A six-gene-based prognostic model predicts complete remission and overall survival in childhood acute myeloid leukemia.
Acute myeloid leukemia (AML) is a malignant clonal disorder. Despite enormous progress in its diagnosis and treatment, the mortality rate of AML remains high. The aim of this study was to identify prognostic biomarkers by using the gene expression profile dataset from public database, and to improve the risk-stratification criteria of survival for patients with AML. The gene expression data and clinical parameter were acquired from the Therapeutically Applicable Research to Generate Effective Treatment (TARGET) database. A total of 856 differentially expressed genes (DEGs) were obtained from the childhood AML patients classified into first complete remission (CR1) group (n=791) and not CR group (n=249). We performed a series of bioinformatics analysis to screen key genes and pathways, further comprehending these DEGs through Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Six genes (SLC17A7, MSX2, CDC26, MSLN, CTSZ and DEFA3) identified by univariate, Kaplan-Meier survival and multivariate Cox regression analyses were used to develop the prognostic model. Further analysis showed that the survival estimations in the high-risk group had an increased risk of death compared with the low-risk group based on the model. The area under the curve of the receiver operator characteristic curve in the prognostic model for predicting the overall survival was 0.729, confirming good prognostic model. We also performed a nomogram to provide an individual patient with the overall probability, and internal validation in the TARGET cohort. We identified a six-gene prognostic signature for risk-stratifying in patients with childhood AML. The risk classification model can be used to predict CR markers and may assist clinicians in providing realize the individualized treatment in this patient population.


Effect-directed analysis of municipal landfill soil reveals novel developmental toxicants in the zebrafish Danio rerio.
Effect-directed analysis (EDA) is an approach used to identify (unknown) contaminants in complex samples which cause toxicity, using a combination of biology and chemistry. The goal of this work was to apply EDA to identify developmental toxicants in soil samples collected from a former municipal landfill site. Soil samples were extracted, fractionated, and tested for developmental effects with an embryotoxicity assay in the zebrafish Danio rerio. Gas chromatograph mass selective detection (GC-MSD) chemical screening was used to reveal candidate developmental toxicants in fractions showing effects. In a parallel study, liquid chromatography-hybrid linear ion trap Orbitrap mass spectrometry was also applied to one polar subfraction (Hoogenboom et al. J. Chromatogr. A2009, 1216, 510-519). EDA resulted in the identification of a number of previously unknown developmental toxicants, which were confirmed to be present in soil by GC-MS. These included 11H-benzo[b]fluorene, 9-methylacridine, 4-azapyrene, and 2-phenylquinoline, as well as one known developmental toxicant (retene). This work revealed the presence of novel contaminants in the environment that may affect vertebrate development, which are not subject to monitoring or regulation under current soil quality assessment guidelines.


Adult hippocampal neurogenesis reduces memory interference in humans: opposing effects of aerobic exercise and depression.
Since the remarkable discovery of adult neurogenesis in the mammalian hippocampus, considerable effort has been devoted to unraveling the functional significance of these new neurons. Our group has proposed that a continual turnover of neurons in the DG could contribute to the development of event-unique memory traces that act to reduce interference between highly similar inputs. To test this theory, we implemented a recognition task containing some objects that were repeated across trials as well as some objects that were highly similar, but not identical, to ones previously observed. The similar objects, termed lures, overlap substantially with previously viewed stimuli, and thus, may require hippocampal neurogenesis in order to avoid catastrophic interference. Lifestyle factors such as aerobic exercise and stress have been shown to impact the local neurogenic microenvironment, leading to enhanced and reduced levels of DG neurogenesis, respectively. Accordingly, we hypothesized that healthy young adults who take part in a long-term aerobic exercise regime would demonstrate enhanced performance on the visual pattern separation task, specifically at correctly categorizing lures as "similar." Indeed, those who experienced a proportionally large change in fitness demonstrated a significantly greater improvement in their ability to correctly identify lure stimuli as "similar." Conversely, we expected that those who score high on depression scales, an indicator of chronic stress, would exhibit selective deficits at appropriately categorizing lures. As expected, those who scored high on the Beck Depression Inventory (BDI) were significantly worse than those with relatively lower BDI scores at correctly identifying lures as "similar," while performance on novel and repeated stimuli was identical. Taken together, our results support the hypothesis that adult-born neurons in the DG contribute to the orthogonalization of incoming information.


The dopamine-synthesizing cells in the swimming larva of the tunicate Ciona intestinalis are located only in the hypothalamus-related domain of the sensory vesicle.
Dopamine is a major neuromodulator synthesized by numerous cell populations in the vertebrate forebrain and midbrain. Owing to the simple organization of its larval nervous system, ascidian tunicates provide a useful model to investigate the anatomy, neurogenesis and differentiation of the dopaminergic neural network underlying the stereotypical swimming behaviour of its chordate-type larva. This study provides a high-resolution cellular analysis of tyrosine hydroxylase (TH)-positive and dopamine-positive cells in Ciona intestinalis embryos and larvae. Dopamine cells are present only in the sensory vesicle of the Ciona larval brain, which may be an ancestral chordate feature. The dopamine-positive cells of the ascidian sensory vesicle are located in the expression domain of homologues of vertebrate hypothalamic markers. We show here that the larval coronet cells also arise from this domain. As a similar association between coronet cells and the hypothalamus was reported in bony and cartilaginous fishes, we propose that part of the ascidian ventral sensory vesicle is the remnant of a proto-hypothalamus that may have been present in the chordate ancestor. As dopaminergic cells are specified in the hypothalamus in all vertebrates, we suggest that the mechanisms of dopamine cell specification are conserved in the hypothalamus of Ciona and vertebrates. To test this hypothesis, we have identified new candidate regulators of dopaminergic specification in Ciona based on their expression patterns, which can now be compared with those in vertebrates.


Plasticity of skeletal muscle: regenerating fibers adapt more rapidly than surviving fibers.
The properties of mammalian skeletal muscle demonstrate a high degree of structural and functional plasticity as evidenced by their adaptability to an atypical site after cross-transplantation and to atypical innervation after cross-innervation. We tested the hypothesis that, regardless of fiber type, skeletal muscles composed of regenerating fibers adapt more readily than muscles composed of surviving fibers when placed in an atypical site with atypical innervation. Fast muscles of rats were autografted into the site of slow muscles or vice versa with the donor muscle innervated by the motor nerve to the recipient site. Surviving fibers in donor muscles were obtained by grafting with vasculature intact (vascularized muscle graft), and regenerating fibers were obtained by grafting with vasculature severed (free muscle graft). Our hypothesis was supported because 60 days after grafting, transposed muscles with surviving fibers demonstrated only a slight change from the contractile properties and fiber typing of donor muscles, whereas transplanted muscles with regenerating fibers demonstrated almost complete change to those of the muscle formerly in the atypical site.


The importance of timescales for the emergence of environmental self-regulation.
Models which explore the possibilities of emergent self-regulation in the Earth system often assume the timescales associated with changes in various sub-systems to be predetermined. Given their importance in guiding the fixed point dynamics of such models, relatively little formalism has been established. We analyse a classic model of environmental self-regulation, Daisyworld, and interpret the original equations for model temperature, changes in insolation, and self-organisation of the biota as an important separation of timescales. This allows a simple analytical solution where the model is reduced to two states while retaining important characteristics of the original model. We explore the consequences of relaxing some key assumptions. We show that increasing the rate of change of insolation relative to adaptation of the biota shows a sharp transition between regulating, and lifeless states. Additionally, in slowing the rate of model temperature change relative to the adapting biota we derive expressions for the damping rate of fluctuations, along with a threshold beyond which damped oscillations occur. We relax the assumption that seeding occurs globally by extending this analysis to solve a two-dimensional cellular automata Daisyworld. We conclude by reviewing a number of previous Daisyworld models and make explicit their respective timescales, and how their behaviour can be understood in light of our analysis.


Hyperthermia catheter implantation and therapy in the brain. Technical note.
For the treatment of malignant gliomas, a technique for implanting hyperthermia catheters was developed that utilized a stereotactic template and head-stabilization frame mounted on a computerized tomography (CT) scanner. Computerized tomography scans were used to measure tumor dimensions and to determine the number, implantation depths, and active heating lengths of the catheters, which were implanted through twist-drill holes while the patient was in the CT room. Heat was subsequently delivered via implanted catheters using a computer-controlled hyperthermia system, which partially compensates for heterogeneous and time-varying tumor blood flow.


[Toxicology of carteolol].
Studies of the acute toxicity of 5-(3-tert-butylamino-2-hydroxy-propoxy)-3, 4-dihydro-2(1H)-quinolinone hydrochloride (carteolol hydrochloride, Endak, Endak mite) in various species by different modes of administration revealed comparatively slight necropsy and histological changes despite characteristic clinical features of poisoning, There were only minor discrepancies in LD50 between the different species, and no sex differences were observed. The LD50 was 2000-4000 times the therapeutic dose. Death is thought to be due to excessive enhancement of the pharmacological action of the sympathomimetic component with extreme abnormalities of blood distribution and interference with cardiac and lung function. In subchronic and chronic toxicity tests in rats no effects due to the drug were demonstrable for doses of up to 150 mg/kg. In dogs the highest dose free from side-effects was between 3 and 30 mg/kg. Above 10 times the therapeutic dose there was some increase in brown adipose tissue, but this is not thought to be of any pathological significance. No teratogenic effects were detected in experiments on mice, rats and rabbits, and no embryotoxic or fetotoxic activity was seen except for doses high enough to produce toxic effects in the mother animals. No carcinogenic properties were identified. Tests for mutagenic effects (S. typhimurium, E. coli, cytogenetic studies in rats, dominant lethal test) yielded negative results.


