone marrow stem cell therapy for the ischemic myocardium during coronary artery bypass grafting.
Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Especially the treatment of ischemic heart disease challenges physicians despite recent advances in medical and operative strategies. Due to the considerable developments in regenerative medicine cell-based treatment for ischemic heart disease has attracted great interest in the last decade. Numerous experimental and clinical approaches employing stem cell treatment from various sources and using different methods of cell delivery have shown improvement in cardiac function after acute or chronic ischemic jeopardy. In this report we will focus on our long-term experience on the safety of bone marrow derived CD133(+) stem cell transplantation with concomitant coronary artery bypass surgery and provide an overview of the current knowledge on utilizing cell-based treatment for ischemic heart disease.


Identification of novel therapeutic targets for blocking acantholysis in pemphigus.
Pemphigus is caused by autoantibodies against desmoglein (Dsg) 1, Dsg3, and/or non-Dsg antigens. Pemphigus vulgaris (PV) is the most common manifestation of pemphigus, with painful erosions on mucous membranes. In most cases, blistering also occurs on the skin, leading to areas of extensive denudation. Despite improvements in pemphigus treatment, time to achieve remission is long, severe adverse events are frequent and 20% of patients do not respond adequately. Current clinical developments focus exclusively on modulating B cell function or autoantibody half-life. However, topical modulation of PV autoantibody-induced blistering is an attractive target because it could promptly relieve symptoms. To address this issue, we performed an unbiased screening in a complex biological system using 141 low MW inhibitors from a chemical library. Specifically, we evaluated PV IgG-induced Dsg3 internalization in HaCaT keratinocytes. Validation of the 20 identified compounds was performed using keratinocyte fragmentation assays, as well as a human skin organ culture (HSOC) model. Overall, this approach led to the identification of four molecules involved in PV IgG-induced skin pathology: MEK1, TrkA, PI3Kα, and VEGFR2. This unbiased screening revealed novel mechanisms by which PV autoantibodies induce blistering in keratinocytes and identified new treatment targets for this severe and potentially life-threatening skin disease.


Second modified localized approximation for use in generalized Lorenz-Mie theory and other theories revisited.
Arbitrary electromagnetic shaped beams may be described by using expansions over a set of basis functions, with expansion coefficients containing subcoefficients named "beam shape coefficients" (BSCs). When BSCs cannot be obtained in closed form, and/or when the beam description does not exactly satisfy Maxwell's equations, the most efficient method to evaluate the BSCs is to rely on localized approximations. One of them, named the second modified localized approximation, has been presented in a way that may be found ambiguous in some cases. The aim of the present paper is to remove any ambiguity on the use of the second modified localized approximation.


Increased mortality associated with TCDD exposure in mice infected with influenza A virus is not due to severity of lung injury or alterations in Clara cell protein content.
Most studies examining the cause of increased mortality in mice infected with a normally non-lethal dose of influenza A virus after exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) have focused on defects in the immune system. This study examined other possible consequences of TCDD exposure, which could alter pulmonary inflammation during infection. We measured bronchoalveolar lavage (BAL) fluid lactate dehydrogenase (LDH) and protein concentrations and lung wet to dry weight ratios to assess lung damage and edema formation. Immunohistochemistry for Cyp1A1 was used to evaluate the responsiveness of the lung to TCDD. Additionally, we characterized the effects of TCDD on Clara cell secretory protein (CCSP), which plays a regulatory role in pulmonary inflammation. There were no differences in BAL fluid LDH and protein levels, lung wet to dry weight ratios, or the amount of CCSP in the lungs from mice treated with TCDD or vehicle control. The amount of Cyp1A1 in endothelial cells, Clara cells, and Type II pneumocytes was greatly induced after TCDD exposure. Although lung tissue was clearly responsive to TCDD as shown by Cyp1A1 induction, the increased mortality in infected mice exposed to TCDD did not correlate with increased damage to the lung or decreased CCSP concentrations.


["My life will be much better than before": a qualitative study on the relationship between renewal of public housing, quality of life, and health].
The objective was to understand the link between housing, health and quality of life in a context of social housing regeneration, through the experiences and perceptions of its inhabitants, exploring the mechanisms that sustain this link before regeneration, and those elements derived from housing regeneration that result in improvements in quality of life and potentially in health. Between 1980 and the 2000s, Chile faced a massive quantitative housing deficit through a policy that delivered more than 120,000 low-cost social housing apartments. Today, thousands present severe habitability problems, generating negative consequences for their inhabitants, their health and well-being. Seeking to solve the deterioration of housing and neighborhoods, the Chilean Ministry of Housing and Urbanism developed the Housing Complex Regeneration Program. The RUCAS project seeks to evaluate the effects of the program on health and to assess the impact of interventions such as these on vulnerable populations in Latin America. We present results of 8 interviews and 2 focus groups conducted in a social housing complex in process of intervention in Viña del Mar. Using discursive content analysis, results show that the poor material quality of housing is perceived as harmful to health. Regenerated housing, on the other hand, promotes the recovery and re-appropriation of spaces and their uses, sociability, new healthy practices, positive feelings and psychological well-being, bringing to the fore the psychosocial component of people's relationship with their house. It is concluded that housing regeneration has the potential to benefit physical and mental health through both direct mechanisms, derived from the renovated materiality, and indirect mechanisms related to the practices and experiences of the lived space.


Effects of Eu3+ on the metabolism of amino acid and protein in xerophytic Lathyrus sativus L.
The contents of amino acids and proteins and the activity of Na+,K+-ATPase were determined in roots, stems, and leaves of Eu3+-treated Lathyrus sativus L. The results showed that the treatment of Eu3+ made the contents of amino acid and protein and the activity of Na+,K+-ATPase change. The first possible mechanism was that Eu3+ directly made the electric potential of -NH2 or -COOH of amino acid change. The second possible mechanism was that Eu3+ played a role in metallic-activated factors of certain enzymes, which catalyze the catabolism and anabolism of protein. Then, the contents of amino acids and proteins were relatively changed. The third possible mechanism was that Eu3+ regulated the activity of ATPase through changing the Na+/K+ ratio. The energy released by ATPase was the driving force for the translocation of amino acids and proteins in the plant cell. Because of the changeability of its valence, Eu3+ played an important role in regulating certain physiological reactions to increase the adaptability of L. sativus in arid environment.


Current challenges in de novo plant genome sequencing and assembly.
Genome sequencing is now affordable, but assembling plant genomes de novo remains challenging. We assess the state of the art of assembly and review the best practices for the community.


Variation in microbial feature perception in the Rutaceae family with immune receptor conservation in citrus.
Although much is known about the responses of model plants to microbial features, we still lack an understanding of the extent of variation in immune perception across members of a plant family. In this work, we analyzed immune responses in Citrus and wild relatives, surveying 86 Rutaceae genotypes with differing leaf morphologies and disease resistances. We found that responses to microbial features vary both within and between members. Species in 2 subtribes, the Balsamocitrinae and Clauseninae, can recognize flagellin (flg22), cold shock protein (csp22), and chitin, including 1 feature from Candidatus Liberibacter species (csp22CLas), the bacterium associated with Huanglongbing. We investigated differences at the receptor level for the flagellin receptor FLAGELLIN SENSING 2 (FLS2) and the chitin receptor LYSIN MOTIF RECEPTOR KINASE 5 (LYK5) in citrus genotypes. We characterized 2 genetically linked FLS2 homologs from "Frost Lisbon" lemon (Citrus ×limon, responsive) and "Washington navel" orange (Citrus ×aurantium, nonresponsive). Surprisingly, FLS2 homologs from responsive and nonresponsive genotypes were expressed in Citrus and functional when transferred to a heterologous system. "Washington navel" orange weakly responded to chitin, whereas "Tango" mandarin (C. ×aurantium) exhibited a robust response. LYK5 alleles were identical or nearly identical between the 2 genotypes and complemented the Arabidopsis (Arabidopsis thaliana) lyk4/lyk5-2 mutant with respect to chitin perception. Collectively, our data indicate that differences in chitin and flg22 perception in these citrus genotypes are not the results of sequence polymorphisms at the receptor level. These findings shed light on the diversity of perception of microbial features and highlight genotypes capable of recognizing polymorphic pathogen features.


Optimal enzyme utilization suggests that concentrations and thermodynamics determine binding mechanisms and enzyme saturations.
Deciphering the metabolic functions of organisms requires understanding the dynamic responses of living cells upon genetic and environmental perturbations, which in turn can be inferred from enzymatic activity. In this work, we investigate the optimal modes of operation for enzymes in terms of the evolutionary pressure driving them toward increased catalytic efficiency. We develop a framework using a mixed-integer formulation to assess the distribution of thermodynamic forces and enzyme states, providing detailed insights into the enzymatic mode of operation. We use this framework to explore Michaelis-Menten and random-ordered multi-substrate mechanisms. We show that optimal enzyme utilization is achieved by unique or alternative operating modes dependent on reactant concentrations. We find that in a bimolecular enzyme reaction, the random mechanism is optimal over any other ordered mechanism under physiological conditions. Our framework can investigate the optimal catalytic properties of complex enzyme mechanisms. It can further guide the directed evolution of enzymes and fill in the knowledge gaps in enzyme kinetics.


Cannabis use and cognitive function in first episode psychosis: differential effect of heavy use.
First episode patients and patients with schizophrenia exhibit increased rates of cannabis use compared to the general population. Contrary to what has been reported in studies with healthy people, most of the published studies so far have reported no impairments or even beneficial effects on neurocognition associated with cannabis consumption in psychotic patients. However, these studies did not address the effects of very high cannabis consumption. Our aim in this study was to assess the effects on neurocognition of medium and heavy cannabis consumption in first psychotic episode patients. A total of 74 patients were included in the study and assigned to three different groups according to their mean cannabis consumption during the last year (non-users, medium users, and heavy users). Participants were administered verbal memory and other neurocognitive tasks. Heavy cannabis users were significantly impaired in all the verbal memory measures with respect to non-users, including immediate (p = .026), short-term (p = .005), and long-term (p = .002) memory. There were no significant differences between medium and non-users. Moreover, non-users performed better than all cannabis users in the arithmetic task (p = .020). Heavy cannabis consumption was associated with more commission errors in the continuous performance task (CPT) (p = .008) and more time to complete trail making test A (TMT-A) (p = .008), compared to the group of medium users. Heavy cannabis consumption seems to impair verbal memory in first psychotic episode patients. Heavy users also perform worse than medium users in other neurocognitive tasks. Based on the results and the available evidence, a dose-related effect of cannabis consumption is suggested.


