Myoclonic absence epilepsy with photosensitivity and a gain of function mutation in glutamate dehydrogenase.
Activating mutations in glutamate dehydrogenase (GDH), de novo or dominantly inherited, are responsible for the hyperinsulinism/hyperammonemia (HI/HA) syndrome. Epilepsy has been frequently reported in association with mutations in GDH, but the epilepsy phenotype has not been clearly determined. Here, we describe a family with a dominantly inherited mutation in GDH. The mother, brother and both sisters had myoclonic absence seizures, but only the mother and one sister had the complete HI/HA pattern. For the two sisters with myoclonic absences, epilepsy started during the second year of life while the brother, it started at 6 years. All 3 children showed the same EEG pattern characterized by photosensitive generalized and irregular spike-wave discharges and runs of multiple spikes. The mother's EEG recordings were normal without photosensitivity. Magnetic resonance imaging (MRI) and spectroscopy (MRS) were normal. A direct effect of the GDH mutation, perhaps in combination with recurrent hypoglycemia and chronic hyperammonemia could provide a pathophysiological explanation for the epilepsy observed in this syndrome and these are discussed.


Molecular cloning and characterization of farnesoid X receptor from large yellow croaker (Larimichthys crocea) and the effect of dietary CDCA on the expression of inflammatory genes in intestine and spleen.
In the present study, farnesoid X receptor (FXR) was cloned and characterized from liver of large yellow croaker (L crocea) and the effects of dietary chenodeoxycholic acid (CDCA), a nature ligand of FXR, on the inflammatory genes expression in the intestine and spleen of large yellow croaker were investigated. Multiple alignments showed that FXR of large yellow croaker contained highly conserved DNA-binding domain and ligand binding domain compared with other species. The subcellular localization analysis showed that FXR-GFP fusion protein could target to the nucleus in HEK 293t. The tissue specific results demonstrated that FXR was highly expressed in liver, intestine and kidney of large yellow croaker. In addition, dietary soybean oil decreased the expression of FXR and IL-10 and significantly increased the expression of the pro-inflammatory genes in the intestine or spleen, such as TNFα, COX-2, IL-1β, IL-6, while the supplementation of CDCA could partly reverse these effects. These results suggested that the supplementation of CDCA may relieve the inflammation of intestine and spleen in large yellow croaker via the activation of FXR.


Control of the Balb/c-3T3 cell cycle by nutrients and serum factors: analysis using platelet-derived growth factor and platelet-poor plasma.
Much controversy regarding the relationship between nutrients and serum in regulation of cell growth can be reconciled by recognizing that serum contains multiple factors which regulate different events in the cell cycle. Serum was fractionated into a platelet-derived growth factor (PDGF), which induces cells to become competent to synthesize DNA, and plasma which allows competent cells to traverse G0/G1 and enter the S phase. Nutrients are not required for the cellular response to PDGF; however amino acids are required for plasma to promote the entry of PDGF-treated, competent cells into S phase. The nutrient independent, PDGF-modulated, growth regulatory event (competence) is located 12 hours prior to the G1/S phase boundary in quiescent, density-arrested Balb/c-3T3 cells. The nutrient dependent, plasma-modulated event is located six hours prior to the G1/S phase boundary and corresponds in concentration of amino acids required for DNA synthesis. Infection of density-arrested Balb/c3T3 cells with SV40 overrides both the nutrient independent and the nutrient dependent growth regulatory events.


Tumor progression of culture-adapted human embryonic stem cells during long-term culture.
Human embryonic stem cells (hESCs) during long-term culture acquire chromosomal changes similar to those occurring in tumorigenesis. This was raised concerns about the progression from hESCs to malignant cells. This study aimed to investigate the changes in chromosomes, cell phenotype, and genes in culture-adapted hESCs to ascertain whether tumorigenic transformation occurred. By cytogenetic analysis we found progressive karyotypic changes from simple to complex in chHES-3, one of the hESC lines established in our laboratory, during a long-term suboptimal culture. We further compared chHES-3 cells at different karyotypic stages in cell surface markers, in vivo differentiation, cell cycle, apoptosis, and gene expression profiles. We found that the karyotypically aberrant chHES-3 had higher S-phase fraction in cell cycle distributions and antiapoptosis ability. In vivo differentiation of karyotypically normal chHES-3 resulted in relatively mature teratoma, whereas karyotypically aberrant chHES-3 formed immature teratoma (grade III), in which more primary neural epithelium was revealed by pathological analysis. The microarray analysis and real-time PCR results showed that some oncogenes were upregulated in karyotypically aberrant chHES-3 cells, whereas the genes related to differentiation were downregulated, and that Wnt signal pathway was activated. In conclusion, chHES-3 cells underwent deregulation of self-renewal and dysfunction of related genes in long-term culture adaptation, leading to malignant transformation.


On the interface reactions and stability of nonfullerene organic solar cells.
Long-term stability is critical for organic solar cells (OSCs) for practical applications. Several factors affect the stability of OSCs, including materials stability, morphology stability of bulk-heterojunctions and interface stability. In this perspective, we focus on interface stability due to interfacial reactions between the emerging acceptor-donor-acceptor (A-D-A) type nonfullerene active layers and interfacial layers. The description covers the initial phenomena of interfacial instability, mechanism of interfacial reactions, and strategies adopted to suppress interfacial reactions between the nonfullerene active layers and interfacial layers. Methods to test and analyze the chemical instability of nonfullerene acceptors are also included. The C[double bond, length as m-dash]C vinyl linker between the donor moiety and acceptor moiety is chemically or photochemically reactive and is a weak point for interface stability. The interface stability of OSCs could be enhanced by reducing the reactivity of the C[double bond, length as m-dash]C vinyl linker or removing it directly, modifying the surface of interfacial layers, and developing other novel interfacial materials.


Regulation of mitotic exit by the RNF8 ubiquitin ligase.
RNF8 is a ubiquitin ligase with a FHA domain near its N terminus, and a RING-finger domain at its C terminus, through which it recruits several ubiquitin-conjugating enzymes. In metazoans, only the mitotic checkpoint regulator CHFR shares this domain architecture. Here we show that RNF8 is a nuclear protein that follows a cell-cycle-dependent turnover, reaching its highest levels in mitosis, followed by a strong decline in late mitotic stages. Overexpression of RNF8 caused a delay in cytokinesis and the frequent appearance of aberrant mitotic figures. These effects were dependent on the ubiquitin ligase activity of RNF8, since they were significantly attenuated when a RING-finger mutant, inactive as an E3, was overexpressed. Depletion of RNF8 also caused a delay in the exit from the mitotic arrest induced by nocodazole, associated with a reduced turnover of the APC/C substrate cyclin B1. These observations suggest that RNF8 regulates the rate of exit from mitosis and cytokinesis.


Poly(ethylene glycol)-grafted cyclic acetals based polymer networks with non-water-swellable, biodegradable and surface hydrophilic properties.
Cyclic acetals based biomaterial without acidic products during hydrolytic degradation is a promising candidate for tissue engineering applications; however, low hydrophilicity is still one limitation for its biomedical application. In this work, we aim to achieve non-water-swellable cyclic acetal networks with improved hydrophilicity and surface wettability by copolymerization of cyclic acetal units based monomer, 5-ethyl-5-(hydroxymethyl)-β,β-dimethyl-1, 3-dioxane-2-ethanol diacrylate (EHD) and methoxy poly(ethylene glycol) monoacrylate (mPEGA) under UV irradiation, to avoid swelling of conventional hydrogels which could limit their applicability in particular of the mechanical properties and geometry integrity. Various EHD/mPEGA networks were fabricated with different concentrations of mPEGA from 0 to 30%, and the results showed photopolymerization behavior, mechanical property and thermal stability could not be significantly affected by addition of mPEGA, while the surface hydrophilicity was dramatically improved with the increase of mPEGA and could achieve a water contact angle of 37° with 30% mPEGA concentration. The obtained EHD/mPEGA network had comparative degradation rate to the PECA hydrogels reported previously, and MTT assay indicated it was biocompatible to L929 cells.


Phytotoxicity of deoxynivalenol to wheat calli.
The main objective of this study was to determine the toxicity of DON (deoxynivalenol) in wheat tissue culture after two weeks of contact. It was observed that increase of toxin concentration in medium caused decrease of regeneration ability of the calli. Three tested genotypes showed different sensitivity to 25 ppm of DON.


Development of a MLST-biased SNP microarray for Candida albicans.
We have developed a single nucleotide polymorphism (SNP) detection microarray for the human pathogenic yeast, Candida albicans, consisting of synthetic oligonucleotides bound to microscope slides. The array consists of multiple replicates of 79 SNPs, derived from 19 discrete loci located on all eight chromosomes. These loci include seven genes consisting of 57 SNPs that comprise a multi-locus sequence typing (MLST) consensus scheme for the species. The remaining 22 SNPs are from 12 additional loci located at intervals on the remaining chromosomes. In order to include highly informative polymorphisms from the MLST set on the array we performed a linkage analysis of major genotypes between the two pairs of MLST-linked genes. In addition, we performed a matched-set analysis for each SNP located within individual MLST loci. This analysis resulted in the reduction of informatively redundant mutations in the array for a large percentage of strains. We believe that a SNP array will be helpful in extending our knowledge of the epidemiology and genetics of C. albicans as a supplement to MLST typing.


Left atrial myxoma presenting with synchronous carotid and femoral embolism.
Synchronous embolism of the right femoral and the left internal carotid arteries, occurring in a 39-year-old teacher upon physical effort, was found to be due to a left atrial myxoma. Clinical findings, electrocardiogram and chest radiographs had suggested myocarditis. The patient died of cerebral infarction. In cases of suspected myocarditis, left atrial myxoma has to be considered in the differential diagnosis. Histological examination is recommended of any material obtained by embolectomy.


Calmodulin binds to the Rab GTPase activating protein required for insulin-stimulated GLUT4 translocation.
Recently, we described a 160 kDa protein with a Rab GTPase activating protein domain that is phosphorylated on multiple sites by the protein kinase Akt (designated AS160). Phosphorylation of AS160 in adipocytes is required for insulin-stimulated translocation of the glucose transporter GLUT4 to the plasma membrane. In the present study, we searched for proteins that interact with the GTPase activating protein (GAP) domain region of AS160 by the yeast two-hybrid screen. This search indicated that calmodulin bound to a small domain just amino terminal to the GAP domain of AS160, and this association has been confirmed by three other methods, including co-immunoprecipitation from lysates of adipocytes. The association was Ca ion dependent. The role of calmodulin binding to AS160 in insulin-stimulated GLUT4 translocation was examined through the generation of a point mutant of AS160 that did not bind calmodulin. This mutation did not interfere with the capacity of AS160 lacking Akt phosphorylation sites to inhibit GLUT4 translocation. Consequently, calmodulin binding is probably not required for the participation of AS160 in insulin-stimulated GLUT4 translocation.