Anomalous Diffusion in Inverted Variable-Lengthscale Fluorescence Correlation Spectroscopy.
Using fluorescence correlation spectroscopy (FCS) to distinguish between different types of diffusion processes is often a perilous undertaking because the analysis of the resulting autocorrelation data is model dependant. Two recently introduced strategies, however, can help move toward a model-independent interpretation of FCS experiments: 1) the obtention of correlation data at different length scales and 2) their inversion to retrieve the mean-squared displacement associated with the process under study. We use computer simulations to examine the signature of several biologically relevant diffusion processes (simple diffusion, continuous-time random walk, caged diffusion, obstructed diffusion, two-state diffusion, and diffusing diffusivity) in variable-length-scale FCS. We show that, when used in concert, length-scale variation and data inversion permit us to identify non-Gaussian processes and, regardless of Gaussianity, to retrieve their mean-squared displacement over several orders of magnitude in time. This makes unbiased discrimination between different classes of diffusion models possible.


Intraocular pressure reduction after argon laser trabeculoplasty in open-angle glaucoma. A two-year follow-up.
One hundred and twenty-eight eyes of 113 pre-surgical patients with open-angle glaucoma, treated with 360-degree orgon laser trabeculoplasty, were followed up for 24 months. Success was defined as an intraocular pressure below 23 mmHg as well as an intraocular pressure reduction of at least 20% with the same medical therapy as given before laser treatment, or less. The total success rate was 64%. In 79 eyes with capsular glaucoma the success rate was 76%, whereas in 49 eyes with simple glaucoma it was 45%. The success rate increased in groups with higher degrees of trabecular pigmentation, probably an effect of a higher proportion of eyes with capsular glaucoma in these groups. Baseline intraocular pressure had no influence on the success rate. No correlation was found between the amount of laser energy delivered and the degree of pressure reduction after 6 months. Neither was there any significant difference in laser energy levels between eyes showing successful results and those regarded as failures at the end of the 2-year follow-up period.


Continuous ambulatory peritoneal dialysis patients are unable to increase dietary intake to recommended levels.
This study's objective was to determine whether offering dietary advice was effective in supporting patients in adjusting energy intake. We performed a prospective, randomized, controlled trial of dietary intervention involving 59 patients on continuous ambulatory peritoneal dialysis over a 4-month follow-up period. The study involved outpatients on home-based renal replacement therapy. All participants were adult patients on continuous ambulatory peritoneal dialysis. All eligible patients were invited to take part. Subjects were randomized into two groups: control and intervention. Those with diabetes mellitus, malabsorption, malignancy, or eating disorders were excluded. Baseline measurements to assess current dietary intake and nutritional status were performed in all subjects. Measurements included a 5-day food diary, subjective global assessment (SGA), anthropometry, and serum biochemistry. After analysis of the food diaries, the participants in the control group were given follow-up dietary advice that would enable them to match intake with current dietary recommendations for this group of 1.2 g of protein per kilogram of ideal body weight, 25 cal/kg ideal body weight. Participants in the intervention group were given follow-up dietary advice that would encourage them to match energy intake with an estimate of total energy expenditure based on their calculated basal metabolic rate and physical activity level as designated using information from SGA, with a significantly lower protein intake of 0.8 to 1.0 g/kg ideal body weight and an emphasis on calories from carbohydrate and fat. Both groups completed further 5-day food diaries at 2 and 4 months to assess their ability to make the recommended changes. SGA, anthropometry, and biochemistry were all remeasured at the end of the study period. Differences in energy and protein intakes between and within the two groups from baseline to 4 months were assessed. Protein and energy intakes did not change during 4 months in either group, and there was no significant difference in intake between the two groups. In the control group (n = 27), 18 subjects (69%) matched their reported dietary energy intake to the recommended intake. In the intervention group (n = 28), 17 subjects (63%) matched their reported dietary intake to their estimated total energy expenditure. In the control group (n = 27), 8 subjects (28%) achieved the protein intake recommended to them of 1.2 g/kg. In the intervention group (n = 28), 23 subjects (85%) achieved the protein intake recommended to them of greater than 0.8 g/kg. Patients not meeting their dietary prescription did not adjust their intake to match the recommended advice they had been given from a dietitian. Food diary analysis showed that subjects ate less than the recommended intakes for energy and protein. This inability to change suggests that subjects may be eating to the limit of their appetite. SGA sections concerning appetite, body weight, body mass index, and estimates of energy expenditure support the view that energy intake matches requirements.


Can domestic helpers moderate distress of offspring caregivers of cognitively impaired older adults?
This study examined the moderating effect of domestic helpers on distress of offspring caring for parents with cognitive impairments and with or without behavioural problems. This secondary analysis of data involved 5086 Hong Kong Chinese adults aged 60 or older applying for public long-term care services from 2010 to 2012. All variables were measured using the mandatory Hong Kong version of the Minimum Data Set-Home Care 2.0. Regarding taking care of parents with cognitive impairments, 10.7% of offspring primary caregivers were aided by domestic helpers, 55.54% reported distress, and 75.70% lived with their parents. Assistance from domestic helpers reduced offspring caregiver distress if the offspring provided psychological support to parents (ratio of OR = 0.655, p < .05) and were not living with parents (ratio of OR = 1.183, p < .01). These findings might suggest: a) the positive effects of audience on psychological responses to stress; b) caregiving is usually less stressful for informal caregivers not residing with care recipients. Conversely, having a domestic helper could add to caregiving distress if offspring caregivers live with their parents, most likely because offspring may witness difficulties that domestic helpers face in providing dementia care.


Short and ultrashort Barrett's esophagus--what does it mean?
Most studies on Barrett's esophagus have included patients with severe gastroesophageal reflux disease (GERD) for whom endoscopic examinations revealed long segments of columnar epithelium extending well above the esophagogastric junction. Biopsy specimens of this extensive columnar lining have usually revealed an incomplete form of intestinal metaplasia (specialized intestinal metaplasia) that has been shown to predispose to the development of adenocarcinoma. Recent studies suggest that short segments of specialized intestinal metaplasia can be found in approximately 20% of white adults undergoing elective endoscopic examinations in a general endoscopy unit, regardless of the indication for the procedure. This condition has been called "short-segment Barrett's esophagus," although "columnar lined esophagus with intestinal metaplasia" may be a more appropriate terminology for reasons discussed in detail later. Specialized intestinal metaplasia can be found in one third to one half of patients whose squamocolumnar junction appears jagged, irregular, or especially prominent. However, up to 15% of patients with a healthy-appearing squamocolumnar junction, exhibiting none of the aforementioned features, harbor small foci of intestinal metaplasia at the esophagogastric junction. Unlike patients with traditional (long-segment) Barrett's esophagus, many patients with short segments of intestinal metaplasia in the distal esophagus have no signs of GERD. Furthermore, these short segments do not appear to be as predisposed to malignancy as are long segments of intestinal metaplasia in the esophagus. Until the cancer risk is better defined, it is not recommended that endoscopists routinely obtain biopsy specimens from a healthy-appearing distal esophagus to look for specialized intestinal metaplasia.


The Roles of β-Oxidation and Cofactor Homeostasis in Peroxisome Distribution and Function in Arabidopsis thaliana.
Key steps of essential metabolic pathways are housed in plant peroxisomes. We conducted a microscopy-based screen for anomalous distribution of peroxisomally targeted fluorescence in Arabidopsis thaliana This screen uncovered 34 novel alleles in 15 genes affecting oil body mobilization, fatty acid β-oxidation, the glyoxylate cycle, peroxisome fission, and pexophagy. Partial loss-of-function of lipid-mobilization enzymes conferred peroxisomes clustered around retained oil bodies without other notable defects, suggesting that this microscopy-based approach was sensitive to minor perturbations, and that fatty acid β-oxidation rates in wild type are higher than required for normal growth. We recovered three mutants defective in PECTIN METHYLESTERASE31, revealing an unanticipated role in lipid mobilization for this cytosolic enzyme. Whereas mutations reducing fatty acid import had peroxisomes of wild-type size, mutations impairing fatty acid β-oxidation displayed enlarged peroxisomes, possibly caused by excess fatty acid β-oxidation intermediates in the peroxisome. Several fatty acid β-oxidation mutants also displayed defects in peroxisomal matrix protein import. Impairing fatty acid import reduced the large size of peroxisomes in a mutant defective in the PEROXISOMAL NAD+ TRANSPORTER (PXN), supporting the hypothesis that fatty acid accumulation causes pxn peroxisome enlargement. The diverse mutants isolated in this screen will aid future investigations of the roles of β-oxidation and peroxisomal cofactor homeostasis in plant development.


Adenocarcinoma in an ileoanal pouch formed for ulcerative colitis in a patient with primary sclerosing cholangitis and a liver transplant: report of a case and review of the literature.
This is a report of the first case of adenocarcinoma arising in an ileal pouch after proctocolectomy for ulcerative colitis in a patient who had also undergone orthotopic liver transplantation for primary sclerosing cholangitis. Previously reported cases of adenocarcinoma developing after formation of an ileoanal pouch are reviewed as is the evidence for neoplastic transformation of the ileal mucosa. The risk factors for the development of colorectal cancer in patients with ulcerative colitis and the possibility that these may be risk factors for the development of pouch malignancy are discussed. We conclude that this patient exemplifies a small group of patients who may be at increased risk of developing pouch malignancy and need endoscopic follow-up. There is also the need for longer-term follow-up data to determine the risk of this rare and potentially devastating complication of restorative proctocolectomy.