Spectroscopic snapshots of the proton-transfer mechanism in water.
The Grotthuss mechanism explains the anomalously high proton mobility in water as a sequence of proton transfers along a hydrogen-bonded (H-bonded) network. However, the vibrational spectroscopic signatures of this process are masked by the diffuse nature of the key bands in bulk water. Here we report how the much simpler vibrational spectra of cold, composition-selected heavy water clusters, D+(D2O)n, can be exploited to capture clear markers that encode the collective reaction coordinate along the proton-transfer event. By complexing the solvated hydronium "Eigen" cluster [D3O+(D2O)3] with increasingly strong H-bond acceptor molecules (D2, N2, CO, and D2O), we are able to track the frequency of every O-D stretch vibration in the complex as the transferring hydron is incrementally pulled from the central hydronium to a neighboring water molecule.


Corrigendum: Radiomics Analysis of Multi-Sequence MR Images For Predicting Microsatellite Instability Status Preoperatively in Rectal Cancer.
[This corrects the article DOI: 10.3389/fonc.2021.697497.].


Biocomputing security system: concatenated enzyme-based logic gates operating as a biomolecular keypad lock.
A biomolecular security system mimicking a keypad lock device was developed using enzyme-based concatenated AND logic gates resulting in the implication logic network.


The effect of fluoridation and its discontinuation on fluoride profiles in the alveolar bone of rat.
We investigated the effect of fluoridation and its discontinuation on fluoride content in the alveolar portion of the mandible in rats. Drinking water with three different fluoride contents (0, 50, 100 ppmF) was given to rats for three different periods (4, 13 and 25 weeks). Fluoride concentrations were measured in the crest, the middle, and the apical parts of the alveolar bone and in the body of the mandible. Furthermore, after fluoridated drinking water was given to rats for 4 or 13 weeks, distilled water was given to them for 21 or 12 weeks respectively; and the effect of the discontinuation on fluoride profiles was investigated. Layer samples were analyzed by abrasive microsampling. Fluoride and phosphorus concentrations were determined by ion-specific electrode and colorimetric procedures, respectively. There was an increase in fluoride concentrations in the mandible in proportion to the fluoride content in the drinking water and the duration of fluoridation. After fluoridation was discontinued, fluoride concentrations in the surface layers of the mandible presented a decrease. Among the four different parts of the mandible, the upper part of the alveolar bone and the alveolar crest part presented the highest rates of reduction. The relative reduction rate of fluoride concentration was closely related to the duration of discontinuation. The alveolar crest was affected most by the discontinuation of fluoridation, presenting the greatest reduction.


Assessing the role of oxygen on ring current formation and evolution through numerical experiments.
Low O+/H+ ratio produced stronger ring currentInclusion of physics-based ionospheric outflow leads to a reduction in the CPCPOxygen presence is linked to a nightside reconnection point closer to the Earth.


Unfolding and Translocation of Proteins Through an Alpha-Hemolysin Nanopore by ClpXP.
Proteins present a significant challenge for nanopore-based sequence analysis. This is partly due to their stable tertiary structures that must be unfolded for linear translocation, and the absence of regular charge density. To address these challenges, here we describe how ClpXP, an ATP-dependent protein unfoldase, can be harnessed to unfold and processively translocate multi-domain protein substrates through an alpha-hemolysin nanopore sensor. This process results in ionic current patterns that are diagnostic of protein sequence and structure at the single-molecule level.


In situ monitoring of Lentilactobacillus parabuchneri biofilm formation via real-time infrared spectroscopy.
Foodborne pathogenic microorganisms form biofilms at abiotic surfaces, which is a particular challenge in food processing industries. The complexity of biofilm formation requires a fundamental understanding on the involved molecular mechanisms, which may then lead to efficient prevention strategies. In the present study, biogenic amine producing bacteria, i.e., Lentilactobacillus parabuchneri DSM 5987 strain isolated from cheese were studied in respect with biofilm formation, which is of substantial relevance given their contribution to the presence of histamine in dairy products. While scanning electron microscopy was used to investigate biofilm adhesion at stainless steel surfaces, in situ infrared attenuated total reflection spectroscopy (IR-ATR) using a custom flow-through assembly was used for real-time and non-destructive observations of biofilm formation during a period of several days. The spectral window of 1700-600 cm-1 provides access to vibrational signatures characteristic for identifying and tracking L. parabuchneri biofilm formation and maturation. Especially, the amide I and II bands, lactic acid produced as the biofilm matures, and a pronounced increase of bands characteristic for extracellular polymeric substances (EPS) provide molecular insight into biofilm formation, maturation, and changes in biofilm architecture. Finally, multivariate data evaluation strategies were applied facilitating the unambiguous classification of the observed biofilm changes via IR spectroscopic data.


Phosphorylated 4E-binding protein 1 expression is associated with poor prognosis in small-cell lung cancer.
Phosphorylation of eukaryotic translation initiation factor 4E (eIF4E) binding protein (4E-BP1) results in release of eIF4E, which sequentially relieves translational repression and enhances oncogenic protein synthesis. We assessed the expression of phosphorylated 4E-BP1 (p-4E-BP1) in small-cell lung cancer (SCLC) and its correlation with clinicopathological factors and patient survival. This study included 117 SCLCs, which comprised 108 primary and 9 metastatic tumor tissues. We performed immunohistochemical staining for p-4E-BP1 in 117 tumors and found that 77 (66 %) were positive for p-4E-BP1 with cytoplasmic and/or nuclear immunostaining. The positive rate of p-4E-BP1 staining was significantly higher in never smokers (p = 0.034) and metastatic tumor tissues (p = 0.027). Patients with p-4E-BP1-positive SCLC tended to have poor performance status, although the difference was not statistically significant (p = 0.087). High p-4E-BP1 expression was significantly correlated with worse overall survival (OS) in all cohorts (p = 0.016). After stratification by clinical stage, p-4E-BP1 expression showed a stronger relationship with OS in patients with limited disease (p = 0.008). In addition, when stratified by treatment status, p-4E-BP1 expression was still significantly associated with worse OS in a subgroup of patients who completed treatment (p = 0.021). Our results indicate that p-4E-BP1 expression could represent oncogenic potential and contribute to the progression and aggressiveness of SCLC, suggesting it could be a candidate prognostic biomarker of SCLC, especially in limited disease.


Positive association of phencyclidine-responsive genes, PDE4A and PLAT, with schizophrenia.
As schizophrenia-like symptoms are produced by administration of phencyclidine (PCP), a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptors, PCP-responsive genes could be involved in the pathophysiology of schizophrenia. We injected PCP to Wistar rats and isolated five different parts of the brain in 1 and 4 hr after the injection. We analyzed the gene expression induced by the PCP treatment of these tissues using the AGILENT rat cDNA microarray system. We observed changes in expression level in 90 genes and 21 ESTs after the treatment. Out of the 10 genes showing >2-fold expressional change evaluated by qRT-PCR, we selected 7 genes as subjects for the locus-wide association study to identify susceptibility genes for schizophrenia in the Japanese population. In haplotype analysis, significant associations were detected in combinations of two SNPs of BTG2 (P = 1.4 × 10(-6) ), PDE4A (P = 1.4 × 10(-6) ), and PLAT (P = 1 × 10(-3) ), after false discovery rate (FDR) correction. Additionally, we not only successfully replicated the haplotype associations in PDE4A (P = 6.8 × 10(-12) ) and PLAT (P = 0.015), but also detected single-point associations of one SNP in PDE4A (P = 0.0068) and two SNPs in PLAT (P = 0.0260 and 0.0104) in another larger sample set consisting of 2,224 cases and 2,250 controls. These results indicate that PDE4A and PLAT may be susceptibility genes for schizophrenia in the Japanese population.


Increased association of Trypanosoma cruzi with sialoadhesin positive mice macrophages.
Trypanosoma cruzi is a parasite with large amounts of sialic acid (SA) residues exposed at its surface that seems to be involved in macrophages infection. Some macrophages, present in T. cruzi infected tissues, expresses sialoadhesin (Sn), a receptor that recognizes SA. Thus, the involvement of Sn in the association of T. cruzi to macrophages was investigated. Sn was induced in mice peritoneal macrophages by homologous serum (HS) cultivation. Epimastigotes and trypomastigotes associated more to HS cultured macrophages than to fetal bovine serum (FBS). Blocking of Sn with antibodies reduced the association of trypomastigotes to similar level as for FBS cultured macrophages. Desialylation reduced the association of parasites to HS cultured macrophages indicating the Sn importance. Furthermore, the entrance mechanism of trypomastigotes to Sn positive macrophages has a phagocytic nature as demonstrated by scanning electron microscopy and cytochalasin D treatment. Sn positive macrophages may important in the initial trypomastigote infection, thus in the establishment of Chagas disease.


Ab Initio Modeling of Donor-Acceptor Interactions and Charge-Transfer Excitations in Molecular Complexes: The Case of Terthiophene-Tetracyanoquinodimethane.
This work presents a thorough quantum chemical study of the terthiophene-tetracyanoquinodimethane complex as a model for π-π donor-acceptor systems. Dispersion-corrected hybrid (B3LYP-D) and double hybrid (B2PLYP-D), hybrid meta (M06-2X and M06-HF), and recently proposed long-range corrected (LC-wPBE, CAM-B3LYP, and wB97X-D) functionals have been chosen to deal with π-π intermolecular interactions and charge-transfer excitations in a balanced way. These properties are exhaustively compared to those computed with high-level ab initio SCS-MP2 and CASPT2 methods. The wB97X-D functional exhibits the best performance. It provides reliable intermolecular distances and interaction energies and predicts a small charge transfer from the donor to the acceptor in the ground state. In addition, wB97X-D is also able to yield an accurate description of the charge-transfer excitations in comparison to benchmark CASPT2 calculations.


Developing and implementing universal guidelines for oral patient presentation skills.
Oral case presentations are important for patient care and clinical education. Previously published attempts to improve oral presentation skills have been labor intensive and have focused primarily on medical students. We created a multifaceted intervention to improve oral case presentations of medical students and internal medicine residents. Our intervention included a written handout with detailed instructions, pocket cards, model presentations, and multiple teaching sessions. The intervention was developed by consensus, supported by the department of medicine and endorsed by key faculty within the department. In addition to soliciting feedback from students and residents, we evaluated our intervention with prospectively acquired ratings of student oral case presentation skills recorded on a standardized evaluation for the internal medicine clerkship. Students, residents, and faculty gave positive feedback, although they noted some practical obstacles to effective oral case presentations. After dissemination of the guidelines, 44% of students (42/96) were rated as "excellent" in oral presentation skills on standardized evaluations of the internal medicine clerkship, compared to 30% in the previous academic year (33/111; odds ratio [OR]=1.8, 95% confidence interval=1.04-3.3; p=.036). A multifaceted intervention improved medical student oral case presentation skills. Although participants noted barriers that need further attention, we demonstrated modest improvement in student performance.