Microbial transglutaminase displays broad acyl-acceptor substrate specificity.
The great importance of amide bonds in industrial synthesis has encouraged the search for efficient catalysts of amide bond formation. Microbial transglutaminase (MTG) is heavily utilized in crosslinking proteins in the food and textile industries, where the side chain of a glutamine reacts with the side chain of a lysine, forming a secondary amide bond. Long alkylamines carrying diverse chemical entities can substitute for lysine as acyl-acceptor substrates, to link molecules of interest onto peptides or proteins. Here, we explore short and chemically varied acyl-acceptor substrates, to better understand the nature of nonnatural substrates that are tolerated by MTG, with the aim of diversifying biocatalytic applications of MTG. We show, for the first time, that very short-chain alkyl-based amino acids such as glycine can serve as acceptor substrates. The esterified α-amino acids Thr, Ser, Cys, and Trp--but not Ile--also showed reactivity. Extending the search to nonnatural compounds, a ring near the amine group--particularly if aromatic--was beneficial for reactivity, although ring substituents reduced reactivity. Overall, amines attached to a less hindered carbon increased reactivity. Importantly, very small amines carrying either the electron-rich azide or the alkyne groups required for click chemistry were highly reactive as acyl-acceptor substrates, providing a robust route to minimally modified, "clickable" peptides. These results demonstrate that MTG is tolerant to a variety of chemically varied natural and nonnatural acyl-acceptor substrates, which broadens the scope for modification of Gln-containing peptides and proteins.


Nitrous oxide inhalation anaesthesia in the presence of intraocular gas can cause irreversible blindness.
Nitrous oxide inhalation sedation is frequently used in dental and other surgical procedures. We report the case of a patient with intraocular gas who developed sudden elevation in intraocular pressure and blindness as a result of nitrous oxide anaesthesia. All medical and dental personnel administering nitrous oxide inhalation should be aware that this is contraindicated in patients with intraocular gas.


Cell death, axonal damage, and cell birth in the immature rat brain following induction of hydrocephalus.
We hypothesized that hydrocephalus can cause death of brain cells and that generation of new brain cells might compensate for the cell loss. Hydrocephalus was induced in 3-week-old rats by injection of kaolin into the cisterna magna. The brains were studied 1 to 4 weeks later by histochemical, immunochemical, and ultrastructural methods. The ventricles enlarged progressively. Some axons in the corpus callosum were injured as early as 1 week, but axonal damage was not prevalent until 4 weeks when ventriculomegaly became severe. Dying cells detected by DNA end labeling and often identified as oligodendrocytes by electron microscopy were evident in white matter. Late-stage hydrocephalus was associated with a significant increase in the quantity of dying cells. Hydrocephalus was associated with increased Ki67 labeling and bromodeoxyuridine incorporation in the subependymal zone. Reactive changes were identified among astrocytes, oligodendroglia, and microglia. We conclude that hydrocephalus causes, in addition to axonal injury, gradual cell death in the cerebrum, particularly the white matter. The brain response includes production of new glial cells, but whether the new cells play any beneficial role remains unknown.


Response retrieval in a go/no-go priming-of-popout task.
Priming of popout is the finding that singleton search is faster when features of a target and of nontargets are repeated across trials than when the features switch. Theoretical accounts suggest that intertrial repetition influences perceptual and attentional selection processes, episodic retrieval processes, or both. The present study combined a popout search task with a go/no-go task. In Experiment 1, the nontarget distractors in each display carried the go/no-go feature, and in Experiment 2, the texture of all items carried the go/no-go feature. Results showed that the go/no-go task moderated the intertrial repetition effects. In Experiment 1, the target color elicited retrieval of the preceding distractor color and associated no-go response, resulting in larger interference effects. In Experiment 2, the target color elicited retrieval of the preceding target color and no-go response, resulting in reduced facilitation effects. Additional results from both experiments showed that the colors in a search display also influenced target selection on the following trial. Taken together, the results of both experiments suggest that intertrial repetition influences both early selection and postselection retrieval processes.


Role of Stromal Fibroblast-Induced WNT7A Associated with Cancer Cell Migration Through the AKT/CLDN1 Signaling Axis in Oral Squamous Cell Carcinoma.
Wnt signaling plays a crucial role in the progression of various cancers, including oral squamous cell carcinoma (OSCC). However, the tumor microenvironment (TME) regulating Wnt signaling has not yet been fully elucidated. In this study, we investigated whether cancer-associated fibroblasts (CAFs), the primary components of the TME, activate Wnt signaling and promote tumor progression in OSCC. We conducted a Transwell coculture assay using human OSCC cell lines and normal human dermal fibroblasts (NHDFs). NHDFs stimulated WNT7A expression in several OSCC cell lines, especially HO-1-N-1 and HSC-5. An immunohistochemical study using 122 human OSCC samples indicated that high WNT7A expression in tumor cells was significantly associated with invasion depth and poor prognosis. Moreover, WNT7A expression in OSCC cells was positively correlated with α-smooth muscle actin expression in CAFs. WNT7A knockdown in OSCC cells demonstrated that OSCC cells cocultured with NHDFs significantly promoted tumor cell migration and invasion, which was dependent on WNT7A expression in OSCC cells. We also isolated HSC-5 cells from the coculture and conducted microarray analysis to investigate the factors that promote tumor progression induced by WNT7A. Among the various differentially expressed genes, we identified a downregulated gene encoding CLDN1 and confirmed that WNT7A negatively regulated CLDN1 expression in OSCC cells and CLDN1 knockdown in OSCC cells promoted their migration. Phosphokinase array analysis showed that WNT7A activates protein kinase B (AKT) phosphorylation. Activating AKT signaling using the SC79 agonist induced CLDN1 downregulation in OSCC cells. In the coculture assay, the AKT inhibitor MK2206 significantly recovered CLDN1 expression downregulated by WNT7A, resulting in OSCC cell migration suppression. These results suggest that CAFs stimulate OSCC cells to produce WNT7A, following CLDN1 expression downregulation by activating AKT signaling, promoting cancer cell migration. These findings highlight the importance of molecular therapies targeting the TME in OSCC.


Physical Therapists' Knowledge, Skills, Beliefs, and Organizations Impact Physical Activity Promotion: A Systematic Review and Meta-Analysis.
The purpose of this study was to characterize factors that influence physical therapists' physical activity (PA) promotion practices and map these factors to the Theoretical Domains Framework (TDF) to inform future implementation efforts. Six databases (MEDLINE, EMBASE, Scopus, CINAHL, PsychInfo, and Web of Science) were searched from inception to March 11, 2021. Studies were included if they reported physical therapists' PA promotion practices and factors influencing these practices. Study quality was assessed with a modified Newcastle-Ottawa Scale and the Critical Appraisal Skills Programme checklist. Studies were excluded if they did not separate physical therapist PA promotion practices and influencing factors from other health professionals. The search yielded 12,835 references and 27 included studies. Twenty studies were included in a meta-analysis of proportions, whereas 15 studies were included in a meta-analysis of correlations. Very-low to moderate-quality evidence suggests that factors at the individual and organizational levels have very small to moderate associations with PA promotion practices. Efforts to improve PA promotion by physical therapists should consider incorporating combinations of individual and organizational factors. Limitations to the body of evidence highlight the need for future research. With PA projected to decrease in the general population by an additional 20% by 2050, PA promotion is urgently needed to maximize physical therapists' impact on the health of society. This study identifies factors that may prove useful for guiding the development of strategies to encourage greater engagement in PA promotion by physical therapists.


Nickel detoxification and plant growth promotion by multi metal resistant plant growth promoting Rhizobium species RL9.
Pollution of the biosphere by heavy metals is a global threat that has accelerated dramatically since the beginning of industrial revolution. The aim of the study is to check the resistance of RL9 towards the metals and to observe the effect of Rhizobium species on growth, pigment content, protein and nickel uptake by lentil in the presence and absence of nickel. The multi metal tolerant and plant growth promoting Rhizobium strain RL9 was isolated from the nodules of lentil. The strain not only tolerated nickel but was also tolerant o cadmium, chromium, nickel, lead, zinc and copper. The strain tolerated nickel 500 μg/mL, cadmium 300 μg/mL, chromium 400 μg/mL, lead 1,400 μg/mL, zinc 1,000 μg/mL and copper 300 μg/mL, produced good amount of indole acetic acid and was also positive for siderophore, hydrogen cyanide and ammonia. The strain RL9 was further assessed with increasing concentrations of nickel when lentil was used as a test crop. The strain RL9 significantly increased growth, nodulation, chlorophyll, leghaemoglobin, nitrogen content, seed protein and seed yield compared to plants grown in the absence of bioinoculant but amended with nickel The strain RL9 decreased uptake of nickel in lentil compared to plants grown in the absence of bio-inoculant. Due to these intrinsic abilities strain RL9 could be utilized for growth promotion as well as for the remediation of nickel in nickel contaminated soil.


Age Differences in Death and Suicidal Ideation in Anxious Primary Care Patients.
The objective of this study was to examine age differences in the likelihood of endorsing of death and suicidal ideation in primary care patients with anxiety disorders. Participants were drawn from the Coordinated Anxiety Learning and Management (CALM) Study, an effectiveness trial for primary care patients with panic disorder (PD), generalized anxiety disorder (GAD), post-traumatic stress disorder (PTSD), and/or social anxiety disorder (SAD). Approximately one third of older adults with anxiety disorders reported feeling like they were better off dead. Older adults with PD and SAD were more likely to endorse suicidal ideation lasting at least more than half the prior week compared with younger adults with these disorders. Older adults with SAD endorsed higher rates of suicidal ideation compared with older adults with other anxiety disorders. Multivariate analyses revealed the importance of physical health, social support, and comorbid MDD in this association. Suicidal ideation is common in anxious, older, primary care patients and is particularly prevalent in socially anxious older adults. Findings speak to the importance of physical health, social functioning, and MDD in this association. When working with anxious older adults it is important to conduct a thorough suicide risk assessment and teach skills to cope with death and suicidal ideation-related thoughts.