Epidemiology of Lassa Fever and Factors Associated with Deaths, Bauchi State, Nigeria, 2015-2018.
We report the epidemiology of Lassa fever in Bauchi State, a disease-endemic region, in Nigeria. Since 2015, major increases in Lassa fever attack rate and in the case-fatality rate have occurred in this state. A delay in seeking care by a case-patient for >7 days after symptom onset was the major predictor of death.


The distribution of henipaviruses in Southeast Asia and Australasia: is Wallace's line a barrier to Nipah virus?
Nipah virus (NiV) (Genus Henipavirus) is a recently emerged zoonotic virus that causes severe disease in humans and has been found in bats of the genus Pteropus. Whilst NiV has not been detected in Australia, evidence for NiV-infection has been found in pteropid bats in some of Australia's closest neighbours. The aim of this study was to determine the occurrence of henipaviruses in fruit bat (Family Pteropodidae) populations to the north of Australia. In particular we tested the hypothesis that Nipah virus is restricted to west of Wallace's Line. Fruit bats from Australia, Papua New Guinea, East Timor and Indonesia were tested for the presence of antibodies to Hendra virus (HeV) and Nipah virus, and tested for the presence of HeV, NiV or henipavirus RNA by PCR. Evidence was found for the presence of Nipah virus in both Pteropus vampyrus and Rousettus amplexicaudatus populations from East Timor. Serology and PCR also suggested the presence of a henipavirus that was neither HeV nor NiV in Pteropus alecto and Acerodon celebensis. The results demonstrate the presence of NiV in the fruit bat populations on the eastern side of Wallace's Line and within 500 km of Australia. They indicate the presence of non-NiV, non-HeV henipaviruses in fruit bat populations of Sulawesi and Sumba and possibly in Papua New Guinea. It appears that NiV is present where P. vampyrus occurs, such as in the fruit bat populations of Timor, but where this bat species is absent other henipaviruses may be present, as on Sulawesi and Sumba. Evidence was obtained for the presence henipaviruses in the non-Pteropid species R. amplexicaudatus and in A. celebensis. The findings of this work fill some gaps in knowledge in geographical and species distribution of henipaviruses in Australasia which will contribute to planning of risk management and surveillance activities.


Changes in U.S. medical students' specialty interests over the course of medical school.
Studies have examined factors affecting medical students' specialty choice, but little research exists on stability of these specialty interests. To describe patterns of change in specialty interests during medical school and examine associations between specialty change patterns and gender, desire for a high-prestige career, and interest in prevention. Medical students (Class of 2003) at 15 representative US schools were invited to complete surveys during freshman orientation, entry to wards, and senior year. This analysis used data from 942 students who completed all 3 surveys. In addition to a number of other items, students were asked to choose the 1 specialty they were most interested in pursuing. The most common specialty choices among freshman students were pediatrics (20%) and surgery (18%); least common choices were psychiatry and preventive medicine (1% each). General internal medicine was the initial specialty choice for 8%. Most students changed their specialty choices, regardless of initial interest. Only 30% of those initially interested in primary care (PC) remained interested at all 3 time points, compared to 68% of those initially interested in non-PC. Female versus male students were more commonly interested in PC at all 3 time points. Senior students interested in non-PC specialties were more likely to desire a high-prestige career (48%) than those interested in PC (31%). Medical students may benefit from more intensive introduction to some specialties earlier in pre-medical and medical education. In addition, increasing the prestige of PC fields may shape the physician workforce.


Immunocytochemical localization of polyamines in the tiger salamander retina.
The polyamines spermine and spermidine are present in neural tissue, but their functions there are not well understood. Recent work suggests that the NMDA subtype of glutamate receptors, other glutamate receptor subtypes, and certain K(+)-channels, are neural targets for polyamines. To better understand the neuron-specific roles of polyamines, we have developed antibodies that interact with spermine and spermidine in aldehyde-fixed tissue and used these antibodies in immunocytochemical studies to determine the cellular localization of these polyamines in the tiger salamander retina. The affinity-purified, polyclonal antibodies were highly specific for spermine and spermidine, exhibiting < 1% cross reactivity with putrescine, and virtually no cross-reactivity with GABA, arginine, lysine, or glutaraldehyde. Polyamine labeling was most abundant in cells in the inner half of the inner nuclear layer and in the ganglion cell layer. Some cells in the outer half of the inner nuclear layer are labeled, and there was some labeling in both synaptic layers. Double-labeling experiments indicated (1) all GABAergic amacrine cells were polyamine-positive; and (2) all ganglion cells (identified by back-filling after microinjections of rhodamine in the optic nerve) were polyamine-positive. These results are consistent with a role for polyamines as modulators of NMDA receptor function and channel function in the inner retina.


[Bullous eruption in systemic lupus erythematosus].
A 39 years old black woman with systemic lupus erythematosus developed tense bullae on erythematous bases on the flexor surfaces of the forearms and oral cavity. Some blisters healed with atrophy and pruritus was a striking feature. The diagnosis of systemic lupus erythematosus was based upon the following criteria: the typical blush in the butterfly area, alopecia, a painful macular papular eruption on the palms and fingers, fever, arthralgia, anemia, leukopenia, elevation of erythrocyte sedimentation rate and positive ANA. Histologic examination showed a subepidermal bulla formation and perivascular inflammatory infiltrate containing lymphocytes and eosinophils. By indirect immunofluorescence no autoantibodies were detected. Direct immunofluorescence showed deposition of linear IgG. High doses of prednisone brought about clinical remission but there was no response to sulfone. The patient is on maintenance dose. The authors discuss the differences between the three diseases and conclude that the bullous eruption cannot be classified.


It Blinks, It Thinks? Luminous Brains and a Visual Culture of Electric Display, circa 1930.
This article traces attempts in the 1930s to create a spatio-temporal model of the active, living brain. Images and models of electric, illuminated displays – derived from electro-technology and engineering – allowed for a changing imaginary of a brain that was immediately accessible. The example of the Luminous Brain Model, a three-dimensional science education model, demonstrates how the visual language of illumination could serve as a flexible rhetorical tool that offered sensations of liveliness to modern viewers and promised to show a transparent view of a dynamic brain. Alternatively, various scientists in the 1930s used the analogy of the brain as an illuminated electric news ticker to conceptualize temporal patterns of changing brain activity, thus drawing the brain into a new metropolitan sphere of material surfaces with real-time mediation. These two historical imaginaries of blinking brains reveal new trajectories of the 'metaphorical circuits' through which technology and cerebral biology are mutually articulated.


Impact of whole-genome and tandem duplications in the expansion and functional diversification of the F-box family in legumes (Fabaceae).
F-box proteins constitute a large gene family that regulates processes from hormone signaling to stress response. F-box proteins are the substrate recognition modules of SCF E3 ubiquitin ligases. Here we report very distinct trends in family size, duplication, synteny and transcription of F-box genes in two nitrogen-fixing legumes, Glycine max (soybean) and Medicago truncatula (alfafa). While the soybean FBX genes emerged mainly through segmental duplications (including whole-genome duplications), M. truncatula genome is dominated by locally-duplicated (tandem) F-box genes. Many of these young FBX genes evolved complex transcriptional patterns, including preferential transcription in different tissues, suggesting that they have probably been recruited to important biochemical pathways (e.g. nodulation and seed development).


Functional Skeletal Muscle Regeneration with Thermally Drawn Porous Fibers and Reprogrammed Muscle Progenitors for Volumetric Muscle Injury.
Skeletal muscle has an inherent capacity for spontaneous regeneration. However, recovery after severe injuries such as volumetric muscle loss (VML) is limited. There is therefore a need to develop interventions to induce functional skeletal muscle restoration. One suggested approach includes tissue-engineered muscle constructs. Tissue-engineering treatments have so far been impeded by the lack of reliable cell sources and the challenges in engineering of suitable tissue scaffolds. To address these challenges, muscle extracellular matrix (MEM) and induced skeletal myogenic progenitor cells (iMPCs) are integrated within thermally drawn fiber based microchannel scaffolds. The microchannel fibers decorated with MEM enhance differentiation and maturation of iMPCs. Furthermore, engraftment of these bioengineered hybrid muscle constructs induce de novo muscle regeneration accompanied with microvessel and neuromuscular junction formation in a VML mouse model, ultimately leading to functional recovery of muscle activity.


Oxygen Coordination on Fe-N-C to Boost Oxygen Reduction Catalysis.
The coordination environments of iron (Fe) in Fe-N-C catalysts determine their intrinsic activities toward oxygen reduction reactions (ORR). The precise atomic-level regulation of the local coordination environments is thus of critical importance yet quite challenging to achieve. Here, atomically dispersed Fe-N-C catalyst with O-Fe-N2C2 moieties is thoroughly studied for ORR catalysis. Advanced synchrotron X-ray characterizations, along with theoretical modeling, explicitly unraveled the penta-coordinated nature of the Fe center in the catalytic domain and the energetically optimized ORR pathways on the well-tailored O-Fe-N2C2 moieties. The combined structure identification from both experiments and theory provides an opportunity to understand the role of the coordination environments in directing the catalytic activity of single-atom or single-site catalysts; not only the center metal atom but also the whole coordinating atoms participate in the catalytic cycle.