Association of the T-cell regulatory gene CTLA4 with Graves' disease and autoimmune thyroid disease in the Japanese.
Autoimmune thyroid disease (AITD) is caused by an immune response to self-thyroid antigen. The cytotoxic T-lymphocyte antigen-4 ( CTLA4) gene, encoding a negative regulator of the T-lymphocyte immune response, had been reported to be associated and/or linked to AITD. Recently, AITD susceptibility in the Caucasians was mapped to the 6.1-kb 3'UTR of the CTLA4 gene, in which the three single-nucleotide polymorphisms (SNPs) CT60, JO31, and JO30 were strongly associated with AITD. In order to determine the association of the CTLA4 gene with AITD in the Japanese, case-control association analysis for the four SNPs of the CTLA4 gene using 380 AITD patients and 266 healthy controls was done. Among the SNPs examined, the SNP JO31 was most significantly associated with AITD in the Japanese, whereas the association of the JO30 with AITD was not observed. The frequency of the disease-susceptible G allele of the JO31 of the Japanese control was higher than that of the Caucasians (67.1% vs 50.2%); however, the G allele of the JO31 was associated with Graves' disease (GD) (67.1% vs 76.3%, P=0.0013) and AITD in the Japanese (67.1% vs 74.2%, P=0.0055). Furthermore, the G allele of the JO31 was associated with the increased risk for GD [ P=0.0051, odds ratio (OR)=1.7] and AITD ( P=0.016, OR=1.5) in a dominant model. These results suggested that the CTLA4 gene is involved in the susceptibility for GD and AITD in the Japanese.


Button battery ingestion: A serious pitfall of diagnosis of ingested foreign bodies in children from resource-limited settings - A case report.
Button battery ingestion and impaction in the oesophagus can result in severe morbidity and even fatality if not diagnosed and managed urgently. Delayed or missed diagnosis due to the sometimes-vague symptomatology and limited investigations in resource-limited settings further increases the complications rate. Case 1: A 2 years old male child presented with a nine months history of recurrent respiratory tract infections not responding well to medical treatment. A radio-opaque round foreign body (FB) was incidentally seen in the chest. Rigid esophagoscopy and removal were done, but the child had developed a trachea oesophagal fistula. The fistula was managed conservatively by retaining a nasogastric tube until spontaneous fistula closure happened. Case 2: A 2 years old female child presented with a one-year history of poor feeding, vomiting, difficulty in breathing and persistent wet cough, and fever. He underwent tonsillectomy with no improvement. A radio-opaque round FB was incidentally seen in the oesophagus near the carina by a chest x-ray. A thoracotomy had to be done after two failed removal attempts by rigid esophagoscopy. The similarity in the symptomatology of common aerodigestive conditions with FB ingestion compounded with low chances of witnessing the ingestion creates a possible pitfall for clinicians when resulting in a missed or a delayed diagnosis, further raising the complications rate of FB impaction in the oesophagus, such as tracheoesophageal fistula formation or the need for a massive surgery such as thoracotomy to remove the button battery. Complications of foreign body ingestion in the paediatric population can have serious complications. High morbidity and mortality may be attributed to delayed diagnosis and intervention.


[A brain abscess of mycotic origin due to Histoplasma capsulatum].
The case here presented is one of the histoplasmosis cases occurring sporadically in Romania. It is the first case with cerebral site and with the aspect of an extensive intracranial process. The diagnosis was made by a careful microscopic examination of the intraoperative specimens.


Pediatric toxicologic concerns.
Pediatric poisonings account for significant morbidity in the United States each year. Clinicians must keep current with advances in toxicology to be familiar with the latest recommended treatment regimens and antidotes. They also must be familiar in identifying toxidromes and important physical examination findings. Having these skills can enable the clinician to determine who is at risk for significant morbidity or mortality and to provide the appropriate medical care.


The effect of bidisomide (SC-40230), a new class Ia/Ib antiarrhythmic agent, on defibrillation energy requirements in dogs with healed myocardial infarctions.
Bidisomide is a Class Ia/Ib antiarrhythmic agent with activity against ventricular and supraventricular arrhythmias. The potential for bidisomide to increase defibrillation threshold (DFT) was tested in anesthetized dogs with healed left ventricular infarcts (> or = 10 days). Defibrillation patches were attached to each ventricle and shocks were delivered via an external cardioverter/defibrillator. Three groups were studied: placebo (saline), canine therapeutic bidisomide (TB, 2-5 micrograms/mL plasma concentration) and supratherapeutic bidisomide (STB, 6-14 micrograms/mL). Each animal received only one treatment. An abbreviated DFT curve was determined before and after treatment. Heart rate, blood pressure, PR, QRS, infarct size, and hematocrit were also measured before and after treatment. DFT was significantly increased (average +3 to +5 joules [J], P < 0.05) by TB and STB. TB (5/5) did not increase DFT beyond 40 J. In 6/7 experiments, STB did not increase DFT beyond 40 J. Placebo (n = 6) had no significant effect on DFT. Infarct size (mean = 11% of the left ventricle) was not significantly different between groups. Heart rate and QRS were not significantly altered but blood pressure was significantly decreased (16%-31% systolic, 29%-45% diastolic) and hematocrit was significantly increased (19% to 25%) in all groups. PR was significantly increased by STB only. therapeutic and supratherapeutic doses of bidisomide slightly but significantly increased DFT (3-5 J) in a canine infarcted heart model.


Structural characterization of lyotropic liquid crystals containing a dendrimer for solubilization and release of gallic acid.
The role of 2nd generation polypropyleneimine (PPIG2) dendrimer in controlling the release of gallic acid (GA) as a model drug from lyotropic liquid crystal was explored. GA (0.2wt%) was solubilized in three types of mesophases: lamellar (Lα), cubic (space group of Ia3d, Q(G)), and reverse hexagonal (HII), composed of GMO and water (and d-α-tocopherol, or tricaprylin in the case of HII mesophases). Small angle X-ray scattering (SAXS) and attenuated total reflectance Fourier transform infrared (ATR-FTIR) along with UV spectrophotometry were utilized to elucidate the structure modifications and release resulting from the cosolubilization of GA and PPIG2. Solubilization of PPIG2 into Lα and Q(G) phases caused transformation of both structures to HII. The diffusion of GA out of the mesophases was found to be dependent on water content and PPIG2 concentration. Rapid release from Lα+PPIG2 and Q(G)+PPIG2 mesophases was recorded. The release from both HII mixtures (with d-α-tocopherol and tricaprylin) was shown to be dependent on the type of oil. Release studies conducted for 72h showed that GA release can be modulated and sustained by the presence of PPIG2, supposedly due to the electrostatic interactions between the dendrimer and the drug molecule.


The evaluation of serial measurements of the NK cell activity in man.
Studies on the NK cell activity require extensive controls because it is known that a series of variables can influence both the quality of effector cells and of target cells. This known variation of the susceptibility to lysis in one target cell line or even in sublines requires "standards", if separately performed experiments should be compared. In some laboratories, the experiments have been controlled for the variation of the target cell's susceptibility to lysis; others control for the differences of NK cell activities among subjects or for the variation of the NK cell activity in individuals from day to day. Each of these methods concentrates the main point of control to a particular variable. To demonstrate the power of several variables in relation to an induced and expected variation of the NK cell activity, we describe in this paper the results of a factorial analysis of variance testing PB-MNC from healthy donors against two target cells. The in vitro treatment of PB-MNC by IFN was chosen as induced variation of NK cell activity. As variables of the system, we defined subjects, days, target cells, and the effect of IFN. It is shown that the induced variable (IFN-treatment) counts for the most powerful variance component (32% of the total variance). Other large variance components are the differences of NK cell activities among subjects (20%), the day to day variation of the subjects' NK cell activities (13%), and the day to day variation of the susceptibility of target cells to lysis (13%). Since it is almost impossible to control for all variables in an experiment, some variables have to be selected which should be controlled for. The quantification of the variables, which is possible by a factorial analysis of variance, is useful for that purpose. This method of data analysis allows to estimate further the relevance of a particular expected effect if several variables, as in NK cell tests, influence the result of the experiment.


'Thrown in at the deep end': a qualitative analysis into the transition from trainee to consultant during the COVID-19 pandemic and lessons for the future.
Sustained crises such as the COVID-19 pandemic would be expected to impact the transition from trainee to consultant for anaesthetists or intensivists, but limited research exists on this important topic. This study aimed to examine the social context of this crucial career transition during the pandemic and post-pandemic periods. We conducted semi-structured interviews with anaesthetists and intensivists who became consultants after the first UK lockdown. Thematic analysis was used and data saturation was reached at 33 interviews. The pandemic substantially impacted the transition to consultant role in various ways, including professional identity, clinical and non-clinical responsibilities, and wellbeing. Participants experienced identity confusion, self-doubt, and moral injury, resulting in intense emotional distress, feelings of guilt and helplessness, which persisted beyond the pandemic. They also felt unprepared for their consultant roles because of disruptions in training. The pandemic exaggerated the vulnerability of those transitioning to consultants, because of increased clinical uncertainties, and pressures of the growing backlog. Additionally, the pandemic impacted on the wellbeing of those transitioning to consultants, intensifying feelings of anxiety and stress. We also identified unique opportunities presented by the pandemic, which accelerated learning and encouraged post-traumatic growth. Our study identified practical solutions that may improve transition experience at individual, organisational, and national levels. Persistent crises significantly impact the transition from trainee to consultant. Our findings generated insights into the challenges of this critical career transition and staff wellbeing, and serve to inform approaches of ongoing support for those transitioning to consultants.


Synthesis of 17-epi-calcitriol from a common androstane derivative, involving the ring B photochemical opening and the intermediate triene ozonolysis.
An efficient synthesis of 17-epi-calcitriol 2, an epimer of natural hormone, via 17-epi-cholesterol 5a is described. Synthesis of 5a includes palladium-catalyzed cyclopropanation of the common androstane derivative 7 with an alkyl diazoacetate, reductive fission of the less shielded side of cyclopropane carboxylic acid esters 6, oxidation of the products into acid 11a, and alkylation of ester 11b. Photolysis of 7,8-dedydro-17-epi-25-hydroxycholesterol 19b and consecutive thermal rearrangement gave a mixture of several products that was subjected to ozonolysis to provide, after chromatography, hydroxy ketone 3a. The silyl derivative 3b was coupled with the respective ring A building block.