Sharing information about cancer with one's family is associated with improved quality of life.
The aim of this study was to investigate the association between cancer patients' ability to share information about their illness with their social network and attachment style dimensions, alexithymia, and quality of life. We hypothesised that ability to share information about one's cancer with family, friends, and medical teams would be positively associated with quality of life and secure attachment and negatively associated with alexithymia. Forty-five cancer patients were recruited from the Psycho-oncology Unit of the San Camillo-Forlanini Hospital in Rome. We collected anamnestic data and self-report data on social sharing ability, quality of life, alexithymia, and attachment. Sharing with family (B = 4.66; SE = 1.82; β = .52; SE = 0.20; t(41) = 2.6; P = .0143) was the only predictor of global health status, and attachment security was the only predictor of mean social sharing (B = 0.25; SE = 0.06; β = .63; SE = 0.14; t(41) = 4.4; P < .0001). Encouraging patients to share information about their experience of cancer may help to improve their quality of life. Attachment security seems to promote social sharing. Psychological assessments of cancer patients should cover both ability to share information about one's cancer with family and attachment security.


Blockade of the VEGF isoforms in inflammatory corneal hemangiogenesis and lymphangiogenesis.
The VEGF-A family plays a crucial role in the induction of pathological corneal neovascularization. The role of the different VEGF-A isoforms during lymphangiogenesis is only little-known. Current anti-angiogenic therapies in the eye and other organs inhibit all VEGF-A isoforms, and have effects on both blood and lymphatic vessels. Here we investigate whether selective targeting of the isoform VEGF 165 is able to inhibit corneal lymphangiogenesis under inflammatory conditions. The mouse model of suture-induced corneal neovascularization was used to assess the antihem- and antilymphangiogenic effect of topically applied pegaptanib. Corneal blood and lymph vascularized areas were analyzed morphometrically. Furthermore, we analyzed the proliferative effects of VEGF A 121, 165, and 189 on blood and lymphatic endothelial cells (BEC/LEC) via a cell-proliferation assay. Pegaptanib significantly inhibited inflammatory corneal hemangiogenesis (p < 0.01), but not lymphangiogenesis in vivo (p > 0.05), both topically as well as systemically, in the inflamed cornea. In vitro, BECs were more susceptible to pegaptanib than LECs. Targeting VEGF-A 165 significantly inhibits hem- but not lymphangiogenesis, suggesting VEGF-A 165 to be critical for hem-, but dispensable for lymphangiogenesis, at least in the inflamed cornea.


Regulation of pacing rate by variations of mixed venous oxygen saturation.
Right ventricular oxygen saturation (SO2) may be an ideal sensor for determining the rate of an implanted pacemaker. In order to prove this hypothesis, the obtained signals were optimally analyzed; determinations of SO2 at rest and during exercise were made in healthy volunteers and in patients with pacemakers; and an algorithm was developed for varying pacing rate as a function of measured SO2. The results suggest that this method may be applicable to the long-term implantee.


Bacteriocin enterocin CRL35 is a modular peptide that induces non-bilayer states in bacterial model membranes.
The mechanism of action of the anti-Listeria peptide enterocin CRL35 was studied with biophysical tools by using lipid mixtures that mimicked Gram-positive plasma membranes. Langmuir monolayers and infrared spectroscopy indicated that the peptide readily interacted with phospholipid assembled in monolayers and bilayers to produce a dual effect, depending on the acyl chains. Indeed, short chain mixtures were disordered by enterocin CRL35, but the gel-phases of membranes composed by longer acyl chains were clearly stabilized by the bacteriocin. Structural and functional studies indicated that non-bilayer states were formed when liposomes were co-incubated with enterocin CRL35, whereas significant permeabilization could be detected when bilayer and non-bilayer states co-existed. Results can be explained by a two-step model in which the N-terminal of the peptide firstly docks enterocin CRL35 on the lipid surface by means of electrostatic interactions; then, C-terminal triggers membrane perturbation by insertion of hydrophobic α-helix.


Beta-cell response to metformin-glibenclamide combination tablets (Glucovance) in patients with type 2 diabetes.
This exploratory double-blind, randomised, 20-week study evaluated the mechanism of action of metformin-glibenclamide combination tablets (Glucovance) vs. metformin and glibenclamide in 50 type 2 diabetes patients inadequately controlled by diet and exercise. A glycaemic target of HbA1C 7.0% was used. Final HbA(1C), fasting glucose and post-oral glucose tolerance test (OGTT) glucose were similar between groups, although average doses of metformin and glibenclamide from combination tablets (708 and 3.5 mg) were lower than monotherapy doses (1500 and 6.6 mg). Second-phase insulin during a hyperglycaemic clamp increased by 93% with combination tablets, 36% with metformin and 46% with glibenclamide. The insulin response post-OGTT was more rapid with the combination tablets vs. glibenclamide. First-phase insulin responses improved modestly in all groups, possibly due to reduced glucotoxicity. Changes in insulin sensitivity were minor. Larger beta-cell responses between combination tablets and glibenclamide may reflect more rapid glibenclamide absorption.


Detection of brain death onset using the bispectral index in severely comatose patients.
To evaluate the accuracy of bispectral index (BIS) monitoring for the diagnosis of brain death in severely comatose patients. A prospective study in an intensive care unit of a university hospital. Fifty-six severely comatose patients (Glasgow Coma Score < or = 5) admitted to the ICU mainly because of intracerebral hemorrhage, head injury, or postanoxic coma. BIS was recorded continuously during the hospitalization in the ICU. Where necessary, clinical brain death was confirmed by EEG or cerebral angiography. Twelve patients were already clinically brain dead at the time of admission, and their individual BIS values were 0. In each of these 12 patients brain death was thereafter confirmed by EEG or cerebral angiography. Forty-four patients were not clinically brain-dead at the time of admission, and their individual BIS values were between 20 and 79. Twenty-seven of these patients became brain-dead, and their individual BIS values dropped to 0 in a few hours to a few days. In these 27 patients EEG or cerebral angiography was performed after the BIS value decreased to 0 and confirmed brain death in all cases. Seventeen patients who did not become brain dead during their hospitalization in the ICU had persistent electrocerebral activity on EEG, and their average BIS values remained above 35. BIS can be used in severely comatose patients as an assessment of brain death onset, enabling appropriate scheduling of either EEG or cerebral angiography to confirm brain death.


Mutagenesis and functional analysis of the Escherichia coli tRNA(1Leu) promoter.
The leuV promoter which produces tRNA(1Leu) in Escherichia coli has been extensively mutagenized in order to determine the effects of altered sequences on promoter efficiency (strength) and on growth-rate-dependent regulation (GDR). Each mutant promoter was ligated with a beta-galactosidase reporter gene into the chromosome of a host cell by phage lambda lysogenization. Reporter gene activities were measured for cells growing in selected media at various growth rates. Sequences which flank the -10 consensus region, when altered, caused remarkable up-promoter effects, increasing efficiency in some cases almost 10-fold. One up mutation which had five successive T residues in the 'discriminator' region completely abolished GDR, whereas several mutations with single base changes in the discriminator had little or no effect on GDR. Another mutation which changed one base in the -35 region to bring it to consensus increased promoter strength 18-fold and sharply reduced GDR. Chimaeric promoters in which segments of leuV were replaced by segments of the his operon showed that only when the discriminator of leuV is replaced by the his discriminator was GDR-disturbed. All upstream sequences which were replaced by his sequences had little effect on GDR. Overall, there appeared to be little correlation between promoter efficiency and GDR.


Studies on changes in DNA polymerase activity during the cell cycle in synchronized KB cells.
We have demonstrated the presence of two DNA polymerases in KB cells and studied the variation of their activities in a synchronous cell population. During the cell cycle we observed in nuclei, only one DNA dependent DNA polymerase, the 3.4 S or minipolymerase, and similarly in the cytoplasm only one enzyme, the 8.3 S or maxipolymerase. The former shows preference for native DNA and the latter for denatured DNA. Their Mg++ and K+ requirements are different and their pH optima are 8.5 and 7 for nuclear polymerase and cytoplasmic polymerase respectively. The cytoplasmic polymerase activity remains stable from one cell cycle to the other with each cell reconstituting its stock at the start of the following cycle (G1 and early S phases). On the contrary nuclear activity decreases in G2, M and early G1, then increases to a maximum in the middle of the S phase. This fluctuation in enzyme activity could be due to degradation, transfer to the cytoplasm or the association of the enzyme with the chromatin and/or the nuclear membrane after completion of DNA synthesis. Our results do not permit us to choose between these three hypotheses. However their significance is discussed in the light of the results obtained by some authors who, on the contrary, have tended to minimise the role of the minipolymerase in DNA duplication, whereas we, from our findings, ascribe a preponderant role to this enzyme. The cytoplasmic maxipolymerase (8.3 S) may simply be a storage form of the enzyme from which minipolymerase can be formed as needed.


[3H]nipecotic acid binding to GABA uptake sites in human brain.
The binding of [3H]nipecotic acid to frozen post-mortem human brain tissue has been characterized. Competition experiments with gamma-aminobutyric acid (GABA), GABA uptake inhibitors, ligands active at post-synaptic GABA receptors and receptors for other neurotransmitter systems, suggest that [3H]nipecotic acid binds to the neuronal (but not glial) GABA uptake site. Competition and kinetic experiments suggest that 85% of the binding is to a high affinity site. The dissociation constants (Kd) measured in kinetic and equilibrium experiments were in the same range (0.5-0.6 microM). The regional distribution was studied in 19 brain regions and the binding was relatively homogenous. It is concluded that [3H]nipecotic acid binding can be used as a marker for neuronal GABA uptake sites in post-mortem human brain tissue.


Coronary revascularization in older women and men in the United States: trends in ethnic differences.
Many reports of ethnic differences in utilization of coronary artery bypass grafting (CABG) have been published in the past 2 decades. However, revascularization trends in elderly ethnic minorities have received little attention. The purpose of the present study was to determine whether ethnic differences in rates of CABG and percutaneous transluminal coronary angioplasty (PTCA) decreased after 1990 among elderly women and men. Data from the Centers for Medicare and Medicaid Services were examined for the years 1990 through 1997-99. Numbers of CABG and PTCA procedures performed in Medicare enrollees were used to compute rates per 100,000 non-HMO beneficiaries by year, sex, and ethnicity for persons aged > or =65 years. In women and men, the rate of CABG increased in African Americans and in European Americans between 1990 and 1996. However, a decline in numbers and rates of CABG was noted for the first time in 1997. Between 1990 and 1997, the ratio of rates in European Americans to those in African Americans declined somewhat (eg, in women, from 1.79 in 1990 to 1.55 in 1997). Along with steady rapid increases in rates of PTCA in both groups, a decrease in this ratio was noted (eg, in women, from 2.09 in 1990 to 1.54 in 1997 to 1.44 in 1999). This ratio was higher at ages 75 to 84 years than at 65 to 74, declining most at 75 to 84. Despite apparent decreases in ratios of rates in European Americans to those in African Americans for CABG and inpatient PTCA from 1990-1999, large ethnic differences in utilization of CABG and PTCA persist in the elderly, requiring further evaluation and possible intervention.