TCR signal strength controls thymic differentiation of iNKT cell subsets.
During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells.


The global burden of chromoblastomycosis.
Chromoblastomycosis (CBM), represents one of the primary implantation mycoses caused by melanized fungi widely found in nature. It is characterized as a Neglected Tropical Disease (NTD) and mainly affects populations living in poverty with significant morbidity, including stigma and discrimination. In order to estimate the global burden of CBM, we retrospectively reviewed the published literature from 1914 to 2020. Over the 106-year period, a total of 7,740 patients with CBM were identified on all continents except Antarctica. Most of the cases were reported from South America (2,619 cases), followed by Africa (1,875 cases), Central America and Mexico (1,628 cases), Asia (1,390 cases), Oceania (168 cases), Europe (35 cases), and USA and Canada (25 cases). We described 4,022 (81.7%) male and 896 (18.3%) female patients, with the median age of 52.5 years. The average time between the onset of the first lesion and CBM diagnosis was 9.2 years (range between 1 month to 50 years). The main sites involved were the lower limbs (56.7%), followed by the upper limbs (19.9%), head and neck (2.9%), and trunk (2.4%). Itching and pain were reported by 21.5% and 11%, respectively. Malignant transformation was described in 22 cases. A total of 3,817 fungal isolates were cultured, being 3,089 (80.9%) Fonsecaea spp., 552 (14.5%) Cladophialophora spp., and 56 Phialophora spp. (1.5%). This review represents our current knowledge on the burden of CBM world-wide. The global incidence remains unclear and local epidemiological studies are required to improve these data, especially in Africa, Asia, and Latin America. The recognition of CBM as NTD emphasizes the need for public health efforts to promote support for all local governments interested in developing specific policies and actions for preventing, diagnosing and assisting patients.


Clinical effects of intranasal corticosteroids on nasal symptoms in subjects with chronic rhinitis during COVID-19.
Background: The clinical effects of intranasal corticosteroids (INC) on nasal symptoms and the clinical course of coronavirus disease 2019 (COVID-19) in subjects with chronic rhinitis (CR) seem unclear. Objective: To evaluate the clinical effects of INCs on nasal symptoms in subjects with CR and with COVID-19. Methods: In subjects with CR and diagnosed with COVID-19 at four tertiary centers, quality of life and nasal symptoms were assessed by using the 22-item Sino-Nasal Outcome Test (SNOT-22) and the visual analog scale (VAS), respectively. In subjects with allergic rhinitis, nasal symptoms were also assessed on the total symptom score-6 (TSS-6) scale. The subjects were then allocated into two groups according to whether or not they used INCs while infected with the severe acute respiratory syndrome coronavirus 2 (group 1 and group 2, respectively). The subjects in group 2 were divided into two subgroups according to the use of antihistamines and/or leukotriene receptor antagonist or not (group 2a and group 2b, respectively). All the scores were compared before and during COVID-19 among the three groups. Results: A total of 71 subjects (21 in group 1, 24 in group 2a, and 26 in group 2b) were enrolled. The total scores of the SNOT-22 increased remarkably in all the groups during the infection when compared with the pre-COVID-19 scores (p < 0.001 in each group). However, the difference between the pre-COVID-19 and COVID-19 values revealed a lower decrease in the senses of smell and/or taste in group 1 than in group 2a and group 2b (p = 0.015, adjusted p = 0.045; and p = 0.001, adjusted p = 0.002, respectively). There were no significant differences in other COVID-19 findings, VAS, and TSS-6 scores among the groups (all p > 0.05). Conclusion: INCs in subjects with CR seemed protective against the decrease in smell and/or taste observed during COVID-19 and do not aggravate the clinical course of COVID-19.


Rp58 is essential for the growth and patterning of the cerebellum and for glutamatergic and GABAergic neuron development.
Cerebellum development depends on the correct differentiation of progenitors into neurons, a process controlled by a transcriptional program that remains poorly understood. Here we show that neural-specific deletion of the BTB/POZ zinc-finger transcription factor-encoding gene Rp58 (Znf238, Zfp238) causes severe cerebellar hypoplasia and developmental failure of Purkinje neurons, Bergmann glia and granule neurons. Deletion of Rp58 in mouse embryonic Atoh1(+) progenitors leads to strong defects in growth and foliation owing to its crucial role in the differentiation of granule neurons. Analysis of the Rp58 mutant at E14.5 demonstrates that Rp58 is required for the development of both glutamatergic and GABAergic neurons. Rp58 mutants show decreased proliferation of glutamatergic progenitors at E14.5. In addition, Rp58 ablation results in a reduced number of GABAergic Pax2(+) neurons at E16.5 together with defects in the transcriptional program of ventricular zone progenitors. Our results indicate that Rp58 is essential for the growth and organization of the cerebellum and regulates the development of both GABAergic and glutamatergic neurons.


Genetic instability of an oligomycin resistance mutation in yeast is associated with an amplification of a mitochondrial DNA segment.
In the yeast Kluyveromyces lactis, mutations affecting mitochondrial functions are often highly unstable. In order to understand the basis of this genetic instability, we examined the case of an oligomycin resistant mutant. When the mutant was grown in the absence of the drug, the resistance was rapidly lost. This character showed a typical cytoplasmic inheritance. The unstable resistance was found to be associated with the presence of a repetitive DNA in which the repeating unit was a specific segment of the mitochondrial DNA. The amplified molecules were co-replicating with the wild type genome in the mutant cells. The spontaneous loss of the drug resistance was accompanied by the disappearance of the amplified DNA. The repetitive sequence came from a 405 base-pair segment immediately downstream of a cluster of two transfer RNA genes (threonyl 2 and glutamyl). Modified processing of these tRNAs was detected in the mutant. A possible mechanism by which these events could lead to drug resistance is discussed.


National healthcare information system in Croatian primary care: the foundation for improvement of quality and efficiency in patient care.
In order to improve the quality of patient care, while at the same time keeping up with the pace of increased needs of the population for healthcare services that directly impacts on the cost of care delivery processes, the Republic of Croatia, under the leadership of the Ministry of Health and Social Welfare, has formed a strategy and campaign for national public healthcare system reform. The strategy is very comprehensive and addresses all niches of care delivery processes; it is founded on the enterprise information systems that will aim to support end-to-end business processes in the healthcare domain. Two major requirements are in focus: (1) to provide efficient healthcare-related data management in support of decision-making processes; (2) to support a continuous process of healthcare resource spending optimisation. The first project is the Integrated Healthcare Information System (IHCIS) on the primary care level; this encompasses the integration of all primary point-of-care facilities and subjects with the Croatian Institute for Health Insurance and Croatian National Institute of Public Health. In years to come, IHCIS will serve as the main integration platform for connecting all other stakeholders and levels of health care (that is, hospitals, pharmacies, laboratories) into a single enterprise healthcare network. This article gives an overview of Croatian public healthcare system strategy aims and goals, and focuses on properties and characteristics of the primary care project implementation that started in 2003; it achieved a major milestone in early 2007 - the official grand opening of the project with 350 GPs already fully connected to the integrated healthcare information infrastructure based on the IHCIS solution.


Cryo-EM structure of a tetrameric photosystem I from Chroococcidiopsis TS-821, a thermophilic, unicellular, non-heterocyst-forming cyanobacterium.
Photosystem I (PSI) is one of two photosystems involved in oxygenic photosynthesis. PSI of cyanobacteria exists in monomeric, trimeric, and tetrameric forms, in contrast to the strictly monomeric form of PSI in plants and algae. The tetrameric organization raises questions about its structural, physiological, and evolutionary significance. Here we report the ∼3.72 Å resolution cryo-electron microscopy structure of tetrameric PSI from the thermophilic, unicellular cyanobacterium Chroococcidiopsis sp. TS-821. The structure resolves 44 subunits and 448 cofactor molecules. We conclude that the tetramer is arranged via two different interfaces resulting from a dimer-of-dimers organization. The localization of chlorophyll molecules permits an excitation energy pathway within and between adjacent monomers. Bioinformatics analysis reveals conserved regions in the PsaL subunit that correlate with the oligomeric state. Tetrameric PSI may function as a key evolutionary step between the trimeric and monomeric forms of PSI organization in photosynthetic organisms.


Entanglement Oscillations near a Quantum Critical Point.
We study the dynamics of entanglement in the scaling limit of the Ising spin chain in the presence of both a longitudinal and a transverse field. We present analytical results for the quench of the longitudinal field in the critical transverse field which go beyond current lattice integrability techniques. We test these results against a numerical simulation on the corresponding lattice model finding extremely good agreement. We show that the presence of bound states in the spectrum of the field theory leads to oscillations in the entanglement entropy and suppresses its linear growth on the time scales accessible to numerical simulations. For small quenches, we exactly determine these oscillatory contributions and demonstrate that their presence follows from symmetry arguments. For the quench of the transverse field at zero longitudinal field, we prove that the Rényi entropies are exactly proportional to the logarithm of the exponential of a time-dependent function, whose leading large-time behavior is linear, hence, entanglement grows linearly. We conclude that, in the scaling limit, linear growth and oscillations in the entanglement entropies can not be simply seen as consequences of integrability and its breaking, respectively.