Planar π-aromatic C3h B6H(3)(+) and π-antiaromatic C2h B8H2: boron hydride analogues of D3h C3H(3)(+) and D2h C4H4.
Based upon extensive density functional theory and wave function theory calculations performed in this work, we predict the existence of the perfectly planar triangle C(3h) B(6)H(3)(+) (1, (1)A') and the double-chain stripe C(2h) B(8)H(2) (9, (1)A(g)) which are the ground states of the systems and the inorganic analogues of cyclopropene cation D(3h) C(3)H (3) (+) and cyclobutadiene D(2h) C(4)H(4), respectively. Detailed adaptive natural density partitioning (AdNDP) analyses indicate that C(3h) B(6)H (3) (+) is π plus σ doubly aromatic with two delocalized π-electrons and six delocalized σ-electrons formally conforming to the 4n + 2 aromatic rule, while C(2h) B(8)H(2) is π antiaromatic and σ aromatic with four delocalized π-electrons and ten delocalized σ-electrons. The perfectly planar C(2h) B(8)H(4) (5, (1)A(g)) also proves to be π antiaromatic analogous to D(2h) C(4)H(4), but it appears to be a local minimum about 50 kJ mol(-1) less stable than the three dimensional C(s) B(8)H(4)(6, (1)A'). AdNDP, nucleus independent chemical shifts (NICS) and electron localization function (ELF) analyses indicate that these boron hydride clusters form islands of both σ- and π-aromaticities and are overall aromatic in nature in ELF aromatic criteria.


Nitric oxide synthase activities in human myocardium.
Myocardial constitutive and inducible nitric oxide (NO) synthase activities were measured in right ventricular tissue from 17 patients with dilated cardiomyopathy (DCM). A significant activity of inducible enzyme was accompanied by a low activity of the constitutive NO synthase. Thus, the myocardium has the capacity to express both NO synthases. NO may have a physiological as well as a pathological role in the human myocardium.


The ECG role in identifying the etiology of tachycardia-induced cardiomyopathy (TIC).
Tachycardia-induced cardiomyopathy (TIC) is a well recognized entity of heart failure (HF) and various mechanisms due to tachyarrhythmias have been postulated to be responsible for impaired cardiac contractility. Previously reported cases showed reversibility of such disorders whenever stable cardiac rhythm is maintained adequately and we report on a 16-year-old boy who has been diagnosed to have TIC, which was misinterpreted initially as sinus tachycardia secondary to dilated cardiomyopathy and heart failure. A complete recovery of his left ventricular function was achieved by radiofrequency catheter ablation and highlights the importance of a 12-lead electrocardiogram (ECG) assessment in such patients.


[Jaundice and pancreatic mass: typical clinical presentation of a rare disease].
An 81-year-old man presented with jaundice and a pancreatic tumor. 6 years ago transperitoneal nephrectomy had been performed because of a clear cell renal cancer (pT3b pN0 pM0). Laboratory tests showed normocytic anemia and signs of cholestasis. Abdominal ultrasonography revealed a well-defined mass of the head of the pancreas with a diameter of about 4 cm, and a previously diagnosed adrenal mass which had slightly increased in size. Contrast-enhanced ultrasound demonstrated a hyperenhancing of the pancreatic mass, untypical for primary adenocarcinoma of the pancreas. Endoscopic ultrasound-guided fine-needle aspiration disclosed a metastasis of the previously resected renal cancer. Bilary spincterotomy and stent insertion were performed. Because of proven pancreatic metastasis and suspected adrenal metastasis of renal cancer palliative treatment with multi-targeted receptor tyrosine kinase inhibitor sunitinib was initiated. Renal cell carcinomas are the most common primary tumors leading to pancreatic metastasis. In contrast to ductal adenocarcinoma pancreatic metastasis shows hyperenhancement when examined by using contrast-enhanced ultrasonography. Endoscopic ultrasound-guided fine-needle aspiration helps to confirm the suspected diagnosis.


Lack of sister-chromatid exchange induction by polymethyl methacrylate bone cement in human lymphocytes cultured in vitro.
Human lymphocytes cultured in vitro were used to assess the ability of polymethyl methacrylate (PMMA), currently used in orthopedic surgery as bone cement, to induce sister-chromatid exchanges (SCE). Under the conditions used in this study, PMMA bone cement did not produce any significant increase in SCEs in phytohemagglutinin-stimulated human lymphocytes. However, a significant decline (p less than 0.05) in the proliferation rate index was observed, which might be an indicator of the cytotoxic effect of PMMA.


Efficacy Outcomes of Brolucizumab Versus Aflibercept in Neovascular Age-Related Macular Degeneration Patients with Early Residual Fluid.
To compare the outcomes of brolucizumab versus aflibercept in patients with neovascular age-related macular degeneration with early residual fluid in the HAWK and HARRIER studies. Post hoc analysis using pooled data from the phase 3 studies HAWK (NCT02307682) and HARRIER (NCT02434328). The early residual fluid cohort for this post hoc analysis consisted of patients treated with either brolucizumab 6 mg (n = 730 patients) or aflibercept 2 mg (n = 729 patients) and who had the presence of intraretinal fluid (IRF), subretinal fluid (SRF), or both verified by spectral-domain OCT at the week 12 clinic visit. After 3 initial monthly doses, patients treated with brolucizumab received injections every 12 weeks (q12w) or every 8 weeks (q8w), depending on the neovascular age-related macular degeneration disease activity, whereas patients treated with aflibercept received fixed q8w dosing. The mean change in best-corrected visual acuity and central subfield thickness (CST) from the baseline to that at weeks 48 and 96, the proportion of patients treated with brolucizumab remaining on q12w dosing to week 96, and the change in fluid status at weeks 48 and 96. All analyses were based on 149 of 730 (20.4%) patients treated with brolucizumab and 217 of 729 (29.8%) patients treated with aflibercept with spectral-domain OCT-verified IRF, SRF, or both at their week 12 visit. The best-corrected visual acuity improvements from baseline at weeks 48 and 96 were numerically better for brolucizumab than for aflibercept (least square mean [standard error] 7.9 ± 1.1 vs. 4.6 ± 0.9 and 7.4 ± 1.3 vs. 2.9 ± 1.1 letters, respectively). The CST reductions from baseline at weeks 48 and 96 were consistently greater with brolucizumab than with aflibercept (least square mean [standard error], μm: -194.9 ± 13.7 vs. -123.9 ± 11.3; and -201.1 ± 14.5 vs. -134.2 ± 12.0, respectively). At weeks 48 and 96, patients treated with brolucizumab had a 40.4% and 31.3% probability of remaining on q12w dosing intervals, respectively. Fewer patients treated with brolucizumab had remaining IRF, SRF, or both at weeks 48 and 96 than patients treated with aflibercept (59.1% vs. 75.1% and 49.0% vs. 60.4%, respectively). In patients with early residual fluid, defined as spectral-domain OCT-verified IRF, SRF, or both at the week 12 clinic visit, brolucizumab resolved the early residual fluid and reduced CST more effectively than aflibercept, resulting in greater best-corrected visual acuity improvements through week 96 of anti-VEGF treatment.


Scleroderma with massive regional lymphadenopathy.
Scleroderma in a two-year-old boy with gross enlargement of the right inguinal lymph nodes, as an early sign, is reported. Repeated lymph node biopsies revealed non-characteristic reactive changes and hyperplasia, but eventually histological examination of skin and muscle from the right leg were diagnostic. The effect of one year of D-penicillamine therapy is briefly mentioned.


Morphometric analysis of gray matter integrity in individuals with early-treated phenylketonuria.
The most widely-reported neurologic finding in individuals with early-treated phenylketonuria (PKU) is abnormality in the white matter of the brain. In contrast, much less is known regarding the impact of PKU on cortical gray matter (GM) structures. Presently, we applied advanced morphometric methods to the analysis of high-resolution structural MRI images from a sample of 19 individuals with early-treated PKU and an age- and gender-matched comparison group of 22 healthy individuals without PKU. Data analysis revealed decreased GM volume in parietal cortex for the PKU group compared with the non-PKU group. A similar trend was observed for occipital GM volume. There was no evidence of group-related differences in frontal or temporal GM volume. Within the PKU group, we also found a significant relationship between blood phenylalanine levels and GM volume for select posterior cortical sub-regions. Taken together with previous research on white matter and gray matter abnormalities in PKU, the present findings point to the posterior cortices as the primary site of neurostructural changes related to early-treated PKU.


Dynamic biomechanical investigation of a novel sulcus bicipitalis plate in combination with a conventional locking plate for the treatment of complex proximal humerus fractures.
Complex proximal humerus fractures place high demands on osteosynthetic treatment. In some cases, double plating has already been used to increase primary stability of the osteosynthesis. This approach was advanced in the present study by developing an additive plate for the sulcus bicipitalis. To demonstrate the superior primary stability of the newly developed plate osteosynthesis, a biomechanical comparison against a conventional locking plate with an additional calcar screw was performed. Ten pairs of cadaveric humeri were treated proximally with a locking plate (PENTA plate small fragment, INTERCUS). Each had a two-part fracture model with a fracture gap of 10 mm. All right humeri were treated with an additive novel plate that extends along the bicipital sulcus and encircles the lesser tuberosity proximally. First, the specimens were loaded sinusoidally at 250 N in 20° abduction for 5000 cycles. Afterwards quasi-static loading until failure was applied. The movement at the fracture gap due to the cyclic loading occurred mainly as rotation around the z-axis, corresponding to a tilt medially and distally. The double plate osteosynthesis reduces the rotation by approximately 39%. For all load cycles observed, except 5000 cycles, medial and distal rotation of the head was significantly reduced by the double plate. The failure loads showed no significant differences between the groups. In the tested scenario under cyclic loading, the novel double plate osteosynthesis showed a significant superiority of primary stability over the conventional treatment with one locking plate. Furthermore, the study showed the advantages of cyclic load application over quasi-static load application until failure.