Methylation QTLs in the developing brain and their enrichment in schizophrenia risk loci.
We characterized DNA methylation quantitative trait loci (mQTLs) in a large collection (n = 166) of human fetal brain samples spanning 56-166 d post-conception, identifying >16,000 fetal brain mQTLs. Fetal brain mQTLs were primarily cis-acting, enriched in regulatory chromatin domains and transcription factor binding sites, and showed substantial overlap with genetic variants that were also associated with gene expression in the brain. Using tissue from three distinct regions of the adult brain (prefrontal cortex, striatum and cerebellum), we found that most fetal brain mQTLs were developmentally stable, although a subset was characterized by fetal-specific effects. Fetal brain mQTLs were enriched amongst risk loci identified in a recent large-scale genome-wide association study (GWAS) of schizophrenia, a severe psychiatric disorder with a hypothesized neurodevelopmental component. Finally, we found that mQTLs can be used to refine GWAS loci through the identification of discrete sites of variable fetal brain methylation associated with schizophrenia risk variants.


TGFBI gene mutation in a Chinese pedigree with Reis-Bücklers corneal dystrophy.
To characterize the molecular defects in the TGFBI gene in a Chinese family with Reis-Bücklers corneal dystrophy (RBCD), and to study the relationship between the gene mutations and the clinical manifestations. Four generations of this family with RBCD were enrolled in the study. In addition to ophthalmic and histopathological examinations, polymerase chain reaction (PCR) amplification and analysis of nucleotide sequencing of exons 4, 12, 14 of TGFBI were performed. The clinical manifestations of the disease were characterized by geographic opacities in the subepithelial layers and anterior stroma of the cornea. Confocal microscopy images of the cornea showed focal hyper-reflective materials deposited in the subepithelium and anterior stroma. It was confirmed by histopathology that Bowman's membrane was mainly replaced by extracellular fibril material, which extended downwards into the superficial corneal stroma. Molecular genetic analysis revealed a single heterozygous G>T change at nucleotide 124 in exon 4 of TGFBI in all members (22) of the pedigree affected with RBCD, but not in the unaffected members. A p.Arg124Leu mutation of the TGFBI gene was detected in this Chinese pedigree with Reis-Bücklers corneal dystrophy. The phenotype of Reis-Bücklers corneal dystrophy in this family belongs to the geographic type. The molecular genetic studies combined with histopathology may be useful for the accurate diagnosis of this type of corneal dystrophy.


Topochemical demonstration of zinc in meningiomas.
In agreement with the atomic absorption tests, histochemical demonstration of zinc in meningiomas using the dithizone method revealed a higher level of zinc in fibromatous meningiomas than in its meningiotheliomatous variant. Calcified psammoma bodies and vessels exhibited an intensely positive reaction on their surface. The metabolic function of zinc in the synthesis of fibre proteins, as well as in metallo-enzymes associated with mineralization, explains these findings.


Lessons learned from COVID-19 pandemic in undergraduate surgical education.
In this editorial, we review our experience on distance teaching and based on our experiences suggest modifications to undergraduate surgical education.


Synthesis, crystallization and preliminary crystallographic analysis of a 52-nucleotide DNA/2'-OMe-RNA oligomer mimicking 10-23 DNAzyme in the complex with a substrate.
A 52-nucleotide DNA/2'-OMe-RNA oligomer mimicking 10-23 DNAzyme in the complex with its substrate was synthesized, purified and crystallized by the hanging-drop method using 0.8 M sodium potassium tartrate as a precipitant. A data set to 1.21 Å resolution was collected from a monocrystal at 100 K using synchrotron radiation on a beamline BL14.1 at BESSY. The crystal belonged to the P21 group with unit-cell a = 49.42, b = 24.69, c = 50.23, β = 118.48.


Multicenter randomized clinical trial on high-dose epirubicin plus cis-platinum versus vinorelbine plus cis-platinum in advanced non small cell lung cancer.
High dose Epirubicin (HD-EPI) (>90 mg/m2) and Vinorelbine (VNR) demonstrated antitumor activity as single agent (about 20%) in the treatment of advanced NSCLC. This trial compares these two agents combined with cisplatin (CP). From August 1992 to February 1996, 228 patients with locally advanced or metastatic NSCLC were randomized to receive either EPI 120 mg/m2 as i.v. bolus plus Cisplatin (CP) 60 mg/m2 on day 1 (regimen A) or VNR 25 mg/m2 as i.v. bolus on day 1 and 8 plus CP 60 mg/m2 on day 1 (regimen B). Both treatments were recycled every 21 days up to a maximum cumulative dose of EPI of 840 mg/m2 or 12 cycles. Eligible patients were 212 and 198 patients were evaluable for objective response (95 in arm A and 103 in arm B). The main characteristics of eligible patients were: male/female 179/33; median age 61 (42-72); median Karnofsky PS 80 (70-100); stage IIIA 12%, stage IIIB 40%, stage IV 41%, recurrence 7%; histotype: epidermoid 48%, adenoca 36%, others 16%. The following response rates were observed in regimens A and B, respectively; CR, 1 and 2%, PR, 32 and 25% (P = 0.4567). Median CR + PR duration was 9 and 8 months, respectively. Median survival was 10.5 and 9.6 months, respectively. Grade III-IV leucopenia occurred in 38 and 21% in arm A and arm B, respectively(P = 0.01), thrombocytopenia in 6 and 0% (P = 0.02), anemia in 8 and 7% (n.s.). Non-hematological toxicity was moderate and the only difference between the treatments was alopecia (88 vs. 33% in arm A and B, respectively). Supraventricular arrhythmia occurred in three patients on regimen A; a >15% LVEF absolute decrease was observed in 9 (22.5%) and three (14%) patients on arm A and arm B, respectively (n.s.). No congestive heart failure was observed. HD-EPI+CP and VNR+CP are both active combinations in advanced NSCLC with a similar response rate, response duration and survival but regimen A was significantly more toxic (myelosuppression and alopecia).


Health outcomes associated with emergency department visits by adolescents for self-harm: a propensity-matched cohort study.
Self-harm is increasing among adolescents, and because of changing behaviours, current data are needed on the consequences of self-harm. We sought to investigate the trends related to hospital presentation, readmission, patient outcome and medical costs in adolescents who presented with self-harm to the emergency department. We used administrative data on 403 805 adolescents aged 13-17 years presenting to Ontario emergency departments in 2011-2013. Adolescents with self-harm visits were 1:2 propensity matched to controls with visits without self-harm, using demographic, mental health and other clinical variables. Five years after the index presentation, hospital or emergency department admission rates for self-harm, overall mortality, suicides and conservative cost estimates were compared between the 2 groups. Of 5832 adolescents who visited Ontario emergency departments in 2011-2013 after self-harm (1.4% of visits), 5661 were matched to 10 731 adolescents who presented for reasons other than self-harm. Adolescents who presented with self-harm had a shorter time to a repeat emergency department or hospital admission for self-harm (hazard ratio [HR] 4.84, 95% confidence interval [CI] 4.44-5.27), more suicides (HR 7.96, 95% CI 4.00-15.86), and higher overall mortality (HR 3.23, 95% CI 2.12-4.93; p < 0.001). The positive predictive value of self-harm-related emergency department visits for suicide was 0.7%. Adolescents with self-harm visits had mean 5-year estimates of health care costs of $30 388 compared with $19 055 for controls (p < 0.001). Adolescents with emergency department visits for self-harm have higher rates of mortality, suicide and recurrent self-harm, as well as higher health care costs, than matched controls. Development of algorithms and interventions that can identify and help adolescents at highest risk of recurrent self-harm is warranted.


Clusters of autochthonous hepatitis A cases in a low endemicity area.
At the University Hospital of Besançon (département of Doubs, France), an unusually high number of patients were hospitalized for hepatitis A during the 1999-2000 period, some of whom had not travelled abroad. This prompted us to conduct an investigation on a population basis and search for clusters of cases possibly related to local sources of contamination. Accordingly, case definition was restricted to autochthonous cases. During the 1999-2002 period, 45 autochthonous cases were classified as possibly originating from local environmental sources. A space-time scan statistic detected one most likely cluster (standardized incidence ratio 20.63, 95% confidence interval 10.6-37.1), consisting of 11 persons (of whom five children had attended the same swimming pool). It remained significant in a sensitivity analysis, strongly supporting the hypothesis of an environmental source of contamination. This study reveals the necessity of regular surveillance for hepatitis A and raises the issue of virological surveys of pool waters.


Investigation of natural food fortificants for improving various properties of fortified foods: A review.
Micronutrient malnutrition (MNM) is called "hidden hunger" due to its invisible vitamin-minerals deficiency symptoms in an individual. In most cases, the prime victim of MNM is children and women. Different strategies such as dietary diversification, supplementation, biofortification, and food fortification are used to fight MNM; however, each method has its own merits and demerits. Therefore, this review discusses an alternate approach, "food-to-food fortification (FtFF)," for combating MNM through enriching the daily diet with essential micronutrients. The main principle behind FtFF is the addition of one or more micronutrient-dense food/s in commonly consumable products. The review highlighted potential natural fortificants rich in iron, folate, zinc, protein, β-carotene, calcium, potassium, and fiber previously used under FtFF. These fortificants are basil, moringa, marjoram, thyme, mint, garden cress, amaranth, fenugreek, and defatted coconut flour. Their effect on nutritional and other properties like antioxidants and antimicrobial, after consuming fortified food, are discussed in detail. At higher substitution levels, a significant impact on sensory and physiochemical properties was observed. Therefore, suitable formulation strategies like mixture design and linear programming were advised to be used before FtFF. A tabulated data on micro-and macronutrients content of fortificants are described for ease in formulation. The review also focused on the latest processing technology in FtFF used for fortifying foods like biscuits, pasta, bread, snack, flakes, porridge, ladoo, dhokla, and many more.


Direct targeting of amplified gene loci for proapoptotic anticancer therapy.
Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci.