St. John's wort extract induces CYP3A and CYP2E1 in the Swiss Webster mouse.
This investigation was designed to determine the ability of St. John's wort (SJW), a readily available antidepressant, to induce various hepatic drug metabolizing enzymes. SJW (140 or 280 mg/kg/day) was administered to male Swiss Webster mice for 1, 2, or 3 weeks. Enzymatic activity was analyzed in hepatic microsomes for all of the following drug metabolizing enzymes: CYP3A, CYP1A, CYP2E1, and UDP-glucuronosyltransferase (UDPGT). The catalytic activity of CYP1A was unchanged from control following any dose or duration of SJW, while both CYP3A and CYP2E1 catalytic activities were increased 2-fold by both SJW concentrations but only following 3 weeks of administration. Results from Western immunoblotting studies supported the changes in catalytic activity, as protein levels for CYP2E1 and CYP3A were increased (2.5-fold and 6-fold, respectively) following 3 weeks of SJW administration. Additionally, the catalytic activity of the conjugation enzyme UDPGT was unchanged from control following all SJW treatments. These results indicate that in the mouse moderate doses of SJW cause an increase in the catalytic activity and polypeptide levels of CYP2E1 and CYP3A but only following 21 days of administration, while the catalytic activity of CYP1A and UDPGT activity remain unaffected.


Automatic lung segmentation in functional SPECT images using active shape models trained on reference lung shapes from CT.
Image segmentation is an essential step in quantifying the extent of reduced or absent lung function. The aim of this study is to develop and validate a new tool for automatic segmentation of lungs in ventilation and perfusion SPECT images and compare automatic and manual SPECT lung segmentations with reference computed tomography (CT) volumes. A total of 77 subjects (69 patients with obstructive lung disease, and 8 subjects without apparent perfusion of ventilation loss) performed low-dose CT followed by ventilation/perfusion (V/P) SPECT examination in a hybrid gamma camera system. In the training phase, lung shapes from the 57 anatomical low-dose CT images were used to construct two active shape models (right lung and left lung) which were then used for image segmentation. The algorithm was validated in 20 patients, comparing its results to reference delineation of corresponding CT images, and by comparing automatic segmentation to manual delineations in SPECT images. The Dice coefficient between automatic SPECT delineations and manual SPECT delineations were 0.83 ± 0.04% for the right and 0.82 ± 0.05% for the left lung. There was statistically significant difference between reference volumes from CT and automatic delineations for the right (R = 0.53, p = 0.02) and left lung (R = 0.69, p < 0.001) in SPECT. There were similar observations when comparing reference volumes from CT and manual delineations in SPECT images, left lung (bias was - 10 ± 491, R = 0.60, p = 0.005) right lung (bias 36 ± 524 ml, R = 0.62, p = 0.004). Automated segmentation on SPECT images are on par with manual segmentation on SPECT images. Relative large volumetric differences between manual delineations of functional SPECT images and anatomical CT images confirms that lung segmentation of functional SPECT images is a challenging task. The current algorithm is a first step towards automatic quantification of wide range of measurements.


Recent advances in understanding and managing infectious diseases in solid organ transplant recipients.
Background: Undergoing solid organ transplantation (SOT) exposes the recipient to various infectious risks, including possible transmission of pathogen by the transplanted organ, post-surgical infections, reactivation of latent pathogens, or novel infections. Recent advances: In the last few years, the emergence of Zika virus has raised concerns in the transplant community. Few cases have been described in SOT patients, and these were associated mainly with moderate disease and favorable outcome; the notable exception is a recent case of fatal meningo-encephalopathy in a heart transplant recipient. Because of the advances in treating hepatitis C, several teams recently started to use organs from hepatitis C-positive donors. The worldwide increasing incidence of multidrug-resistant pathogens, as well as the increasing incidence of Clostridioidesdifficile infection, is of particular concern in SOT patients. In the field of mycology, the main recent therapeutic advance is the availability of isavuconazole for the treatment of invasive aspergillosis and mucormycosis. This drug has the advantage of minimal interaction with calcineurin inhibitors. Regarding the viral reactivations occurring after transplant, cytomegalovirus (CMV) infection is still a significant issue in SOT patients. The management of resistant CMV remains particularly difficult. The approval of letermovir, albeit in bone marrow transplantation, and the therapeutic trial of maribavir bring a ray of hope. Another advancement in management of post-transplant infections is the development of in vitro tests evaluating pathogen-specific immune response, such as immunodiagnostics for CMV and, more recently, tests for monitoring immunity against BK virus. Conclusion: The increasing number of organ transplantations, the use of newer immunosuppressive drugs, and high-risk donors continue to define the landscape of transplant infectious diseases in the current era.


Geometric morphometrics as a tool for improving the comparative study of behavioural postures.
Describing postures has always been a central concern when studying behaviour. However, attempts to compare postures objectively at phylogenetical, populational, inter- or intra-individual levels generally either rely upon a few key elements or remain highly subjective. Here, we propose a novel approach, based on well-established geometric morphometrics, to describe and to analyse postures globally (i.e. considering the animal's body posture in its entirety rather than focusing only on a few salient elements, such as head or tail position). Geometric morphometrics is concerned with describing and comparing variation and changes in the form (size and shape) of organisms using the coordinates of a series of homologous landmarks (i.e. positioned in relation to skeletal or muscular cues that are the same for different species for every variety of form and function and that have derived from a common ancestor, i.e. they have a common evolutionary ancestry, e.g. neck, wings, flipper/hand). We applied this approach to horses, using global postures (1) to characterise behaviours that correspond to different arousal levels, (2) to test potential impact of environmental changes on postures. Our application of geometric morphometrics to horse postures showed that this method can be used to characterise behavioural categories, to evaluate the impact of environmental factors (here human actions) and to compare individuals and groups. Beyond its application to horses, this promising approach could be applied to all questions involving the analysis of postures (evolution of displays, expression of emotions, stress and welfare, behavioural repertoires…) and could lead to a whole new line of research.


SOME EFFECTS OF RADIUM RADIATIONS ON WHITE MICE.
It has been estimated that 92 per cent of the total radiation emitted by radium in equilibrium with its subsequent products is given off in the form of alpha-rays. This, however, cannot be utilized when the source is enclosed in an ordinary container, because the alpha-rays are absorbed completely by even a small thickness of glass. About 3.2 per cent of the total radiation is emitted in the form of beta-rays, and 4.8 per cent as gamma radiation. The effects produced on the radiated mice of these experiments were due mainly to the beta-rays, which are easily absorbed by tissue. The gamma-rays, being only slightly absorbed by organic matter, probably contributed very little to the observed effects. It is interesting to correlate the different effects produced by the same dose of radiation. The mice which received a dose of 1.9 millicurie hours showed no local effects on the skin or hair. Neither females nor males were sterilized, and the time at which they opened their eyes or reached sexual maturity was not affected, as far as we could tell. The only difference noted between the radiated animals and the controls was in the body weight. This dose accelerated the growth of the young mice, that is, while initially of the same weight, soon after irradiation they became distinctly bigger than the controls, but finally the animals of each group had substantially the same average weight. That this variation in body weight should be accidental is unlikely, since it was observed also in the animals treated by a slightly larger dose (2.4 millicurie hours). The number of animals (seven) which showed this effect is too small to prove conclusively the accelerating effect of small doses of radiation on the body growth of mice. But considering that similar results have been. obtained by radiating plants and beetles, it is reasonable that the observed increase in weight might be attributed, at least in part, to the effects of radiation. Since this paper was first written Russ, Chambers, and Scott have shown that small doses of x-rays accelerate the body growth of rats. In view of this additional evidence there can be little doubt that the increase in weight observed in our experiments was due to the radiation. A dose of 2.4 millicurie hours applied over the backs of the animals produced no local skin effects, but it accelerated the growth of the mice as in the previous case. In addition it caused permanent sterilization of all the females. A similar result was obtained with 4.9 millicurie hours, except that the effect on the rate of growth was uncertain. A dose of 6.8 millicurie hours produced a definite but mild skin erythema and retarded the development of lanugo hair. But since in this instance the emanation was applied over the heads of the animals, the dose reaching the ovaries was not sufficient to cause sterilization, as already explained. No other definite effect was noted. In connection with the sterilization of the females it should be noted that a dose of radiation which produced no visible skin changes was sufficient to cause permanent sterility. On account of the greater distance of the ovaries from the source of radiation as compared with that of the skin directly below the tube, and the depth of tissue which the rays had to traverse to reach the ovaries, the amount of radiation acting on the latter was much smaller than the amount falling on the skin. The radiation emitted by the emanation tube is reduced to about 50 per cent of its initial value after traversing 1 mm. of tissue. Still, while the skin was not visibly affected, the mice were sterilized. This shows that the ovaries are influenced very easily by radiation of this type. We can estimate the amount of radiation reaching the ovaries which is sufficient to cause sterility to be less than 25 per cent of the amount necessary to produce visible skin changes in the mice. It should be noted also that whenever sterility of the female mice was induced, it was permanent. Furthermore, those mice which were not rendered sterile by radiation were, as far as the experiments enable us to say, as prolific as the controls. Remembering that a dose of 1.9 millicurie hours had no apparent effect on the ovaries, while a slightly larger dose, 2.4 millicurie hours, caused permanent sterility, it might be concluded that it is not possible to produce temporary sterility by radiation. We know, however, that temporary sterility can be produced, at least when the animals are radiated at a later stage in their development. The mice in our experiments were radiated for the first time soon after birth, and it is not improbable that under these conditions temporary sterility cannot be obtained. Large sublethal doses produced severe skin burns, retarded the body growth of the animals, but failed to sterilize the males. About one-third of the total skin area of the mice showed marked effects from the radiation. The animals were very sick for a time, and their growth was temporarily stunted. But nevertheless they recovered and finally became apparently normal except for the narrow hairless strip of skin which had been closest to the emanation tube. Only the females were rendered permanently sterile. The males did not show even temporary sterility when the doses of radiation were close to the lethal dose. While the testes of mammals are known to be very easily affected by radiation, still they are more resistant than the ovaries. In addition, in these experiments they were at a greater distance from the source of radiation than the ovaries, and they were better protected by the thicker layer of tissue in the path of the rays. The fact that no sublethal dose in these experiments sterilized the males shows that under the conditions of irradiation adopted the amount of radiation reaching the testes was not sufficient to affect them noticeably. If the source of radiation had been applied closer to the reproductive organs of the males, they would have been sterilized by millicurie hour doses much smaller than the lethal dose. Some of the radiated animals were killed with ether, and macroscopic and microscopic examinations of the reproductive organs were made. The ovaries of the sterile females were generally atrophied and colored yellow. The normal histological structure was altered. The characteristic findings were the destruction of the Graafian follicles, with absence of ovum cells. The testes and the epididymis of the radiated mice of the present experiment appeared macroscopically and histologically normal, with the presence of abundant spermatozoa. Owing to the method adopted for the irradiation of the mice, the testes were too far from the source of radiation, and too well protected by the intervening tissue to be definitely affected by the rays.