Early life body size, pubertal timing, and risks of benign breast disease in a large cohort of Danish female adolescents and women.
A high childhood body mass index (BMI) may be protective against benign breast disease (BBD), but little is known about the effects of other early life body size measures. Thus, we examined associations between birthweight, childhood BMI, height, and pubertal timing and BBD risks. We included 171,272 girls, born from 1930 to 1996, from the Copenhagen School Health Records Register, which contains information on birthweight, childhood anthropometry (7-13 years), age at onset of the growth spurt (OGS), and peak height velocity (PHV). During follow-up, 9361 BBD cases (15-50 years) were registered in the Danish National Patient Register. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated by Cox regressions. At all childhood ages, BMI was inversely but non-linearly associated with BBD. The association was slightly stronger in magnitude for BMI z-scores above 0 (HRage 7 = 0.86; 95%CI: 0.83-0.90 per z-score) than below 0 (HRage 7 = 0.95; 95%CI 0.91-0.99 per z-score). Associations between childhood height and BBD differed by age; at 7 years the association was an inverted U-shape, whereas at 13 years height was not associated with BBD. Ages at OGS and PHV were positively associated with BBD. Low and high birthweights were associated with lower BBD risks. Conclusion: A high childhood BMI, a short or tall stature at young childhood ages, an early pubertal onset, and low or high birthweights are associated with reduced risks of BBD. These complex associations suggest that the role of these factors in breast tissue development during early life warrants further investigation in relation to BBD etiology. What is Known: • Benign breast disease (BBD) is common and may be an intermediary marker of breast cancer risks. • Early life body size may relate to the development of BBD, but currently little is known. What is New: • Girls with a high body mass index at school ages or with an early pubertal timing have decreased risks of BBD. • Short and tall heights at young childhood ages and low and high birthweights are associated with lower BBD risks.


Short-Term Impact of the Frequency of COPD Exacerbations on Quality of Life.
Chronic obstructive pulmonary disease (COPD) patients in the Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD (STATCOPE) and Azithromycin for Prevention of Exacerbations of COPD (MACRO) trials provide an opportunity to prospectively study the short-term effect of acute exacerbations of COPD (AECOPDs). We hypothesized that those patients with frequent exacerbations (≥2 AECOPDs per patient year) would experience greater short-term decline in quality of life as measured by the St George's Respiratory Questionnaire (SGRQ). A total of 1934 COPD patients were randomized in STATCOPE or MACRO. Patients who were randomized to azithromycin in MACRO or were followed less than 180 days were excluded. A total of 1219 patients were included. Patients were divided into 2 groups: infrequent exacerbators (< 2 exacerbations per patient year), and frequent exacerbators (≥2 exacerbations per year.) Data were collected at baseline, measured over time, and compared between groups. Of the patients studied, 871 were in the infrequent exacerbators group. A total of 348 were in the frequent exacerbators group. Frequent exacerbators used more respiratory medications, were more likely to have used oxygen, steroids, or antibiotics in the 12 months preceding study entry, had more obstruction on spirometry, and had more severe symptoms as measured by SGRQ at baseline. Over at least 180 days, symptom scores worsened in frequent exacerbators and improved in infrequent exacerbators. Patients with frequent exacerbations of COPD experienced a short-term slight worsening of severely impaired SGRQ symptoms scores, while patients with infrequent exacerbations experienced improvement while on COPD therapies.


Association of Hippocampal Subfields, CSF Biomarkers, and Cognition in Patients With Parkinson Disease Without Dementia.
To examine whether hippocampal volume loss is primarily associated with cognitive status or pathologic β-amyloid 1-42 (Aβ42) levels, this study compared hippocampal subfield volumes between patients with Parkinson disease (PD) with mild cognitive impairment (PD-MCI) and without cognitive impairment (PD-CN) and between patients with low and high Aβ42 levels, in addition exploring the relationship among hippocampal subfield volumes, CSF biomarkers (Aβ42, phosphorylated and total tau), neuropsychological tests, and activities of daily living. Forty-five patients with PD without dementia underwent CSF analyses and MRI as well as comprehensive motor and neuropsychological examinations. Hippocampal segmentation was conducted using FreeSurfer image analysis suite 6.0. Regression models were used to compare hippocampal subfield volumes between groups, and partial correlations defined the association between variables while controlling for intracranial volume (ICV). Linear regressions revealed cognitive group as a statistically significant predictor of both the hippocampal-amygdaloid transition area (HATA; β = -0.23, 95% CI -0.44 to -0.02) and the cornu ammonis 1 region (CA1; β = -0.28, 95% confidence interval [CI] -0.56 to -0.02), independent of disease duration and ICV, with patients with PD-MCI showing significantly smaller volumes than PD-CN. In contrast, no subfields were predicted by Aβ42 levels. Smaller hippocampal volumes were associated with worse performance on memory, language, spatial working memory, and executive functioning tests. The subiculum was negatively correlated with total tau levels (r = -0.37, 95% CI -0.60 to -0.09). Cognitive status, but not CSF Aβ42, predicted hippocampal volumes, specifically the CA1 and HATA. Hippocampal subfields were associated with various cognitive domains, as well as with tau pathology.


Amelioration of osteopenia and hypovitaminosis D by 1alpha-hydroxyvitamin D3 in elderly patients with Parkinson's disease.
A high prevalence of hip and other fractures in elderly patients with Parkinson's disease has been linked to reduced bone mass arising from a defect of renal synthesis of 1, 25-dihydroxyvitamin D (1, 25-[OH]2D). Treatment with 1alpha-hydroxyvitamin D3 (1alpha(OH)D3; an active form of vitamin D) was evaluated for maintaining bone mass and reducing the incidence of hip and other nonvertebral fractures in patients with Parkinson's disease. In a double blind, randomised trial, 86 elderly patients with Parkinson's disease (mean Hoehn and Yahr stage, 3; mean age 70.6 years) were randomised to receive either 1 microg 1alpha(OH)D3 daily (treatment group, n=43) or a placebo (n=43) for 18 months. Bone mineral densities in the second metacarpals were determined by computed radiographic densitometry. Serum bone turnover indices were measured serially, and incidence of nonvertebral fractures was recorded. Bone mineral densities decreased 1.2% in the treatment group compared with 6.7% in the placebo group during 18 months (p<0.0001). At baseline in both groups, the serum concentration of 1, 25-[OH]2D was reduced. Parathyroid hormone was abnormally increased in 15 patients (17%) and correlated negatively with serum 25-hydroxyvitamin D, indicating compensatory hyperparathyroidism. Eight patients sustained fractures (six at the hip and two at other sites) in the placebo group, and one hip fracture occurred among treated patients (odds ratio 9.8; p=0.0028). By increasing serum 1, 25-[OH]2D concentrations, treatment with 1alpha(OH)D3 can reduce the risk of hip and other non-vertebral fractures in osteoporotic elderly patients with Parkinson's disease by slowing the loss of bone mineral densities.


Problem-based learning versus reflective practice on nursing students' moral sensitivity.
Moral sensitivity is one of the prerequisites for nurses' professional competency and patient care. It is critical to teach professional ethics in a student-centered manner in order to increase students' moral sensibility. This study evaluated the effects of professional ethics education via problem-based learning and reflective practice on nursing students' moral sensitivity. This experimental study was performed on 74 nursing students who were randomly divided into three groups of problem-based learning, reflective practice and control. Principles of professional ethics were presented for the two intervention groups in four 2-hour sessions using ethical dilemmas scenarios. Participants completed the Moral Sensitivity Questionnaire before, immediately, and three months after the intervention. Data were analyzed using SPSS16. Demographic characteristics of the three groups were similar (p > 0.05). The total moral sensitivity score significantly differed between the groups immediately and three months after the intervention (p < 0.001). The total mean score for moral sensitivity was significantly different between the two groups of problem-based learning and reflective practice, with the mean scores in the problem-based learning group being higher (p = 0.02). The mean score of moral sensitivity decreased statistically significantly in both experimental groups three months after the intervention as compared to immediately after the intervention (p < 0.001). Nursing students' moral sensitivity can be increased through reflective practice and problem-based learning. While the results indicated that problem-based learning was more successful than reflective practice, additional research is recommended to confirm the influence of these two strategies on moral sensitivity.


Insight in early psychosis: a 1-year follow-up.
Insight was investigated in 180 individuals consecutively admitted to a comprehensive early psychosis treatment program. Insight was assessed on admission and after 3, 6 and 12 months. Insight improved significantly over 12 months, and was negatively correlated with both positive and negative symptoms, and positively correlated with depressive symptoms at admission. There were no associations with cognition.


Establishment of a national network of validated and qualified laboratories for neutralizing anti-vaccinia antibodies titration.
A Proficiency Testing Study (PTS) was organized in France by the French Health Products Safety Agency (Afssaps) aiming at assessing the performance of laboratories in performing a neutralizing anti-vaccinia antibodies titration method by plaque reduction neutralization test (PRNT). The ultimate goal was to establish a national network of qualified and validated laboratories. Five laboratories were included in the PTS and four submitted their data. Three samples of human sera containing various immunoglobulin concentrations (a "high" serum: s-576, a "medium" serum: Ref-19584 and a "low" serum: s-483) were tested by PRNT as described in a procedure supplied by Afssaps and developed in each laboratory during preliminary assays. Data were sent to Afssaps which performed the statistical analysis. The overall performance of the four participating laboratories was satisfactory. This allowed the four participating laboratories to be validated and then to be qualified by the Ministry of Health. Finally a national network for anti-vaccinia immunoglobulins titration was established.


The effect of cigarette smoking on rabbit aortic elastase activity.
Twenty rabbits were divided into three groups: (1) cage controls, (2) machine controls, and (3) cigarette exposed. The cigarette-exposed group was exposed to two 2-R1 reference cigarettes a day for 6 weeks on a Walton-II (Process and Instruments Corp., Brooklyn, N.Y.) smoking machine. Rabbits in the machine control group were placed in the smoking machine for the same period of time without cigarettes. Cage control animals were not placed in the smoking machine. Aortic elastase was significantly higher in the cigarette-exposed group (21.11 +/- 6.15) compared to both the cage control group (3.11 +/- 1.11) and machine control group (14.66 +/- 4.69). Aortic elastase in the machine control group was significantly higher in smoke-exposed rabbits than in both cage control and machine control rabbits. These data indicate that cigarette smoking increases aortic elastase activity in rabbits. If these data were to be extrapolated to humans, then patients with abdominal aortic aneurysms who smoke may have an accelerated rate of aneurysm growth or earlier rupture or both.


Association between gut microbiota and diapause preparation in the cabbage beetle: a new perspective for studying insect diapause.
Gut microbiota mediate the nutritional metabolism and play important roles in human obesity. Diapausing insects accumulate large fat reserves and develop obese phenotypes in order to survive unfavorable conditions. However, the possibility of an association between gut microbiota and insect diapause has not been investigated. We used the Illumina MiSeq platform to compare gut bacterial community composition in nondiapause- (i.e. reproductive) and diapause-destined female cabbage beetles, Colaphellus bowringi, a serious pest of vegetables in Asia. Based on variation in the V3-V4 hypervariable region of 16S ribosomal RNA gene, we identified 99 operational taxonomic units and 17 core microbiota at the genus level. The relative abundance of the bacterial community differed between reproductive and diapause-destined female adults. Gut microbiota associated with human obesity, including Bacteroidetes, Firmicutes, and Proteobacteria, showed a good correlation with diapause. This association between gut microbiota and diapause in the cabbage beetle may open a new avenue for studying insect diapause, as well as developing a natural insect obesity model with which to explore the mechanisms responsible for human obesity.