Results from a multicentre comparison of cryoballoon vs. radiofrequency ablation for paroxysmal atrial fibrillation: is cryoablation more reproducible?
Cryoballoon ablation (Cryoballoon) has emerged as a new alternative for the treatment of symptomatic drug-refractory atrial fibrillation (AF). Whether the results of Cryoballoon are more reproducible than those of radiofrequency (RF) ablation remains to be proved. A total of 860 consecutive patients undergoing a first ablation procedure for paroxysmal AF (467 treated with RF and 393 treated with Cryoballoon) were selected from a prospective multicentre survey of AF ablation (FrenchAF). Radiofrequency and Cryoballoon were compared regarding mid-term efficacy and safety. During a median follow-up of 14 months (interquartile range 8-23), patients treated with Cryoballoon displayed similar rates of freedom from atrial arrhythmia relapse in centres performing this technique (68-80% at 18 months). However, in centres performing RF, a greater heterogeneity in procedural results was observed (46-79% were free from atrial arrhythmia relapse at 18 months). On multivariate analysis, Cryoballoon (HR = 0.47, 95% CI 0.35-0.65, P < 0.001) and annual AF ablation caseload (HR = 0.87 per every 100 AF ablation procedures per year; 95% CI 0.80-0.96, P = 0.003) were independent predictors of procedural success. However, on sensitivity analysis, according to the ablation method, annual AF ablation caseload predicted only sinus rhythm maintenance in the subgroup of patients treated with RF. Analysis of interoperator results with Cryoballoon and RF confirmed lower reproducibility of RF, but suggested that besides caseload, other operator-related factors may play a role. Cryoballoon seems to be less operator-dependent and more reproducible than RF in the setting of paroxysmal AF ablation.


Deep epigastric lymph nodes implication in patients' recurrence pattern after cytoreductive surgery in ovarian peritoneal metastases.
Although complete cytoreductive surgery (CRS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC) offers a good prognosis in patients with peritoneal metastasis of ovarian cancer (PMOC), recurrences are quite common. These recurrences can be intra-abdominal or systemic in nature. Our objective was to study and illustrate the global recurrence pattern in patients operated for PMOC, shedding light on a previously overlooked lymphatic basin at the level of the epigastric artery, the deep epigastric lymph nodes (DELN) basin. This was a retrospective study including patients with PMOC who underwent surgery with curative-intent, from 2012 until 2018, at our cancer center, and who presented with any type of disease recurrence on follow-up. CT-scans, MRIs and PET-scans were reviewed in order to determine solid organs and lymph nodes (LN) recurrences. During the study period, 208 patients underwent CRS ± HIPEC, 115 (55.3%) presented with organ or lymphatic recurrence over a median follow-up of 81 months. Sixty percent of these patients had radiologically enlarged LN involvement. The pelvis/pelvic peritoneum was the most common intra-abdominal organ recurrence site (47%), while the retroperitoneal LN was the most common lymphatic recurrence site (73.9%). Previously overlooked DELN were found in 12 patients, with 17.4% implication in lymphatic basin recurrence patterns. Our study revealed the potential role of the DELN basin, previously overlooked in the systemic dissemination process of PMOC. This study sheds light on a previously unrecognized lymphatic pathway, as an intermediate checkpoint or relay, between the peritoneum, an intra-abdominal organ, and the extra-abdominal compartment.


Protective effect of the hydroalcoholic extract from Lampaya medicinalis Phil. (Verbenaceae) on palmitic acid- impaired insulin signaling in 3T3-L1 adipocytes.
Obesity is strongly associated with insulin resistance (IR). IR at the molecular level may be defined as a diminished activation of insulin signaling-related molecules (IRS-1/Akt/AS160) as well as reduced glucose uptake. Subject with obesity have elevated plasma levels of saturated fatty acids, such as palmitic acid (PA), which triggers insulin signaling disruption in vivo and in vitro. Infusions of Lampaya medicinalis Phil. (Verbenaceae) are used in folk medicine of Northern Chile to counteract inflammatory diseases. Hydroethanolic extracts of lampaya (HEL) contain considerable amounts of flavonoids that may explain the biological activity of the plant. The aim of this study was to assess whether HEL exposure protects against PA-disrupted insulin signaling and glucose uptake in adipocytes. Cytotoxicity of a range of HEL concentrations (0.01-10 μg/mL) was evaluated in 3T3-L1 adipocytes. Cells were exposed or not to 0.1 μg/mL of HEL before adding 0.65 mM PA or vehicle and incubated with 100 nM insulin (or vehicle) for 15 min. Phosphorylation of Tyr-IRS-1, Ser-Akt, Thr-AS160 was evaluated by Western blot. Glucose uptake was assessed using the 2-NBDG analogue. HEL was not cytotoxic at any concentration assessed. PA-induced reduction in insulin-stimulated phosphorylation of IRS-1, Akt and AS160 and glucose uptake were abolished by co-treatment with HEL. These findings give new insights about the effect of HEL ameliorating PA- impaired IRS-1/Akt/AS160 pathway and glucose uptake in adipocytes. More studies should focus on lampaya, since might represent a preventive approach in individuals whose circulating PA levels contribute to IR.


Instrumental neutron activation analysis of Emblica officinalis, Terminalia belerica and Terminalia chebula for trace element efficacy and safety.
To assess the efficacy and safety, essential (Cl, Co, Cr, Fe, K, Mn, Na, Se, Zn), toxic (As, Br, Hg, Sb,) and other elements (Ba, Ce, Cs, Eu, Rb, Sc) were determined in Emblica officinalis (EO), Terminalia belerica (TB) and Terminalia chebula (TC) using instrumental neutron activation analysis. These herbs contain K as a major element, while Co, Cr and Na in EO, Fe, K and Mn in TB and Cl and Zn in TC are the highest.


[NPHS2 Mutation analysis study in children with steroid-resistant nephrotic syndrome].
Podocin is a protein located in the glomerular slit diaphragm where it takes part in the regulation of glomerular filtration. Mutations of the NPHS2 gene that codes podocin are the main cause of autosomal recessive steroid resistant nephrotic syndrome (SRNS). To identify the NPHS2 mutations in Chilean children with SRNS, and to determine the prevalence of the most common variants in a group of healthy adults. Mutation analysis of NPHS2 in 34 Chilean children with SRNS. Once the two most common variants of NPHS2 were identified, screening for these mutations was performed on 233 healthy adults. The mutation analysis was performed by the direct sequencing of the eight coding exons by polymerase chain reaction amplification. The DNA sequencing was performed using a fluorometric method, and then evaluated with SeqPilot software. The relationship between the presence of NPHS2 variants and SRNS was calculated by comparing the allele frequency between patients with SRNS and those of the healthy volunteers using the exact Fisher test. A P<.05 was considered significant. Pathogenic NPHS2 mutations were detected in 7 (21%) of the 34 patients studied, of which 6 were heterozygotes for p.R229Q and p.A284V. The presence of p.R229Q was 2.46% in the healthy volunteers. This study shows that p.R229Q and p.A284V are the most frequent variants in Chilean children with SRNS. It is the first time that this relationship has been reported in Chilean children. Based on this, a screening strategy is proposed for the genetic study in patients with SRNS and their families. A parallel or sequential search strategy for p.R229Q and p.A284V in these patients is proposed.


Radionuclide transport and uptake in coastal aquatic ecosystems: a comparison of a 3D dynamic model and a compartment model.
In safety assessments of underground radioactive waste repositories, understanding radionuclide fate in ecosystems is necessary to determine the impacts of potential releases. Here, the reliability of two mechanistic models (the compartmental K-model and the 3D dynamic D-model) in describing the fate of radionuclides released into a Baltic Sea bay is tested. Both are based on ecosystem models that simulate the cycling of organic matter (carbon). Radionuclide transfer is linked to adsorption and flows of carbon in food chains. Accumulation of Th-230, Cs-135, and Ni-59 in biological compartments was comparable between the models and site measurements despite differences in temporal resolution, biological state variables, and partition coefficients. Both models provided confidence limits for their modeled concentration ratios, an improvement over models that only estimate means. The D-model enables estimates at high spatio-temporal resolution. The K-model, being coarser but faster, allows estimates centuries ahead. Future developments could integrate the two models to take advantage of their respective strengths.


Real-time semi-quantitative assessment of anastomotic blood perfusion in mini‑invasive rectal resections by Sidestream Dark Field (SDF) imaging technology: a prospective in vivo pilot study.
Anastomotic leakage (AL) is one of the severe complications after rectal surgery, and anastomotic ischemia is one of the main factors. This prospective in vivo pilot study aimed to evaluate the effectiveness of Sidestream Dark Field (SDF) imaging in quantitative assessment of anastomotic microcirculation and to analyze its correlation with AL. Thirty-three patients with rectal cancer who underwent laparoscopic low anterior resection from 2019 to 2020 were enrolled. Microcirculation was measured by SDF imaging at the descending colon, the mesocolon transection line (MTL), and 1 cm and 2 cm distal to the MTL. Anastomotic microcirculation was measured at the stapler anvil edge before anastomosis. Quantitative perfusion-related parameters were as follows: microcirculation flow index (MFI), perfused vessel density (PVD), proportion of perfused vessels (PPV), and total vessel density (TVD). All patients obtained stable microcirculation images. Functional microcirculation parameters (MFI, PPV, PVD) decreased successively from the descending colon, the colon at MTL, and 1 cm and 2 cm distal to the MTL (all P < 0.01). Extremely poor microcirculation was found at the intestinal segment 2 cm distal to the MTL. Micro-perfusion was significantly lower at the colonic limb of the anastomosis compared with the descending colon (all P < 0.001). Anastomotic leakage occurred in 3 patients (9.1%) whose anastomotic microcirculation was significantly lower than those without AL (all P < 0.01). Blood perfusion at the colonic limb of the anastomosis was significantly higher in patients with left colic artery preservation than in controls. SDF imaging is a promising technique for evaluating anastomotic microcirculation and has potential clinical significance for risk stratification of AL.


20-MHz phased array ultrasound transducer for in vivo ultrasound imaging of small animals.
In vivo ultrasound imaging with phased array transducers is of great importance for both clinical application and biomedical research. In this work, relaxor ferroelectric PMN-0.28PT single crystal with very high piezoelectric constant d33 ≥ 2000 pC/N and electromechanical coupling coefficient k33 ∼ 0.92 is used to fabricate high-frequency phased array transducers. A 128-element 20-MHz phased array transducer is successfully fabricated, and the optimized performance of -6 dB average bandwidth of ∼ 84 % and insertion loss of -43 dB are achieved. The axial and lateral imaging resolutions of the transducer are determined to be 81 µm and 243 µm, respectively. With Verasonics image platform, in vivo fisheye images are acquired, demonstrating the potential application of our developed high-frequency phased array transducer for biomedical research on small animals.