Relationship between human tumour angiogenic profile and combretastatin-induced vascular shutdown: an exploratory study.
Combretastatin-A4-phosphate (CA4P) acts most effectively against immature tumour vasculature. We investigated whether histological angiogenic profile can explain the differential sensitivity of human tumours to CA4P, by correlating the kinetic changes demonstrated by dynamic MRI (DCE-MRI) in response to CA4P, with tumour immunohistochemical angiogenic markers. Tissue was received from 24 patients (mean age 59, range 32-73, 18 women, 6 men). An angiogenic profile was performed using standard immunohistochemical techniques. Dynamic MRI data were obtained for the same patients before and 4 h after CA4P. Three patients showed a statistically significant fall in K(trans) following CA4P, and one a statistically significant fall in IAUGC(60). No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic parameters other than between ang-2 and K(trans) (P=0.044). In conclusion, we found no strong relationships between changes in DCE-MRI kinetic variables following CA4P and the immunohistochemical angiogenic profile.


Guanylyl cyclase activation reverses resistive breathing-induced lung injury and inflammation.
Inspiratory resistive breathing (RB), encountered in obstructive lung diseases, induces lung injury. The soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway is down-regulated in chronic and acute animal models of RB, such as asthma, chronic obstructive pulmonary disease, and in endotoxin-induced acute lung injury. Our objectives were to: (1) characterize the effects of increased concurrent inspiratory and expiratory resistance in mice via tracheal banding; and (2) investigate the contribution of the sGC/cGMP pathway in RB-induced lung injury. Anesthetized C57BL/6 mice underwent RB achieved by restricting tracheal surface area to 50% (tracheal banding). RB for 24 hours resulted in increased bronchoalveolar lavage fluid cellularity and protein content, marked leukocyte infiltration in the lungs, and perturbed respiratory mechanics (increased tissue resistance and elasticity, shifted static pressure-volume curve right and downwards, decreased static compliance), consistent with the presence of acute lung injury. RB down-regulated sGC expression in the lung. All manifestations of lung injury caused by RB were exacerbated by the administration of the sGC inhibitor, 1H-[1,2,4]oxodiazolo[4,3-]quinoxalin-l-one, or when RB was performed using sGCα1 knockout mice. Conversely, restoration of sGC signaling by prior administration of the sGC activator BAY 58-2667 (Bayer, Leverkusen, Germany) prevented RB-induced lung injury. Strikingly, direct pharmacological activation of sGC with BAY 58-2667 24 hours after RB reversed, within 6 hours, the established lung injury. These findings raise the possibility that pharmacological targeting of the sGC-cGMP axis could be used to ameliorate lung dysfunction in obstructive lung diseases.


Predictors of the discharge dosage of an atypical antipsychotic agent among hospitalized, treatment-naive, first-episode psychosis patients in naturalistic, public-sector settings.
Little is known about determinants of second-generation antipsychotic dosages during initial hospitalization of first-episode psychosis. This study examined potential predictors of dosage of an atypical antipsychotic agent, risperidone, at hospital discharge after initial evaluation and treatment of first-episode nonaffective psychosis in 3 naturalistic, public-sector treatment settings. The number of psychotropic agents prescribed and discharge antipsychotic dosage were abstracted from the medical record. Demographic and extensive clinical characteristics were assessed through a clinical research study conducted at the 3 sites. One-way analyses of variance, trend tests using specific linear combinations of estimates, and χ² tests assessed for associations between atypical antipsychotic dosage and 5 hypothesized predictors, as well as 12 exploratory variables. Among 155 hospitalized first-episode patients, 121 (78.1%) were discharged on risperidone, and subsequent analyses focused on that subset. The mean risperidone dosage among those 121 patients was 4.26 mg; 31 received 1 to 2 mg, 45 received 3 to 4 mg, 37 received 5 to 6 mg, and 8 received more than 6 mg. Analyses suggested that older age at hospitalization, the number of psychotropic agents prescribed, excited symptoms, and premorbid social functioning may be predictors of the discharge dosage. Although several factors emerged, in general, predictors of discharge dosages of second-generation agents, here exemplified by risperidone, in real-world practice settings remain to be clarified. Given the importance of antipsychotic initiation during first hospitalization, future research should test an even broader array of potential predictors.


On immunologists and microbiologists: ground zero in the battle for interdisciplinary knowledge.
The individual disciplines of microbiology and immunology are exploding with new information necessary for understanding host-pathogen relationships, infectious diseases, cancer, and autoimmunity. Because of overlapping scientific interests, immunologists and microbiologists often share common academic affiliations. The coexistence is uneasy. Significant problems arise because the groups have evolved different intellectual traditions. Pressures are intensified by sporadic changes in perceptions of their relative worth. As the mixing of microbiologists and immunologists can be likened to ground zero in the fight for interdisciplinary knowledge, it is useful, at this time of escalating data acquisition and growing appreciation for multidisciplinary research, to examine their histories, the challenges to amalgamation, and the advantages of their association for the advancement of knowledge and the delivery of protection against disease. The exploration supports a recommitment to integration of the disciplines and a proposal to facilitate this by inclusion of expertise bridging the areas.


Ectopic thoracic kidney in a child with congenital diaphragmatic hernia.
Thoracic ectopic kidney with partial or complete renal protrusion above the level of the diaphragma into the posterior mediastinum is the rarest form of all ectopic kidneys with an incidence of less than 1 per 10,000 cases. We present a newborn with right congenital diaphragmatic hernia associated with thoracic ectopic kidney. The diagnosis of ectopia was made prior to surgery. Gerota's fascia of kidney was used to close the diaphragmatic defect. Since this renal anomaly is usually asymptomatic, it does not require any specific treatment. However, a close examination of function and anatomy of the kidney prior to surgery of hernia is important and beneficial. We discuss the embryological context and the importance of renal scintigraphy in patients with ectopic kidney.


Mefloquine-Induced Inner Ear Damage and Preventive Effects of Electrical Stimulation: An Electrophysiological Study.
Mefloquine is an antimalarial medicine used to prevent and treat malaria. This medicine has some side effects, including ototoxicity. This study, which was designed in two phases, aimed to investigate the side effects of mefloquine and evaluate the preventive effects of electrical stimulation on these side effects. In the first phase, two doses of mefloquine (50 and 200 μ<sc>M</sc>) were injected into male rats, and after 7 days, they were evaluated by an auditory brainstem response (ABR) test. In the second phase, electrical stimulation was applied for 10 days, and then a toxic dose of mefloquine was injected. Similar to the first phase of the study, the animals were evaluated by an ABR test after 7 days. In the first phase, the results showed that a high dose of mefloquine increased the ABR threshold and wave I latency; however, these changes were not observed in the second phase. Application of electrical stimulation could prevent the ototoxic effects of mefloquine. According to the findings of the present study, electrical stimulation can be used as a preconditioner to prevent the ototoxic effects of mefloquine.


Are components of a comprehensive medical assessment predictive of work disability after an episode of occupational low back trouble?
One hundred fifty-nine subacute low back work-injured patients completed a full medical assessment at baseline. A full repeat examination was performed 3 months later, when return-to-work status was determined. To determine the prognostic value of a comprehensive medical assessment for the prediction of return-to-work status. A systematic review of the work disability prediction literature of low back trouble prognosis revealed that no high-quality studies included a full medical history and physical examination in the design. The results of studies included in the systematic review were equivocal with respect to predictive usefulness of medical variables. Participants completed medical history questionnaires and then were clinically examined by one of six experienced examiners (three physicians and three physiotherapists). Return-to-work status was measured 3 months later, and predictive validity was evaluated using logistic regression modeling. Medical variables (, medical history subscales, physical examination subscales, and lumbar range-of-motion tests) showed modest correct classification rates varying between 61.6% and 69.1% for participants. Comprehensive medical assessments play a crucial role in the early identification of serious pathology after low back trouble. We were unable to identify, however, any medical evaluation variables that would account for significant proportions of variance in return to work. The weight of evidence obtained in this study suggests that injured workers' subjective interpretations and appraisals may be more powerful predictors of the course of postinjury recovery than exclusively medical assessments.