The role of prostanoid TP- and DP-receptors in the bronchoconstrictor effect of inhaled PGD2 in anaesthetized guinea-pigs: effect of the DP-antagonist BW A868C.
1. In anaesthetized, pump-ventilated guinea-pigs, bolus intravenous injection of prostaglandin D2 (PGD2 5-160 micrograms kg-1) caused a dose-dependent rise in both heart rate and systemic mean arterial blood pressure with only a small monophasic rise in pulmonary inflation pressure (PIP). 2. In contrast, inhaled PGD2 (0.1-1 mg ml-1, 30s) provoked a substantial concentration-dependent biphasic rise in PIP. The bronchoconstrictor action of inhaled PGD2 was accompanied by minimal cardiovascular effects. 3. The 3-benzyl substituted hydantoin BW A868C (0.1-1 mg kg-1 i.v.) a novel prostanoid DP-receptor antagonist, had no significant effect on the cardiovascular or bronchoconstrictor effects of intravenously administered or inhaled PGD2. 4. However, BW A868C (0.1-1 mg kg-1 i.v.) did inhibit the hypotensive actions of the DP-receptor agonist, BW 245C (1-3 micrograms kg-1 i.v.). 5. The prostanoid TP-receptor antagonist BM 13.177 (2.5 mg kg-1 i.v.) strongly inhibited the bronchoconstrictor effect of inhaled PGD2, abolishing the first phase of this response and reducing the peak increase in PIP provoked by PGD2 (0.1 or 1 mg ml-1 for 30 s), by 67 +/- 16% and 44 +/- 5% respectively. 6. A combination of BW A868C (0.1 or 1 mg kg-1 i.v.) with BM 13.177 (2.5 mg kg-1 i.v.) produced no greater inhibition of the bronchoconstrictor effect of inhaled PGD2 than that seen with BM 13.177 (2.5 mg kg-1 i.v.) alone. 7. Neither bilateral vagotomy, nor selective inhibition of arachidonate cyclo-oxygenase with indomethacin or 5-lipoxygenase with the novel acetohydroxamic acid BW A4C, significantly reduced the bronchoconstrictor effect of inhaled PGD2. 8. These findings indicate that the bronchoconstrictor effect of inhaled PGD2 in guinea-pigs in vivo is mediated primarily through direct TP-receptor activation and not through actions on DP-receptors.


Development of a Rare Earth Nanoprobe Enables In Vivo Real-Time Detection of Sentinel Lymph Node Metastasis of Breast Cancer Using NIR-IIb Imaging.
Sentinel lymph node (SLN) biopsy plays a critical role in axillary staging of breast cancer. However, traditional SLN mapping does not accurately discern the presence or absence of metastatic disease. Detection of SLN metastasis largely hinges on examination of frozen sections or paraffin-embedded tissues post-SLN biopsy. To improve detection of SLN metastasis, we developed a second near-infrared (NIR-II) in vivo fluorescence imaging system, pairing erbium-based rare-earth nanoparticles (ErNP) with bright down-conversion fluorescence at 1,556 nm. To visualize SLNs bearing breast cancer, ErNPs were modified by balixafortide (ErNPs@POL6326), a peptide antagonist of the chemokine receptor CXCR4. The ErNPs@POL6326 probes readily drained into SLNs when delivered subcutaneously, entering metastatic breast tumor cells specifically via CXCR4-mediated endocytosis. NIR fluorescence signals increased significantly in tumor-positive versus tumor-negative SLNs, enabling accurate determination of SLN breast cancer metastasis. In a syngeneic mouse mammary tumor model and a human breast cancer xenograft model, sensitivity for SLN metastasis detection was 92.86% and 93.33%, respectively, and specificity was 96.15% and 96.08%, respectively. Of note, the probes accurately detected both macrometastases and micrometastases in SLNs. These results overall underscore the potential of ErNPs@POL6326 for real-time visualization of SLNs and in vivo screening for SLN metastasis. NIR-IIb imaging of a rare-earth nanoprobe that is specifically taken up by breast cancer cells can accurately detect breast cancer macrometastases and micrometastases in sentinel lymph nodes.


A Trp 64 Arg mutation in the beta3-adrenergic receptor gene is not associated with moderate overweight in Japanese workers.
The aim of the present study was to investigate the trend for obesity and the relationship between Trp64Arg mutation in the beta3-adrenergic receptor gene and obesity-related phenotypes in Japanese workers. A total of 658 workers, 483 women and 175 men, responded to this survey. Genomic DNA was prepared from leukocytes, and DNA amplification by polymerase chain reaction was performed using 100 ng genomic DNA. Amplified fragments were digested with BstNI and analyzed by 3% agarose gel electrophoresis. The body mass index (BMI) increased from 21.1 +/- 2.6 to 22.0 +/- 3.0 kg/m2 for women and from 20.9 +/- 2.1 to 22.1 +/- 2.6 kg/m2 for men from 1982 to 1997. Body weight increased 63.3% for women and 67.4% for men over 15 years. The frequency of the Trp64Arg allele was 19.9%, and the frequency of heterozygote and homozygote carriers of the mutation was 32.9% and 3.4%, respectively. Changes in the BMI and body weight over 15 years from 1982 to 1997 did not differ significantly between subjects with or without the mutant allele in either women or men. The BMI was not significantly higher in subjects who were homozygous or heterozygous for the Trp64Arg mutation versus subjects who were homozygous for the normal allele. This mutation of the beta3-adrenergic receptor gene is not likely a major determinant of moderate obesity in the Japanese population.


A hybrid method of application of independent component analysis to in vivo 1H MR spectra of childhood brain tumours.
Independent component analysis (ICA) can automatically extract individual metabolite, macromolecular and lipid (MMLip) components from a series of in vivo MR spectra. The traditional feature extraction (FE)-based ICA approach is limited, in that a large sample size is required and a combination of metabolite and MMLip components can appear in the same independent component. The alternative ICA approach, based on blind source separation (BSS), is weak when dealing with overlapping peaks. Combining the advantages of both BSS and FE methods may lead to better results. Thus, we propose an ICA approach involving a hybrid of the BSS and FE techniques for the automated decomposition of a series of MR spectra. Experiments were performed on synthesised and patient in vivo childhood brain tumour MR spectra datasets. The hybrid ICA method showed an improvement in the decomposition ability compared with BSS-ICA or FE-ICA, with an increased correlation between the independent components and simulated metabolite and MMLip signals. Furthermore, we were able to automatically extract metabolites from the patient MR spectra dataset that were not in commonly used basis sets (e.g. guanidinoacetate).


The combination of electrically stimulated gracilis neoanal sphincter and continent colonic conduit: a step forward for total anorectal reconstruction?
Patients undergoing total anorectal reconstruction for anorectal atresia or following abdominoperineal resection of the rectum do not fare as well after an electrically stimulated gracilis neoanal sphincter as patients with incontinence alone. This retrospective study reports the outcome for the combination of a continent colonic conduit or antegrade continence enema procedure with an electrically stimulated gracilis neoanal sphincter in patients with atresia or following an abdominoperineal resection of the rectum as part of total anorectal reconstruction to overcome combined incontinence and evacuatory dysfunction. Between September 1994 and September 1999, 11 continent colonic conduits were fashioned in 11 patients with an electrically stimulated gracilis neoanal sphincter as part of total anorectal reconstruction for end-stage fecal incontinence. In addition, three patients had an antegrade continence enema procedure in situ, one of which was converted to a colonic conduit at a later stage. Five patients had a colonic conduit fashioned subsequent to an electrically stimulated gracilis neoanal sphincter, four had both procedures in a combined operation, and five had a conduit formed before an electrically stimulated gracilis neoanal sphincter (including the three with an antegrade continence enema procedure). Median follow-up was 53 (range, 7-98) months until July 2002 or until exit from this study group because of end stoma formation (n = 6). Seven patients (50 percent) had a successful outcome, defined as continent to solid and liquid stool. Overall, eight patients (57 percent) reported some degree of improvement in their bowel function and were successfully managed by this combination of procedures. An end stoma was formed in six patients (43 percent). The combination of antegrade irrigation via a colonic conduit or an antegrade continence enema procedure provides a successful outcome for some patients when incorporated into total anorectal reconstruction, provided that sepsis does not occur, thus avoiding permanent stoma formation. The combination of these procedures may represent an improvement in total anorectal reconstruction and warrants further clinical trial.


Affecting Factors of Parturient Women's Privacy Preservation in The Maternity Ward: A Qualitative Study.
Objective: Different factors have an important role in the positive and negative childbirth experiences of the mothers. The parturient mother's privacy preservation is one of the factors for increasing the mothers' satisfaction consistent with natural childbirth. Hence, this study aimed to investigate the factors affecting the parturient mother's privacy preservation. Materials and methods: Content analysis was used in this qualitative study that is based on the semi structured individual interviews with women who had experienced natural vaginal delivery, midwives, and the specialist in a maternity ward from 2018 to 2021 in Shahroud, Iran. The collected data were analyzed simultaneously with the sampling procedure using a five-step qualitative content analysis method. To ensure the robustness of the data, Lincoln and Guba's four criteria (credibility, dependability, confirmability, and transferability) were used. Results: The findings of the study with 40 participants resulted in the extraction of 28 codes, 9 subcategories, and 2 main categories entitled extra-and intra personal factors affecting the mother's privacy. Conclusion: To foster the mother's awareness of her rights and privacy during pregnancy and delivery, continuous education, monitoring, and evaluating both the students and the staff to respect preserving the mother's privacy is necessary to develop an instrument to measure the preservation of the mother's privacy in the maternity ward.


Iduna protects HT22 cells from hydrogen peroxide-induced oxidative stress through interfering poly(ADP-ribose) polymerase-1-induced cell death (parthanatos).
Oxidative stress-induced cell death is common in many neurological diseases. However, the role of poly(ADP-ribose) polymerase-1-induced cell death (parthanatos) has not been fully elucidated. Here, we found that hydrogen peroxide (H2O2) could lead to PARP-1 activation and apoptosis-inducing factor nuclear translocation in a concentration dependent manner. Iduna, as a novel regulator of parthanatos, was also induced by H2O2. Down-regulation of Iduna by genetic ablation promoted H2O2-induced cell damage. Up-regulation of Iduna reduced the loss of mitochondrial potential and ATP and NAD+ production, but did not affect the mitochondrial dysfunction-induced cytochrome c release, increase of Bax/Bcl-2 ratio, and Caspase-9/Caspase-3 activity. In contrast, overexpression of Iduna inhibited activation of PARP-1 and nuclear translocation of AIF. Further study showed that PARP-1 specific inhibitor, DPQ, blocked the protective effect of Iduna against H2O2-induced oxidative stress. Moreover, in the presence of proteasome inhibitor (MG-132) or ubiquitin E1 inhibitor (PYR-41), protective effect of Iduna was significantly weaken. These results indicate that Iduna acts as a potential antioxidant by improving mitochondrial function and inhibiting oxidative stress-induced parthanatos, and these protective effects are dependent on the involvement of ubiquitin-proteasome system.