The speciation and adaptation of the polyploids: a case study of the Chinese Isoetes L. diploid-polyploid complex.
The Chinese Isoetes L. are distributed in a stairway pattern: diploids in the high altitude and polyploids in the low altitude. The allopolyploid I. sinensis and its diploid parents I. yunguiensis and I. taiwanensis is an ideal system with which to investigate the relationships between polyploid speciation and the ecological niches preferences. There were two major clades in the nuclear phylogenetic tree, all of the populations of polyploid were simultaneously located in both clades. The chloroplast phylogenetic tree included two clades with different populations of the polyploid clustered with the diploids separately: I. yunguiensis with partial populations of the I. sinensis and I. taiwanensis with the rest populations of the I. sinensis. The crow node of the I. sinensis allopolyploid system was 4.43 Ma (95% HPD: 2.77-6.97 Ma). The divergence time between I. sinensis and I. taiwanensis was estimated to 0.65 Ma (95% HPD: 0.26-1.91 Ma). The narrower niche breadth in I.sinensis than those of its diploid progenitors and less niche overlap in the pairwise comparisons between the polyploid and its progenitors. Our results elucidate that I. yunguinensis and I. taiwanensis contribute to the speciation of I. sinensis, the diploid parents are the female parents of different populations. The change of altitude might have played an important role in allopolyploid speciation and the pattern of distribution of I. sinensis. Additionally, niche novelty of the allopolyploid population of I. sinensis has been detected, in accordance with the hypothesis that niche shift between the polyploids and its diploid progenitors is important for the establishment and persistence of the polyploids.


An Analysis of Skin of Color Publications in the Journal of Drugs in Dermatology from 2018 to 2020.
As the United States population becomes increasingly diverse, it is exceedingly important for dermatologists to be knowledgeable about treating patients with skin of color (SOC). The published literature is an especially valuable resource for treating SOC.


Pitfalls in using fluorescence tagging of nanomaterials: tecto-dendrimers in skin tissue as investigated by Cluster-FLIM.
Targeted topical application promises high drug concentrations in the skin and low systemic adverse effects. To locate drugs and drug-delivery systems like nanocarriers, fluorescent dyes are commonly used as drug surrogates or nanocarrier labels in micrographs of tissue sections. Here, we investigate how labeling degree, concentration of fluorophore, and nanocarrier may affect the interpretation of these micrographs. False-negative penetration results due to inter- and intramolecular quenching effects are likely. Using tecto-dendrimers as an example, we present a detailed analysis of pitfalls in the (semi-)quantitative evaluation of skin nanocarrier penetration. Fluorescence lifetime imaging microscopy (FLIM) allows distinguishing the target fluorescence of dye-tagged nanocarriers from skin autofluorescence, providing a highly sensitive tool for clear-cut localization of the nanocarriers. Cluster-FLIM images reveal that FITC-labeled tecto-dendrimers penetrate the stratum corneum of human skin ex vivo and reconstructed human skin but do not cross the tight junction barrier.


Analysis of mycotoxins in cereals and animal feed using a multi-toxin gel permeation chromatography clean-up method.
Gel permeation chromatography has been used to clean up extracts from cereals and animal feeds containing a range of mycotoxins. A mixture of dichloromethane: IM hydrochloric acid, 10:1 by volume is used as the extraction solvent and clean-up is carried out on a Bio - Beads S-X3 column using dichloromethane: ethyl acetate containing a small amount of formic acid as the elution solvent. Chromatographic separation and detection was by HPLC with fluorescence or ultraviolet detection although the choice of detection method is left to the user. The method has been tested for 14 mycotoxins and results are presented for cereals fortified with mycotoxins and for samples naturally contaminated with aflatoxins, citrinin, zearalenone, and ochratoxin A.


The neural basis of effort valuation: A meta-analysis of functional magnetic resonance imaging studies.
Choosing how much effort to expend is critical for everyday decisions. While several neuroimaging studies have examined effort-based decision-making, results have been highly heterogeneous, leaving unclear which brain regions process effort-related costs and integrate them with rewards. We conducted two meta-analyses of functional magnetic resonance imaging data to examine consistent neural correlates of effort demands (23 studies, 15 maps, 549 participants) and net value (15 studies, 11 maps, 428 participants). The pre-supplementary motor area (pre-SMA) scaled positively with pure effort demand, whereas the ventromedial prefrontal cortex (vmPFC) showed the opposite effect. Moreover, regions that have been previously implicated in value integration in other cost domains, such as the vmPFC and ventral striatum, were consistently involved in signaling net value. The opposite response patterns of the pre-SMA and vmPFC imply that they are differentially involved in the representation of effort costs and value integration. These findings provide conclusive evidence that the vmPFC is a central node for net value computation and reveal potential brain targets to treat motivation-related disorders.


The empire of the narrative: Plan making through the prism of classical and postclassical narratologies.
This article theorizes the "narrative turn" in urban planning studies, using Gérard Genette's work to differentiate first- and second-degree narratives. Genette defines the latter as paratexts that determine the public's reception of the former. The article assesses how second-degree narratives work with different perceptual regimes to construct the reception of the political vision of territory. To that end, it resorts to the recent work of postclassical narratology. Indeed, the latter is particularly interested in the way in which the narrative, in various forms, affects its addressee. Postclassical narratology allows us to renew the theory of narrative in urban planning by focusing on what hypothetically happens in the consciousness of the receiver of the narrative when he or she becomes aware of it. Consequently, the paper sheds light on an emerging aspect of the design process: disambiguating signals embedded in urban planning documents intended for a wider public.


Effect of onion and ginger consumption on platelet thromboxane production in humans.
The effects of onion and ginger consumption on platelet thromboxane production were examined. Volunteers, all Danish women, consumed either 70 g raw onion or 5 g raw ginger daily for a period of 7 days. Each participant in each (onion or ginger) group served as her own control. TxB2 determination was made in serum obtained after blood clotting. The following are the results. TxB2 (pmol/ml serum): (i) onion group--before consumption 910 +/- 327, after consumption 1005 +/- 713 (Mean +/- SD, N = 5); (ii) ginger consumption 782 +/- 482, after consumption 498 +/- 164 (Mean +/- SD, N = 7).


Simvastatin dose and risk of rhabdomyolysis: nested case-control study based on national health and drug dispensing data.
Two randomised controlled trials have found a higher risk of rhabdomyolysis in users of 80 mg versus 20 mg simvastatin, but there is very limited information about the risk associated with other doses. We undertook a nested case-control study, using routinely collected national health and drug dispensing data, to estimate the relative and absolute risks of rhabdomyolysis resulting in hospital admission or death according to simvastatin dose. The underlying study cohort comprised all patients (n=313,552) who initiated a new episode of simvastatin use in New Zealand between 1 May 2005 and 31 December 2009. Cases (n=29) were patients with a diagnosis of rhabdomyolysis after cohort entry, confirmed by hospital discharge letter or death records. Ten controls, matched by year of birth and sex, were randomly selected from the study cohort using risk set sampling. Current users of 40 mg simvastatin daily were about five times as likely to develop rhabdomyolysis as those taking 20mg; the adjusted odds ratio was 5.3 (95% CI 1.9-15.0). The absolute excess risk of rhabdomyolysis associated with the use of 40 mg versus 20mg was about 10 per 100,000 person-years; the crude incidence rates were 11.5 (95% CI 7.1-17.5) and 2.1 (95% CI 0.7-4.8) per 100,000 person-years respectively. These findings provide reassurance that the absolute risk of rhabdomyolysis in a general population of simvastatin users is very low. Nonetheless, they also raise questions about the optimal simvastatin regimen to maximise cardiovascular benefits and minimise the risk of serious muscle injury.


Craniocervical computed tomography angiography with adaptive iterative dose reduction 3D algorithm and automatic tube current modulation in patients with different body mass indexes.
The aim of this study was to investigate the feasibility of head and neck computed tomography angiography (CTA) using the 80-kV tube voltage and the adaptive iterative dose reduction (AIDR) 3D algorithm in patients with different body mass indexes (BMIs).From November 2016 to January 2017, 128 consecutive patients scheduled for head and neck CTA examinations were randomized into the 100-kV group (n = 60) and the 80-kV group (n = 68). Both groups used the automatic tube current modulation technique and the AIDR 3D algorithm. The patients were further grouped as slender (BMI < 22 kg/m), normal weight (22 kg/m≤BMI < 25 kg/m), and overweight (BMI ≥25 kg/m). The image quality and the radiation dose of each subgroup were analyzed.The images of the head and neck vessels and the brain tissue obtained with 100 kV were all of diagnostic quality. Slender and normal weight patients imaged with 80 kV also produced images of diagnostic quality. However, 80 kV in the overweight patients failed to produce images of diagnostic quality. The radiation dose in the patients imaged with 80 kV was significantly decreased in comparison with those imaged with 100 kV. The effective dose was 0.36 ± 0.06 and 0.41 ± 0.05 mSv in the slender and normal weight patients imaged with 80 kV.Head and neck CTA scanning with 80 kV, automatic tube current modulation, and AIDR 3D algorithm can produce high quality images with reduced radiation dose in slender or normal weight patients.


Accelerated atrioventricular conduction during acute myocardial infarction.
Three cases are described in which accelerated atrioventricular conduction occurred during an acute myocardial infarction. The first patient, an 82-year-old woman, developed a WPW syndrome suggesting posterior right ventricular preexcitation, a pattern which persisted for four months until her death. An accessory bundle was found on autopsy. Fibrotic changes, associated with acute lesions (hemorrhage, polymorphonuclear infiltrates) were present in the atrioventricular node and His-Purkinje system. Two men, of 47 and 74 years, developed a short PR interval associated with supraventricular tachycardia during the course of an acute myocardial infarction. The PR interval returned to its initial value in one case and remained unchanged for three months in the other. Accessory atrioventricular connections which became functional during myocardial ischemia may explain the various electrocardiographic patterns of preexcitation.