There are two major types of skeletal keratan sulphates.
High-field 1H-n.m.r.-spectroscopic studies supported by chemical carbohydrate analyses show that skeletal keratan sulphates (KS-II) of bovine origin may be sub-classified into two groups. Keratan sulphate chains from articular and intervertebral-disc cartilage (KS-II-A) contain two structural features, namely alpha(1----3)-fucose and alpha(2----6)-linked N-acetyl-neuraminic acid residues, that are absent from keratan sulphates from tracheal or nasal-septum cartilage (KS-II-B).


SecYEG activates GTPases to drive the completion of cotranslational protein targeting.
Signal recognition particle (SRP) and its receptor (SR) comprise a highly conserved cellular machine that cotranslationally targets proteins to a protein-conducting channel, the bacterial SecYEG or eukaryotic Sec61p complex, at the target membrane. Whether SecYEG is a passive recipient of the translating ribosome or actively regulates this targeting machinery remains unclear. Here we show that SecYEG drives conformational changes in the cargo-loaded SRP-SR targeting complex that activate it for GTP hydrolysis and for handover of the translating ribosome. These results provide the first evidence that SecYEG actively drives the efficient delivery and unloading of translating ribosomes at the target membrane.


[Autoimmune granulomatous orchitis: its incidence in surgical specimens].
We report on three patients (28, 55 and 87 years old) with autoimmune granulomatous orchitis (AGO). Of a total of 182 surgical specimens examined, AGO accounted 1.64%. Clinically, it can be misdiagnosed as tuberculosis or tumor of the testis since most patients have a previous history of trauma, respectively. With respect to its pathogenesis, the lipid fraction of spermatozoa may be responsible for its characteristic granulomatous pattern.


Managing the outer limits of reconstruction with microsurgical free tissue transfer.
Six patients had major deficits reconstructed with microsurgical free tissue transfer. In contrast to some opinions that free tissue transfer is a "method of last resort," these patients were selected for microsurgical reconstruction as a method of first choice due to the qualities desired in the reconstruction, the reliability of the technique, and the desire to minimize the functional or aesthetic deficit at the donor site. Microsurgical techniques allowed a reconstruction in these cases that would have been difficult or impossible by conventional techniques, while they markedly improved the quality and reliability of the reconstruction and decreased the donor morbidity. Microsurgical free tissue transfer has been reported to have a success rate of 94% in centers where a significant volume of surgery is done. We believe the continued refinement of microsurgical techniques and their increased application will improve the results of reconstruction in a large category of severe traumatic and cancer defects.


A METHOD FOR THE DETERMINATION OF HUMAN CHORIONIC GONADOTROPHIN IN URINE EXTRACTS.
A method is described for the preparation in rabbits of a specific antiserum to human chorionic gonadotrophin. The ability of this antiserum to fix complement in the presence of urinary human chorionic gonadotrophin is demonstrated. The standardization of antiserum against the international standard preparation of human chorionic gonadotrophin, the determination of antiserum specificity using appropriate controls, and the value of antiserum in the diagnosis of pregnancy and conditions associated with high urinary levels of human chorionic gonadotrophin is emphasized.By the complement-fixation test it is possible to detect a minimum of 1.5 international units of human chorionic gonadotrophin contained in 0.1 ml. of a 1 in 2 dilution of urine extract. In the Hogben pregnancy test, using 2.5 ml. of urine extract per animal, a minimum concentration of 70 international units of human chorionic gonadotrophin is required to give a positive response. The ease and economy of the complement-fixation test are described and results are compared with those of the Hogben test.


[Impacts of electroacupuncture on ubiquitin-proteasome system in rats with Parkinson's disease].
To explore action mechanism of electroacupuncture (EA) on treatment and prevention of Parkinson's disease (PD). Fifty clean-grade SD rats were randomly divided into a normal group, a control group, a model group, a pretreatment group and a treatment group, ten rats in each one. The PD model was established by subcutaneous injection of rotenone in neck-back skin (2 mg/kg, dissolved in sun-flower oil, 2 mg/mL in density). The equal-volume sun-flower oil that didn't include rotenone was applied in the control group at the same area as the model group. EA was applied in the treatment group at "Fengfu" (GV 16) and "Taichong" (LR 3) with interrupted wave, 2 Hz in frequency, 1 mA in density, for 20 min. The treatment was given once day for conti-nuous 28 days. Rats in the pretreatment group received the same EA as the treatment group for 7 days, and then put into model establishment. After the model establishment, the rats received no treatment and were sacrificed after 28 days. No EA was given in the normal group, model group and control group. The ethology changes were observed and scored. The expression of Parkin, ubiquitin C terminal hydrolase-L1 (UCH-L1) and ubiquitin activating enzyme-1 (UBE1) in substantia nigra was tested by Western-blot method. The positive cell numbers of alpha-synuclein, ubiquitin (UB) and tyrosine hydroxylase (TH) in substantia nigra was tested by immunohistochemical method. There were abnormal ethology manifestation such as yellow and coarse hair, arched back, weaken behavior of resisting arrest and slow movement, which was more relieved in the treatment group and pretreatment group. Compared with normal group and control group, the expression of Parkin, UCH-L1, UBE1, UB, TH in the model group was obviously decreased while alpha-synuclein was obviously increased (all P<0.01). After EA or pretreatment, the expression of Parkin, UCH-L1, UBE1, UB, TH in the treatment group and pretreatment group was higher than that in the model group while expression of alpha-synuclein in the treatment group and pretreatment group was lower than that in the model group (all P<0.01). EA or pretreatment could not only have protective effect for rats with PD, but also increase function of ubiquitin-proteasome system, indicating action mechanism of EA on treatment and prevention of PD may be related with ubiquitin-proteasome system.


Changing needs, opportunities and constraints for the 21st century microbiology laboratory.
Clinical microbiologists and microbiology laboratories are experiencing changes due to evolving views on 'healthcare delivery' as an economic activity, due to changes in the medical environment and the demographics of the workforce, and technical evolution. Cost-effectiveness of laboratory procedures has been achieved through consolidation and integration of laboratories. Consolidation offers economy of scale and reduction in numbers of on-site staff, but also leads to separation of microbiologists from their clinical colleagues. Integration puts different laboratory disciplines under a single management, and leads to reorganisation of laboratories along common work-lines. Cost-savings combined with on-site availability of laboratories are achieved at the expense of a reduction in the influence of microbiologists in the daily running of the laboratory. Medically, there is growing emphasis on evidence-based diagnostics. Because of time-delays inherent in culturing, microbiology through rapid testing is mandatory. There is an increasing shortage in Europe and the USA of trained microbiology laboratory technicians and microbiologists. This reinforces the trend towards more automation and integration. Technological advances, particularly in molecular diagnostics, offer the possibility of rapid reporting and improvement of the impact of clinical microbiology on patient management. Molecular tests, however, fit perfectly the concept of an integrated laboratory and may further loosen the link between microbiologist and microbiology tests. The challenge for clinical microbiology will be to use new techniques to improve its cost-effectiveness and impact on infectious disease management. The future organisation of microbiology laboratories must support this but is itself of secondary importance. The training of future microbiologist must prepare them for this changing environment.


A real-world study comparing pre-post billed annualized bleed rates and total cost of care among non-inhibitor patients with hemophilia A switching from FVIII prophylaxis to emicizumab.
Factor VIII (FVIII) replacement and emicizumab have demonstrated efficacy for prevention of bleeds among patients with hemophilia A (PwHA) compared to on-demand (OD) use. Evidence investigating clinical outcomes and healthcare costs of non-inhibitor PwHA switching from prophylaxis with FVIII concentrates to emicizumab has not been well-established within large real-world datasets. This study aimed to investigate billed annualized bleed rates (ABRb) and total cost of care (TCC) among non-inhibitor PwHA switching from FVIII-prophylaxis to emicizumab-prophylaxis. This retrospective, observational study was conducted using IQVIA PharMetrics Plus, a US administrative claims database. The date of first claim for emicizumab was defined as the index date. OD patients and inhibitor patients were excluded. Bleeds were identified using a list of 535 diagnosis codes. Bayesian models were developed to estimate the probability ABRb worsens and TCC increases after switching to emicizumab. Wilcoxon rank-sum tests were used to test statistical significance of changes in ABRb and TCC after switch. Among the 121 identified patients, the difference in mean ABRb between FVIII-prophylaxis (0.68 [SD = 1.28]) and emicizumab (0.55 [SD = 1.48]) was insignificant (p = .142). The mean annual TCC significantly increased for patients switching from FVIII-prophylaxis ($518,151 [SD = $289,934]) to emicizumab ($652,679 [SD = $340,126]; p < .0001). The Bayesian models estimated a 21.0% probability of the ABRb worsening and a 99.9% probability of increasing TCC after switch. This study found that in male non-inhibitor PwHA, switching from FVIII prophylaxis to emicizumab incurs substantial cost increase with no significant benefit in ABRb. This evidence may help guide providers, payers, and patients in shared decision-making conversations around best treatment options.