Telmisartan inhibits microglia-induced neurotoxic A1 astrocyte conversion via PPARγ-mediated NF-κB/p65 degradation.
Astrocytes are crucially involved in neuroinflammation. Activated astrocytes exhibit at least two phenotypes, A1 (neurotoxic) and A2 (neuroprotective). The A1 phenotype is the major reactive astrocyte phenotype involved in aging and neurodegenerative diseases. Telmisartan, which is an antihypertensive agent, is a promising neuroprotective agent. This study aimed to investigate the effects of telmisartan on the phenotype of reactive astrocytes. Astrocytes were activated by culturing with the conditioned medium derived from lipopolysaccharide-stimulated microglia. This conditioned medium induced early, transient A2 astrocyte conversion (within 24 h) and late, sustained A1 conversion (beginning at 24 h and lasting up to 7 days), with a concomitant increase in the production of pro-inflammatory cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]α, and IL-6) and phosphorylation of nuclear factor-κB (NF-κB)/p65. Telmisartan treatment promoted and inhibited A2 and A1 conversion, respectively. Telmisartan reduced total and phosphorylated p65 protein levels. Losartan, a specific angiotensin II type-1 receptor (AT1R) blocker, did not influence the reactive state of astrocytes. Additionally, AT1R activation by angiotensin II did not induce the expression of pro-inflammatory cytokines and A1/A2 markers, indicating that the AT1R signaling pathway is not involved in the astrocyte-mediated inflammatory response. A peroxisome proliferator-activated receptor γ (PPARγ) antagonist reversed the effects of telmisartan. Moreover, telmisartan-induced p65 downregulation was reversed by the proteasome inhibitor MG132. These results indicate that telmisartan suppresses activated microglia-induced neurotoxic A1 astrocyte conversion through p65 degradation. Our findings contribute towards the elucidation of the anti-inflammatory activity of telmisartan in brain disorders.


Adding a selective enrichment step to the iQ-Check real-time PCR improves the detection of Salmonella in naturally contaminated retail turkey meat products.
The aim of this study was to compare the real-time iQ-Check Salmonella kit (Bio-Rad) with the immunocapture assay RapidCheck Salmonella method, and a conventional culture method (FSIS, USDA) in detecting Salmonella in naturally contaminated turkey meat products. This study was also designed to determine if a selective enrichment step might improve the real-time detection of Salmonella. Using the culture method, Salmonella was recovered from 49 out of 99 retail turkey meat samples collected. RapidCheck failed to detect 11 Salmonella samples that were positive by the culture method. The iQ-Check real-time PCR also failed to detect three samples that were positive by the culture method. However, when carried out after a selective enrichment step, the iQ-Check real-time PCR detected all 49 Salmonella samples recovered by the culture method. The iQ-Check real-time PCR detected the presence of Salmonella in some samples that were not recovered by the culture method. Adding a selective enrichment step to the iQ-Check real-time PCR improves the detection of Salmonella in naturally contaminated turkey meat samples. The iQ-Check Salmonella real-time PCR can be used as a rapid method to monitor Salmonella in turkey meat, together with conventional culture methodology.


Pseudo-tumours of the urinary tract in patients with spinal cord injury/spina bifida.
To raise awareness of pseudo-tumours of urinary tract, as pseudo-tumours represent benign mass lesions simulating malignant neoplasms. Accurate diagnosis helps to avoid unnecessary surgery in spinal cord injury patients. Regional Spinal Injuries Centre, Southport, UK CASE REPORTS: Pseudo-tumour of kidney: A 58-year-old man with tetraplegia developed a right perirenal haematoma while taking warfarin; ultrasound and CT scanning showed no evidence of tumour in the right kidney. The haematoma was drained percutaneously. After 8 months, during investigation of a urine infection, ultrasound and CT scan revealed a space-occupying lesion in the mid-pole of the right kidney. CT-guided biopsy showed features suggestive of an organising haematoma; the lesion decreased in size over the next 13 months, thus supporting the diagnosis. Pseudo-tumour of urinary bladder: A frail, 34-year-old woman, who had spina bifida, marked spinal curvature and pelvic tilt, had been managing her neuropathic bladder with pads. She had recurrent vesical calculi and renal calculi. CT scan was performed, as CT would be the better means of evaluating the urinary tract in this patient with severe spinal deformity. CT scan showed a filling defect in the base of the bladder, and ultrasound revealed a sessile space-occupying lesion arising from the left bladder wall posteriorly. Flexible and, later, rigid cystoscopy and biopsy demonstrated necrotic slough and debris but no tumour. Ultrasound scan after 2 weeks showed a similar lesion, but ultrasound-guided biopsy was normal with nothing to explain the ultrasound appearances. A follow-up ultrasound scan about 7 weeks later again showed an echogenic mass, but the echogenic mass was seen to move from the left to the right side of the bladder on turning the patient, always maintaining a dependent position. The echogenic bladder mass thus represented a collection of debris, which had accumulated as a result of chronic retention of urine and physical immobility. Recognising the true, non-neoplastic nature of these lesions enabled us to avoid unnecessary surgical procedures in these patients, who were at high risk of surgical complications because of severely compromised cardiac and respiratory function.


Relapse tendency in maxillary arch width in unilateral cleft lip and palate patients with different maxillary arch forms.
The aim of this study was to investigate the relapse tendency in the maxillary dental arch widths in unilateral cleft lip and palate patients with different types of maxillary arch form. Thirty-two unilateral cleft lip and palate patients treated by one-stage surgical palatal closure were included. The subjects were divided into three groups according to the types of the maxillary arch forms: group A, symmetrical arch form; group B, collapse of minor segment; group C, collapse of both segments. Using dental casts obtained at three different times, relapse in the intercanine, interpremolar, and intermolar widths in each group was assessed and differences between groups were investigated. Patients in group A showed stable results in all measurements. Patients in group B showed posttreatment relapse in the intercanine width only, whereas patients in group C demonstrated significant posttreatment relapses in the interpremolar and intermolar widths. Comparison between groups showed more significant relapse in the interpremolar and intermolar widths of group C than in those of group B. The types of the maxillary arch forms in unilateral cleft lip and palate patients might play a stronger role in the stability of the maxillary dental arch widths after orthodontic treatment in patients with collapse of both segments and a severe degree of maxillary narrowness.


Functional inhibition by methadone of N-methyl-D-aspartate receptors expressed in Xenopus oocytes: stereospecific and subunit effects.
Methadone is a strong opioid analgesic that is finding increasing use in chronic pain therapeutics. We explored its reported efficacy for inhibiting N-methyl-D-aspartate (NMDA) receptors in a functional electrophysiologic assay (Xenopus laevis oocyte expression). Racemic methadone inhibited all subtypes of rat NMDA receptors with derived 50% inhibitory concentrations in the low micromolar range. These concentrations overlap with clinically achievable concentrations reported in pharmacokinetic studies. In contrast, morphine inhibited these functional ion channels only at 8-16 times larger concentrations. The NR1/2A and NR1/2B subtype combinations were in general significantly more sensitive to inhibition by methadone and morphine compared with the NR1/2C and NR1/2D subtypes. In the presence of racemic methadone, the maximum NMDA-stimulated currents were markedly decreased, but the NMDA concentration producing 50% of maximal activation was altered only slightly, indicating that methadone blocks by a noncompetitive mechanism. Although stereoisomers of methadone showed minimal stereoselectivity in most subtypes, R(-) methadone was highly selective in its inhibition of the NR1/2A combination. These results provide further functional data describing the NMDA receptor inhibitory actions of methadone and support the hypothesis that methadone acts through both opioid and NMDA receptor mechanisms. At clinically achievable concentrations, methadone inhibits functional N-methyl-D-aspartate receptors. These results indicate a unique mode of action by this opioid that may enhance its ability to treat chronic pain and to limit opioid tolerance.


De-escalating chemotherapy for stage I-II gastric neuroendocrine carcinoma? A real-world competing risk analysis.
The role of adjuvant chemotherapy in gastric neuroendocrine neoplasms (GNEC) has not been well clarified yet. The study was designed to investigate the potential effect of adjuvant chemotherapy in stage I-II GNEC patients and construct a predictive nomogram. Stage I-II GNEC patients were included in the Surveillance, Epidemiology, and End Results (SEER) database and divided into chemotherapy and no-chemotherapy groups. We used Kaplan-Meier survival analyses, propensity score matching (PSM), and competing risk analyses. The predictive nomogram was then built and validated. Four hundred four patients with stage I-II GNEC were enrolled from the SEER database while 28 patients from Hangzhou TCM Hospital were identified as the external validation cohort. After PSM, similar 5-year cancer-specific survival was observed in two groups. The outcomes of competing risk analysis indicated a similar 5-year cumulative incidence of cancer-specific death (CSD) between the two cohorts (35.4% vs. 31.4%, p = 0.731). And there was no significant relation between chemotherapy and CSD in the multivariate competing risks regression analysis (HR, 0.79; 95% CI, 0.48-1.31; p = 0.36). Furthermore, based on the variables from the multivariate analysis, a competing event nomogram was created to assess the 1-, 3-, and 5-year risks of CSD. The 1-, 3-, and 5-year area under the receiver operating characteristic curve (AUC) values were 0.770, 0.759, and 0.671 in the training cohort, 0.809, 0.782, and 0.735 in the internal validation cohort, 0.786, 0.856, and 0.770 in the external validation cohort. Furthermore, calibration curves revealed that the expected and actual probabilities of CSD were relatively consistent. Stage I-II GNEC patients could not benefit from adjuvant chemotherapy after surgery. De-escalation of chemotherapy should be considered for stage I-II GNEC patients. The proposed nomogram exhibited excellent prediction ability.