Effects of chronic exposure to toxic metals on haematological parameters in free-ranging small mammals.
Blood circulates through the vascular system to carry oxygen, nutrients and metabolites to and away from tissues, and as such is a key-component of animal physiology. The impacts of metal pollution on blood, however, are poorly documented in free-ranging vertebrates. While the counteracting effect of selenium on mercury toxicity is well known in marine mammals, its potential role against the toxicity of other metals is less studied, especially on terrestrial wildlife. We explored the consequences of chronic exposure to two non-essential metals (cadmium and lead) along a pollution gradient in Northern France, on eleven haematological parameters in two free ranging small mammals, the wood mouse Apodemus sylvaticus and the bank vole Myodes glareolus. We hypothesized that haematology was related to metal concentrations in tissues, and that selenium might exert modulating effects. Concentrations of cadmium and lead in the tissues indicated an increased chronic exposure to and accumulation of metals along the gradient. Some haematological parameters were not explained by any measured variables while some others varied only with gender or age. Red blood cells, red blood cells distribution width, and blood iron concentration, however, decreased with increasing cadmium in the tissues in wood mice. Red blood cells and haemoglobin decreased with increasing renal lead and hepatic cadmium, respectively, in bank voles. Red blood cells distribution width in wood mice increased with cadmium concentrations in the liver but this was counteracted by high selenium levels in the same organ. An interaction of selenium and lead on red blood cells was also observed in bank voles. Further, selenium concentrations were associated with an increase of monocytes in wood mice. The present results show that toxic metals were related to haematology changes, particularly erythrocyte indicators, and that some essential elements like selenium should be measured as well since they may counteract toxic effects.


Subungual keratoacanthoma in the hand.
A subungual keratoacanthoma of the thumb with a 5-year follow-up is reported. Recurrence after initial curettage necessitated amputation of the terminal phalanx as definitive treatment. The 22 subungual keratoacanthomas of the hand reported in the literature are reviewed. Although conservative treatment sparing the digit in the form of excision and curettage is recommended as the initial treatment of choice, this uncommon benign, but aggressive, lesion of the nail bed may require amputation of the involved phalanx as definitive treatment.


Reduced aminergic synthesis in the hypothalamus of the infertile, genetically diabetic (C57BL/KsJ-db/db) male mouse.
Diabetes mellitus is commonly associated with reproductive neuroendocrinopathy in both humans and animal models for the disease. Diabetes-associated reproductive failure in the male is a result of multilevel dysfunction within the hypothalamo-pituitary-testicular axis. In view of the known effects of diabetes on hypothalamic gonadotropin-releasing hormone (GnRH) and gonadotropins in chemically-induced animal models for diabetes, we examined hypothalamic aminergic activities (important to the regulation of GnRH release), circulating gonadotropin levels and testicular morphology in the infertile, genetically diabetic (C57BL/KsJ-db/db) male mouse. Groups of 2-5 month old (average age: 3.4 months) and 6-11 month old (average age: 8.8 months) diabetic mice were compared with age-matched non-diabetic (C57BL/KsL(-)+/?) male mice. Diabetic mice in both age groups were markedly obese and hyperglycemic. Hypothalamic serotonin synthesis was inhibited in the preoptic area-anterior hypothalamus (POA-AH) in both 2-5 month old and 6-11 month old diabetic mice as well as in the mediobasal hypothalamus-median eminence (MBH-ME) of 6-11 month old diabetic mice. Catecholamine synthesis (norepinephrine and dopamine) was reduced in the POA-AH of 2-5 month old diabetic mice and in the MBH-ME of 6-11 month old mice. These aminergic changes were associated in 2-5 month old diabetic mice with reduced circulating levels of LH and in 6-11 month old diabetic mice, of both LH and FSH. In 6-11 month old diabetic mice, testes were characterized by a thickened tunica albuginea, numerous Sertoli cells and the near absence of any spermatogenic cells. The epididymis from these diabetic mice was devoid of spermatozoa.(ABSTRACT TRUNCATED AT 250 WORDS)


Comparison of the immunostimulatory and proinflammatory activities of candidate Gram-positive endotoxins, lipoteichoic acid, peptidoglycan, and lipopeptides, in murine and human cells.
The role of lipopolysaccharide (LPS) in the pathogenesis of Gram-negative septic shock is well established. The corresponding proinflammatory and immunostimulatory molecule(s) on the Gram-positive bacteria is less well understood, and its identification and characterization would be a key prerequisite in designing specific sequestrants of the Gram-positive endotoxin(s). We report in this paper the comparison of NF-kappaB-, cytokine- and chemokine-inducing activities of the TLR2 ligands, lipoteichoic acid (LTA), peptidoglycan (PGN), and lipopeptides, to LPS, a prototype TLR4 agonist, in murine macrophage cell-lines as well as in human blood. In murine cells, di- and triacyl liopopeptides are equipotent in their NF-kappaB inducing activity relative to LPS, but elicit much lower proinflammatory cytokines. However, both LPS and the lipopeptides potently induce the secretion of a pattern of chemokines that is suggestive of the engagement of a TLR4-independent TRIF pathway. In human blood, although the lipopeptides induce p38 MAP kinase phosphorylation and CD11b upregulation in granulocytes at ng/ml concentrations, they do not elicit proinflammatory cytokine production even at very high doses; LTA, however, activates neutrophils and induces cytokine secretion, although its potency is considerably lower than that of LPS, presumably due to its binding to plasma proteins. We conclude that, in human blood, the pattern of immunostimulation and proinflammatory mediator production elicited by LTA parallels that of LPS.


Functional characterization of Chlamydomonas reinhardtii with alterations in the atpE gene.
The FUD17 strain of Chlamydomonas reinhardtii is a photosynthesis-deficient, acetate-requiring mutant with a defect in the chloroplast atpE gene, which codes for the epsilon subunit of the chloroplast ATP synthase. In this work, the FUD17 mutant was examined in relation to other known ATP synthase mutants as an initial step toward using this strain to generate altered versions of the atpE gene for site-directed mutagenesis of the epsilon subunit. The FUD17 strain grows well and is normally pigmented in the dark (heterotrophic conditions), but cannot grow autotrophically in the light, even when media are supplemented with acetate. Under heterotrophic conditions, it shows no accumulation of the epsilon subunit, and much lower levels of the alpha and beta subunits of the chloroplast ATP synthase. FUD17 shows no light-dependent oxygen evolution and shows a strong, light-dependent alteration in its chlorophyll fluorescence. These results show that FUD17 possesses similar characteristics to other ATP synthase mutants and fails to express an assembled ATP synthase complex on its thylakoid membrane. A preliminary attempt at site-directed mutagenesis is described which produced a slightly truncated form of the epsilon subunit, which is expressed normally in the cell.


Functional interaction between KChIP1 and GFP-fused Kv4.3L co-expressed in HEK293 cells.
The trafficking and electrophysiological characteristics of Kv4 subfamily are regulated by K+-channel-interacting proteins (KChIPs), which bind to the N-terminus of Kv4. We examined in HEK293 expression system whether the fusion of a green fluorescence protein (GFP) with Kv4.3L at the N-terminus would affect the functional interaction of KChIP1 with Kv4.3L. GFP-fused Kv4.3L showed A-type K+ current (I(A)) with significantly slower recovery from inactivation (tau=218 and 496 ms) and much lower density than those of original Kv4.3L expressed in HEK293 cells. The co-expression of KChIP1 with Kv4.3L strikingly increased the density of I(A) and hastened the recovery from inactivation (tau=133 ms). Surprisingly, co-expression of KChIP1 with GFP-fused Kv4.3L markedly enhanced the current density and hastened the recovery (tau=135 ms), just as the co-expression of KChIP1 with Kv4.3L did. In conclusion, the fusion of GFP to the N-terminus of Kv4.3L per se changed the channel kinetics but did not affect the functional interaction of KChIP1 with Kv4.3L at all. The trafficking of Kv4.3L by KChIP1 to the cell membrane was visualized with GFP fusion to the N-terminus without any significant modification of changes in channel kinetics and density.


Electrophysiological analysis of motor control in patients with vascular hemichorea.
An EMG analysis of motor control was performed in 4 patients with unilateral choreic movements of sudden onset, 3 of whom presented CT scan evidence of lacunar infarcts involving the contralateral striatum. The choreic dyskinesias were correlated with EMG bursts of variable duration occurring with a random order of activation. Ballistic elbow flexion movements were performed with a normal triphasic EMG pattern, but both size and duration of the first agonist burst were increased on the affected side. Abnormalities of cerebral somatosensory evoked responses were observed in 3 patients on stimulation of the side with choreic movements.


Complications of ear rings.
In this paper the complications of ear piercing are considered and the treatment of resultant deformities is described.


En bloc incorporation of coatomer subunits during the assembly of COP-coated vesicles.
The cDNA encoding epsilon-COP, the 36-kD subunit of coatomer, was cloned from a bovine liver cDNA library and sequenced. Immunoblotting with an anti-epsilon-COP antibody showed that epsilon-COP exists in COP-coated vesicles as well as in the cytosolic coatomer. Using the cloned cDNA, recombinant His6- tagged epsilon-COP was overexpressed in cultured Chinese hamster ovary (CHO) cells, from which metabolically radiolabeled coatomer was purified by taking advantage of the His6 tag. Radiolabeled coatomer was employed to establish that all the subunits of the coatomer enter coated vesicles as an intact unit.


MRI tumor volume reduction rate vs tumor regression grade in the pre-operative re-staging of locally advanced rectal cancer after chemo-radiotherapy.
To compare tumor volume reduction rate (TVRR) measured by MR volumetry after preoperative chemoradiotherapy (CRT) and pathological tumor regression grade (TRG) in locally advanced rectal cancer (LARC). In total, 20 patients with LARC (cT3-T4) treated with CRT followed by Total Mesorectal Excision (TME) between April 2011 and April 2013 were analyzed retrospectively. Pre- and post- CRT tumor volumes (MR volumetry) were measured on 3D MR sequences. TVRR was determined using the equation TVRR (%)=(pre-CRT tumor volume-post-CRT tumor volume)×100/pre-CRT tumor volume. The downstaging (defined as ypT0-T2) of tumor mass was evaluated and the correlation between TVRR and TRG was calculated with the method proposed by Dworak using the Spearman rank test. The median TVRR was 77.3% (range, 26.4-99.3%); TVRR was >60% in 18 cases (90%) and in 8 of these patients (44.4 %) it was >80%. Downstaging of tumor lesions was obtained in 15 patients (75%). In 4 cases there was a complete tumor regression (TRG4) at histological examination and in the same patients there was also a TVRR>80% measured by MR volumetry. A statistically significant correlation between TVRR and TRG (r(s)=0.5466, p=0.0126) was observed. TVRR after preoperative CRT correlates with TRG in LARC. The MR volumetry is a prognostic factor to estimate the tumor response after preoperative CRT. TVRR data may be an useful biomarker for tailoring surgery and postoperative adjuvant chemotherapy.