Pigmented spindle cell carcinoid tumour of the thymus with ectopic adrenocorticotropic hormone secretion: report of a rare variant and differential diagnosis of mediastinal spindle cell neoplasms.
A variety of histological variants of thymic carcinoid tumour have been described. A rare case of pigmented spindle cell carcinoid tumour of the thymus is documented and compared with the reported cases of thymic pigmented carcinoid tumour in the literature, with a discussion of the differential diagnosis of spindle cell tumours of the mediastinum. A thymic tumour with ectopic adrenocorticotropic hormone (ACTH) secretion was resected from a 24-year-old man suffering from Cushing's syndrome. Histological, immunohistochemical, and ultrastructural studies revealed an ACTH-producing spindle cell carcinoid tumour harbouring pigmented melanocytes. Among four thymic pigmented carcinoid tumours reported before, only one was similar to the present case by being also an ACTH-secreting pigmented spindle cell thymic carcinoid tumour. The clinicopathological features of this tumour distinguish it from a spindle cell thymoma, spindle cell thymic carcinoma, and other mediastinal spindle cell tumours. This case illustrates an extremely rare variant of thymic carcinoid tumour exhibiting a spindle cell morphology and harbouring pigmented melanocytes. Awareness of this histological variant is important in the differential diagnosis of spindle cell tumours of the mediastinum.


Exploring the extent of postmenopausal osteoporosis among Saudi Arabian women using dynamic simulation.
The prevalence of postmenopausal osteoporosis among Saudi Arabian women is difficult to estimate because it is a large country with a diverse widely dispersed population. There have been reports of localized prevalence estimates but these are difficult to compare. In the absence of reliable national data, a theoretical approach may be useful. We have extended our mathematical model of the WHO scheme for osteoporosis diagnosis so that it is capable of predicting the prevalence of postmenopausal osteoporosis in a population of women on a year-by-year basis. These calculations are based on the area under a theoretical Gaussian bone mineral density (BMD) distribution bounded by the WHO thresholds for osteoporosis and osteopenia. This simulation approach confirms the pivotal role played by the standard deviation of BMD in the young, healthy normal reference group and it permits the model's sensitivity to other parameters (amplitude and time constant of the postmenopausal decline in BMD) and circumstances (age-related changes in standard deviation) to be accurately quantified: For Saudi Arabian women aged 50-70 yr, we estimate the prevalence of osteoporosis to be approximately 23%. The precise value depends strongly on the underlying standard deviation of BMD across the various age groups, which still remains to be accurately determined within the Saudi Arabian population.


Functional mechanisms of apoptosis-related proteins in neonatal rat cerebellum are differentially influenced by ethanol at postnatal days 4 and 7.
Exposure of the developing nervous system to ethanol (EtOH) produces neurological aberrations associated with fetal alcohol syndrome. During a well-defined period, cerebellar neurons are highly susceptible to EtOH-induced death, primarily through apoptosis. Neonatal rodent cerebellum is exquisitely sensitive to EtOH on postnatal days 4-6 (P4-6); however, at slightly later developmental ages (P7 and later), EtOH effects are minimal. We have previously shown that EtOH differentially influences expression of apoptosis-related proteins of the Bcl-2 survival-regulatory gene family in P4 and P7 cerebellum. In the present study, the effects of EtOH on multiple functional mechanisms of Bcl-2, Bcl-xL, and Bax were investigated to characterize further the processes underlying these disparate EtOH sensitivities. For these analyses, we addressed the following questions, by using P4 and P7 cerebellar tissue following in vivo exposure: 1) Are there differential patterns of expression of antiapoptotic Bcl-2 or proapoptotic Bax in EtOH-vulnerable Purkinje cells that could contribute to the different degrees of temporal EtOH vulnerability? 2) How does EtOH affect intracellular localization of apoptosis-related proteins? 3) Does cleavage of Bax contribute to EtOH sensitivity? 4) Does EtOH differentially modulate cerebellar protein-protein interactions of Bcl-2, Bcl-xL, and Bax at the vulnerable vs. the resistant ages? Overall, we show that, at P4, the EtOH-mediated effects on Bcl-2, Bcl-xL, and Bax favor a prodeath response, whereas most of the intracellular responses to EtOH exposure at P7 promote survival. Such differential responsiveness likely plays a major role in the disparate ethanol vulnerability at these two postnatal ages.


Identification of a battery of tests for drug candidate evaluation in the SMNDelta7 neonate model of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is characterized by selective loss of alpha-motor neurons and is caused by homozygous loss or mutation in the survival motor neuron (SMN1) gene. Loss of SMN1 is partially compensated by the copy gene, SMN2. Currently, there are no specific treatments for SMA. Key features of SMA are modeled in mice by deletion of murine Smn, and insertion of both full length human SMN2 gene and the major aberrant splice isoform of the SMN2 gene (SMNDelta7; [Le, T.T., Pham, L.T., Butchbach, M.E., Zhang, H.L., Monani, U.R., Coovert, D.D., Gavrilina, T.O., Xing, L., Bassell, G.J., and Burghes, A.H. 2005. SMNDelta7, the major product of the centromeric survival motor neuron (SMN2) gene, extends survival in mice with spinal muscular atrophy and associates with full-length SMN. Hum Mol Genet 14: 845-857]). The present study identified moderate-throughput, quantitative behavioral tests in neonatal SMN2(+/+);SMNDelta7(+/+);Smn(-/-) mice. It also addresses methodological approaches and common interpretational challenges in a neonatal model with motor deficiencies and frequent deaths. Animals were assessed daily for body weight and survival, and every other day for neonatal well-being indices and tests of motor function such as performance on the hind-limb suspension test (a.k.a. tube test) and geotaxis. The tube test is a novel non-invasive motor function test specifically designed for neonatal rodents. We found progressive deterioration in SMA model mice for most measures studied particularly body weight, survival, body temperature and motor function with differences appearing as early as P3. Power analysis showed that body weight, survival, righting reflex, geotaxis and tube test had highest predictive power for drug efficacy studies. This multi-functional component battery of tests provides a rapid and efficient means to identify, evaluate and develop candidate therapies as a prelude to human clinical trials.


Ultrasound scanning for detecting morbidity due to Schistosoma haematobium and its resolution following treatment with different doses of praziquantel.
A study to assess the resolution of urinary tract morbidity due to Schistosoma haematobium was conducted on 2 cohorts of schoolchildren attending neighbouring schools in Kilombero District, southern Tanzania. Schoolchildren were screened for S. haematobium infection using the standard World Health Organization filtration technique and subsequently examined for urinary tract pathology using a portable 3.0 MHz sector scanner (Siemens Sonoline 1300). Treatment with praziquantel was given to all infected children. Children with observed urinary tract pathology received either 20 (n = 52) or 40 (n = 79) mg/kg body weight and were sonographically re-examined one, 2, 3 and 6 months following treatment. Geometric mean outputs of 21 and 19 eggs/ml of urine were detected in the 2 cohorts before treatment. Urinary tract pathology correlated positively with egg output (chi 2, P = 0.02) and microhaematuria (P = 0.0001). Bladder (wall irregularities and polyps) and kidney (congestive changes) pathologies were found in 81% and 36%, respectively, of the group that received 20 mg/kg of praziquantel, and in 78% and 46% of the group that received 40 mg/kg. Six months after treatment, 90.4% and 88.0% parasitological cure rates were obtained using 20 or 40 mg praziquantel/kg body weight. The respective pathology clearances were 88% and 91%. 20 mg/kg of praziquantel was as effective with regard to cure rates and reversibility of morbidity as 40 mg/kg.


[Fatal delayed hemolytic transfusion reaction in a postoperative case of traumatic aortic rupture].
A 52-year-old woman with traumatic rupture of the thoracic descending aorta had a history of previous blood transfusion 23 years ago. This time, she received 4,600 ml of blood transfusion during the replacement procedure of thoracic aorta. On the 12th postoperative day, she had acutely progressive severe jaundice, anemia and hepatosplenomegaly. All transfused blood was compatible by bromelin method before operation. Serological studies revealed a secondary response of hemolytic transfusion reaction due to anti E and anti c antibodies. She fell into severe bilirubinemia (66 mg/dl) and anuria, and died on 19th day after operation. A positive Coombs test in a patient who has been transfused recently must be interpreted with great caution. The "coated" cells may be incompatible donor cells in a patient who has antibodies from a prior transfusion. The incompatibility occasionally leads to delayed transfusion reaction that may stimulate "autoimmune" hemolytic anemia.


Management of acute coronary syndrome in a tertiary care general medical unit in Sri Lanka: how closely do we follow the guidelines?
Acute coronary syndrome (ACS) is a leading cause of death. Correct implementation of evidence-based guidelines should improve outcome. We conducted this study to determine to what extent management of ACS in a tertiary care medical ward in Sri Lanka adhered to current guidelines. This prospective observational study was carried out in the University Medical Unit of the National Hospital, Colombo, Sri Lanka, for a 5-month period commencing April 2008. All patients presenting with ACS to the unit were included. During the period of study, there were 101 admissions of confirmed ACS. Thirty-one (30.6%) and 40 (39.6%) patients had not received the required correct loading dose of aspirin and clopidogrel, respectively. There were 34 cases of ST-elevation myocardial infarction (STEMI); 26 patients were eligible for thrombolysis and streptokinase was given to 22 (84.6%). The rest were treated with low-molecular-weight heparin (LMWH). Of the 67 patients who did not have STEMI, 66 received the correct dose of LMWH. Fifty-two patients (51.4%) were started on a b-blocker at presentation. None of the patients received intravenous b-blockers. Seventy-four patients (73.2%) were started on either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker on presentation. None of the patients underwent primary percutaneous intervention. Adherence to guidelines is limited by lack of funds and resources in our setting; however, attention must be paid to non-costly easily correctable deficits.


Mesenchymal stem cells and conditioned media in the treatment of multiple sclerosis patients: Clinical, ophthalmological and radiological assessments of safety and efficacy.
This open-label prospective phase I/IIa clinical study used autologous bone marrow-derived mesenchymal stromal cells (BM-MSCs) followed by mesenchymal stromal cells conditioned media (MSC-CM) for the first time to treat multiple sclerosis (MS) patients. The primary goal was to assess the safety and feasibility and the secondary was efficacy. The correlation between the MSC-CM content and treatment outcome was investigated. Ten MS patients who failed conventional therapy were enrolled. Adverse events were recorded to assess safety. The Expanded Disability Status Scale (EDSS) was the primary efficacy measurement, the secondary included clinical (25WFT, 9-PHT), cognitive (MMS), ophthalmology (OCT, VEP), and radiological (MRI lesion and volume) tests. The MSCs-CM concentration of 27 inflammatory biomarkers was investigated. The treatment protocol was well tolerated by patients. There was an overall trend of improvement in all the tests, except the lesion volume which increased significantly. A decrease of 4 and 3.5 points on the EDSS was achieved in two patients. We report a correlation between a decreased lesion number at baseline and higher IL-6, IL-8, and VEGF MSC-CM content. The used protocol was safe and feasible with possible efficacy. The addition of MSC-CM could be related to the magnitude of EDSS improvement observed.