The role of autologous bone marrow transplantation in the treatment of malignant disease.
This short review of autologous bone marrow transplantation (ABMT) has a distinct clinical emphasis and concentrates particularly on adult acute leukaemia and lymphoma in which the greatest amount of current clinical experience lies. In the early part of the review we discuss how escalations of dose of chemoradiotherapy might allow ablation of both marrow-derived (leukaemia) and non-marrow-derived disease (lymphoma and solid tumour) provided that haemopoiesis is reintroduced into the host in the form of autologous marrow stem cells, and how cryopreservation techniques have allowed this to proceed. Whilst discussing ABMT in acute leukaemia we describe initial results possibly suggestive of an improvement on current consolidation/maintenance chemotherapy regimens but emphasis that we are dealing only with heterogeneous registry data and not randomised controlled trials. We also suggest that there is no useful data as yet as to the value of purging autologous acute leukaemia marrow. The lymphoma data is described which may suggest a useful role of high dose therapy with ABMT in relapsed disease-timing of ABMT may need to differ profoundly in HD from NHL. Current ABMT data in lymphoma suggests that local relapse at sites of previous disease remain the major problem and emphasises the difficulties of finding satisfactory ablative regimens and timing the selection of patients at particular points in the natural history of their disease. Finally, we emphasise that although solid tumours may numerically represent the largest group of potential candidates for ABMT, the picture in this area remains essentially one of failure to be able to ablate the underlying disease despite increments in chemoradiotherapy and ABMT.


[The treatment of imported Plasmodium falciparum malaria with halofantrine. Apropos of 59 case reports (corrected and republished article orginally printed in Med Trop (Mars) 1990 Jan-Mar;50(1):113-7)].
59 cases of Plasmodium falciparum malaria fever occurring in non-immune Caucasian subjects having got a correct chemoprophylaxis by chloroquine were treated by halofantrine (HALFAN). They were given 1500 mg divided in 3 doses of 500 mg every 6 hours from D1 to D8. All them were back from a malarial highly endemic zone with chloroquine resistance. Analysis of the main biological and clinical efficiency parameters displayed very satisfactory results: disappearances of fever (mean 22 H) and parasitemia (mean 36 H) are short. After two months of monitoring, no malaria recrudescence was noted. With an efficacy of 10 p.c. associated to a noticeable clinical and biological tolerance Halofantrine is a first-class treatment of chloroquine resistant malaria fever.


Estrogen contributes to structural recovery after a lesion.
Over the last decade neuroscientists have accumulated a wealth of information confirming the trophic effects of 17beta-estradiol (E2) on a variety of brain regions, such as the effects on hippocampal spine density, as well as other measures of structural reorganization. Here, we explore the hypothesis that E2 exerts a positive trophic effect on the cholinergic neurons of the basal forebrain, an area heavily implicated in memory and attentional processes. Female rats were ovariectomized at 3 months of age and lesioned with the immunotoxin 192 IgG-saporin before receiving a subcutaneous pellet containing .25 mg of estrogen or placebo, released over 60 days. The control, non-ovariectomized group was treated identically. At the end of the treatment, the brains were histologically prepared and we used image analysis procedures to evaluate changes in the dendritic arborization of surviving cholinergic neurons. As expected, infusion of the immunotoxin induced a reduction in dendritic arborization in all subjects, but was significantly different from control values only in ovariectomized rats. When differences within animals were factored in, dendritic size in ovariectomized animals treated with E2 was undistinguishable from intact controls. By contrast, in ovariectomized animals treated with placebo, dendritic length remained significantly reduced. These results suggest that E2 can not only protect but also reverse structural neurodegenerative processes in cholinergic neurons. Our data is particularly relevant in the context of female aging and postmenopausal dementia, since preserving an intact cholinergic system may be crucial to prevent at least some of the cognitive decline that occurs in Alzheimer's disease.


Genome-wide identification and expression analysis of the MADS-box gene family during female and male flower development in Juglans mandshurica.
The MADS-box gene family plays a crucial role in multiple developmental processes of plants, especially in floral organ specification and the regulation of fruit development and ripening. Juglans mandshurica is a precious fruit material whose quality and yield are determined by floral organ development. The molecular mechanism of J. mandshurica female and male flower development depending on MADS-box genes remains unclear. In our study, 67 JmMADS genes were identified and unevenly distributed on 15 of 16 J. mandshurica chromosomes. These genes were divided into two types [type I (Mα, Mγ, Mδ) and type II (MIKC)]. The gene structure and motif analyses showed that most genes belonging to the same type had similar gene structures and conserved motifs. The analysis of syntenic relationships showed that MADS-box genes in J. mandshurica, J. sigillata, and J. regia exhibited the highest homology and great collinearity. Analysis of cis-acting elements showed that JmMADS gene promoter regions contained light, stress and hormone response cis-acting elements. The gene expression patterns demonstrated that 30 and 26 JmMADS genes were specifically expressed in the female and male flowers, respectively. In addition, 12 selected genes common to J. mandshurica female and male flowers were significantly upregulated at the mature stage and were used to validate the reliability of the transcriptome data using quantitative real-time PCR. This comprehensive and systematic analysis of J. mandshurica MADS-box genes lays a foundation for future studies on MADS-box gene family functions.


Structure and function of copper uptake transporters.
Owing to their redox and coordination chemistry copper ions play essential roles in cellular function. Research over the past 20 years has shed much light on the biochemistry of copper homeostasis, and the emergence of high-resolution crystal structures for many of the proteins that partake in cellular copper biology have began to provide insight into the molecular mechanisms by which cells handle this important metal. A notable gap in our understanding is related to the process by which cells acquire copper ions. This chapter describes recent progress in the structure determination of cellular copper uptake transporters and how the emerging structural information aids understanding of the molecular mechanisms that govern cellular copper acquisition and distribution.


Instructional methods and cognitive and learning styles in web-based learning: report of two randomised trials.
Adapting web-based (WB) instruction to learners' individual differences may enhance learning. Objectives This study aimed to investigate aptitude-treatment interactions between learning and cognitive styles and WB instructional methods. We carried out a factorial, randomised, controlled, crossover, post-test-only trial involving 89 internal medicine residents, family practice residents and medical students at 2 US medical schools. Parallel versions of a WB course in complementary medicine used either active or reflective questions and different end-of-module review activities ('create and study a summary table' or 'study an instructor-created table'). Participants were matched or mismatched to question type based on active or reflective learning style. Participants used each review activity for 1 course module (crossover design). Outcome measurements included the Index of Learning Styles, the Cognitive Styles Analysis test, knowledge post-test, course rating and preference. Post-test scores were similar for matched (mean +/- standard error of the mean 77.4 +/- 1.7) and mismatched (76.9 +/- 1.7) learners (95% confidence interval [CI] for difference - 4.3 to 5.2l, P = 0.84), as were course ratings (P = 0.16). Post-test scores did not differ between active-type questions (77.1 +/- 2.1) and reflective-type questions (77.2 +/- 1.4; P = 0.97). Post-test scores correlated with course ratings (r = 0.45). There was no difference in post-test subscores for modules completed using the 'construct table' format (78.1 +/- 1.4) or the 'table provided' format (76.1 +/- 1.4; CI - 1.1 to 5.0, P = 0.21), and wholist and analytic styles had no interaction (P = 0.75) or main effect (P = 0.18). There was no association between activity preference and wholist or analytic scores (P = 0.37). Cognitive and learning styles had no apparent influence on learning outcomes. There were no differences in outcome between these instructional methods.


Genetic diversity of Histoplasma capsulatum strains in Brazil.
This study establishes the genetic relatedness among Brazilian Histoplasma capsulatum samples obtained from different sources. A PCR-based random amplified polymorphic DNA (RAPD) assay was used to delineate polymorphisms among isolates in geographically diverse regions in Brazil. RAPD fingerprints revealed distinct DNA profiles and provided a high level of discrimination among H. capsulatum strains from different locations. Cluster I was composed of H. capsulatum isolates from the northeast region. The majority of strains from southeast and south were categorized as major cluster II. The strain 84564 from Rio de Janeiro State showed no genetic correlation to any of the isolates from the same state. The RAPD patterns of H. capsulatum isolates from Goias (Cluster III) were unrelated to DNA fingerprints observed among the other H. capsulatum strains (48% similarity). This study is the first report that stratifies the clusters of H. capsulatum strains from Brazil by molecular typing and associates them with the geographical origin.


Design of a Compensator Network to Stabilize Chaotic Tumor Growth.
Tumorigenesis can be modeled as a system of chaotic, nonlinear differential equations. From the analysis of these equations in state space, a feedback compensator is designed to stabilize the system based on a desired response. The feedback array constants represent four transducer molecules which could be used for any tumor type that obeys the same dynamics as the model, reducing drug investment requirements for a wider range of cancer treatment.


Management decisions of an Academic Radiology Department during COVID-19 pandemic: the important support of a business analytics software.
To analyze the response in the management of both radiological emergencies and continuity of care in oncologic/fragile patients of a radiology department of Sant'Andrea Academic Hospital in Rome supported by a dedicated business analytics software during the COVID-19 pandemic. Imaging volumes and workflows for 2019 and 2020 were analyzed. Information was collected from the hospital data warehouse and evaluated using a business analytics software, aggregated both per week and per quarter, stratified by patient service location (emergency department, inpatients, outpatients) and imaging modality. For emergency radiology subunit, radiologist workload, machine workload, and turnaround times (TATs) were also analyzed. Total imaging volume in 2020 decreased by 21.5% compared to that in 2019 (p < .001); CT in outpatients increased by 11.7% (p < .005). Median global TAT and median code-blue global TAT were not statistically significantly different between 2019 and 2020 and between the first and the second pandemic waves in 2020 (all p > .09). Radiologist workload decreased by 24.7% (p < .001) during the first pandemic wave in 2020 compared with the same weeks of 2019 and showed no statistically significant difference during the second pandemic wave, compared with the same weeks of 2019 (p = 0.19). Despite the reduction of total imaging volume due to the COVID-19 pandemic in 2020 compared to 2019, management decisions supported by a dedicated business analytics software allowed to increase the number of CT in fragile/oncologic outpatients without significantly affecting emergency radiology TATs, and emergency radiologist workload. • During the COVID-19 pandemic, management decisions supported by business analytics software guaranteed efficiency of emergency and preservation of fragile/oncologic patient continuity of care. • Real-time data monitoring using business analytics software is essential for appropriate management decisions in a department of radiology. • Business analytics should be gradually introduced in all healthcare institutions to identify strong and weak points in workflow taking correct decisions.