Specific lipidome signatures in central nervous system from methionine-restricted mice.
Membrane lipid composition is an important correlate of the rate of aging of animals. Dietary methionine restriction (MetR) increases lifespan in rodents. The underlying mechanisms have not been elucidated but could include changes in tissue lipidomes. In this work, we demonstrate that 80% MetR in mice induces marked changes in the brain, spinal cord, and liver lipidomes. Further, at least 50% of the lipids changed are common in the brain and spinal cord but not in the liver, suggesting a nervous system-specific lipidomic profile of MetR. The differentially expressed lipids includes (a) specific phospholipid species, which could reflect adaptive membrane responses, (b) sphingolipids, which could lead to changes in ceramide signaling pathways, and (c) the physiologically redox-relevant ubiquinone 9, indicating adaptations in phase II antioxidant response metabolism. In addition, specific oxidation products derived from cholesterol, phosphatidylcholine, and phosphatidylethanolamine were significantly decreased in the brain, spinal cord, and liver from MetR mice. These results demonstrate the importance of adaptive responses of membrane lipids leading to increased stress resistance as a major mechanistic contributor to the lowered rate of aging in MetR mice.


The Influence of Social Distancing Behaviors and Psychosocial Factors on Physical Activity During the COVID-19 Pandemic: Cross-sectional Survey Study.
The COVID-19 pandemic has arguably facilitated a shift toward increased sedentariness and reduced physical activity. Moreover, there is mounting evidence that mental health has also declined during the pandemic. However, it remains unknown to what extent social distancing (SD) behaviors and mental health have affected the physical activity levels of the general population. The purpose of this study was to determine the influence of SD behaviors and prevailing mental health on the odds of being physically active during the early COVID-19 pandemic response. A total of 4819 adults (2474/4819, 51.3%, female) from the US population with a median age of 46 (IQR 35-59) completed an online survey during the early pandemic response (April-June 2020). The survey included questions on adherence to 11 SD behaviors, and validated questionnaires which assessed self-reported physical activity, depression, anxiety, and mental well-being. Respondents were categorized into 2 physical activity groups: inactive (0-599 metabolic equivalent of task [MET]-minutes/week) and active (≥600 MET-minutes/week). A logistic generalized additive model (GAM) was used to determine which SD factors and mental health outcomes were associated with physical activity level. The GAM analysis revealed that wearing a facemask in public (odds ratio [OR] 1.46, 95% CI 1.14-1.79; P=.003), limiting the use of public transport (OR 1.47, 95% CI 1.19-1.83; P=.001), and restricting travel outside the house (OR 1.56, 95% CI 1.19-2.05; P=.002) were SD behaviors associated with higher odds of being more physically active. Conversely, avoiding physical activity outside the house was associated with higher odds of being inactive (OR 0.52, 95% CI 0.46-0.63; P<.001). Leaving the house more frequently, and a higher mental well-being were associated with increasing odds of being physically active (P<.001). Engaging with a moderate number of SD behaviors (3-7 total) was positively associated with physical activity, whereas a very high SD vigilance (ie, engaging with ≥10 total behaviors) decreased the odds of being active during the early pandemic response. Based on the findings of our study, we suggest that future public health messaging of SD guidelines should include (1) a clear portrayal of the benefits of regular exercise on mental health; and (2) a specific focus on how to be physically active outdoors in a COVID-safe manner.


Structural basis of sterol recognition and nonvesicular transport by lipid transfer proteins anchored at membrane contact sites.
Membrane contact sites (MCSs) in eukaryotic cells are hotspots for lipid exchange, which is essential for many biological functions, including regulation of membrane properties and protein trafficking. Lipid transfer proteins anchored at membrane contact sites (LAMs) contain sterol-specific lipid transfer domains [StARkin domain (SD)] and multiple targeting modules to specific membrane organelles. Elucidating the structural mechanisms of targeting and ligand recognition by LAMs is important for understanding the interorganelle communication and exchange at MCSs. Here, we determined the crystal structures of the yeast Lam6 pleckstrin homology (PH)-like domain and the SDs of Lam2 and Lam4 in the apo form and in complex with ergosterol. The Lam6 PH-like domain displays a unique PH domain fold with a conserved N-terminal α-helix. The Lam6 PH-like domain lacks the basic surface for phosphoinositide binding, but contains hydrophobic patches on its surface, which are critical for targeting to endoplasmic reticulum (ER)-mitochondrial contacts. Structures of the LAM SDs display a helix-grip fold with a hydrophobic cavity and a flexible Ω1-loop as a lid. Ergosterol is bound to the pocket in a head-down orientation, with its hydrophobic acyl group located in the tunnel entrance. The Ω1-loop in an open conformation is essential for ergosterol binding by direct hydrophobic interaction. Structural comparison suggested that the sterol binding mode of the Lam2 SD2 is likely conserved among the sterol transfer proteins of the StARkin superfamily. Structural models of full-length Lam2 correlated with the sterol transport function at the membrane contact sites.


The catastrophic antiphospholipid syndrome in children.
To review the difficult syndrome of catastrophic antiphospholipid syndrome, emphasizing new developments in the diagnosis, pathogenesis and treatment. Few recent publications directly address pediatric catastrophic antiphospholipid syndrome (CAPS). Most articles are case reports or are data from adult and pediatric registries. The major factors contributing to most pediatric catastrophic antiphospholipid syndrome include infection and the presence of antiphospholipid antibodies, but complement activation also is important in creating diffuse thrombosis in the microcirculation. Treatment of the acute emergency requires anticoagulation, suppression of the hyperinflammatory state and elimination of the triggering infection. Inhibition of complement activation appears to improve outcome in limited studies, and suppression of antiphospholipid antibody formation may be important in long-term management. CAPS, an antibody-mediated diffuse thrombotic disease of microvasculature, is rare in childhood but has high mortality (33-50%). It requires prompt recognition and aggressive multimodality treatment, including anticoagulation, anti-inflammatory therapy and elimination of inciting infection and pathogenic autoantibodies.


Charcot-Marie-Tooth Disease and Other Hereditary Neuropathies.
This article provides an overview of Charcot-Marie-Tooth disease (CMT) and other inherited neuropathies. These disorders encompass a broad spectrum with variable motor, sensory, autonomic, and other organ system involvement. Considerable overlap exists, both phenotypically and genetically, among these separate categories, all eventually exhibiting axonal injury and neurologic impairment. Depending on the specific neural and non-neural localizations, patients experience varying morbidity and mortality. Neurologic evaluations, including neurophysiologic testing, can help diagnose and predict patient disabilities. Diagnosis is often complex, especially when genetic and acquired components overlap. Next-generation sequencing has greatly improved genetic diagnosis, with many third-party reimbursement parties now embracing phenotype-based panel evaluations. Through the advent of comprehensive gene panels, symptoms previously labeled as idiopathic or atypical now have a better chance to receive a specific diagnosis. A definitive molecular diagnosis affords patients improved care and counsel. The new classification scheme for inherited neuropathies emphasizes the causal gene names. A specific genetic diagnosis is important as considerable advances are being made in gene-specific therapeutics. Emerging therapeutic approaches include small molecule chaperones, antisense oligonucleotides, RNA interference, and viral gene delivery therapies. New therapies for hereditary transthyretin amyloidosis and Fabry disease are discussed. Comprehensive genetic testing through a next-generation sequencing approach is simplifying diagnostic algorithms and affords significantly improved decision-making processes in neuropathy care. Genetic diagnosis is essential for pathogenic understanding and for gene therapy development. Gene-targeted therapies have begun entering the clinic. Currently, for most inherited neuropathy categories, specific symptomatic management and family counseling remain the mainstays of therapy.


Crystal structures of two tropinone reductases: different reaction stereospecificities in the same protein fold.
A pair of tropinone reductases (TRs) share 64% of the same amino acid residues and belong to the short-chain dehydrogenase/reductase family. In the synthesis of tropane alkaloids in several medicinal plants, the TRs reduce a carbonyl group of an alkaloid intermediate, tropinone, to hydroxy groups with different diastereomeric configurations. To clarify the structural basis for their different reaction stereospecificities, we determined the crystal structures of the two enzymes at 2.4- and 2.3-A resolutions. The overall folding of the two enzymes was almost identical. The conservation was not confined within the core domains that are conserved within the protein family but extended outside the core domain where each family member has its characteristic structure. The binding sites for the cofactor and the positions of the active site residues were well conserved between the two TRs. The substrate binding site was composed mostly of hydrophobic amino acids in both TRs, but the presence of different charged residues conferred different electrostatic environments on the two enzymes. A modeling study indicated that these charged residues play a major role in controlling the binding orientation of tropinone within the substrate binding site, thereby determining the stereospecificity of the reaction product. The results obtained herein raise the possibility that in certain cases different stereospecificities can be acquired in enzymes by changing a few amino acid residues within substrate binding sites.


Somatosensory evoked potential monitoring detection of carotid compression during ACDF surgery in a patient with a vascularly isolated hemisphere.
The authors report herein a case of anterior cervical discectomy and fusion (ACDF) surgery in which findings on somatosensory evoked potential (SSEP) monitoring led to the correction of carotid artery compression in a patient with a vascularly isolated hemisphere (no significant collateral blood vessels to the carotid artery territory). The amplitude of the cortical SSEP component to left ulnar nerve stimulation progressively decreased in multiple runs, but there were no changes in the cervicomedullary SSEP component to the same stimulus. When the lateral (right-sided) retractor was removed, the cortical SSEP component returned to baseline. The retraction was then intermittently relaxed during the rest of the operation, and the patient suffered no neurological morbidity. Magnetic resonance angiography demonstrated a vascularly isolated right hemisphere. During anterior cervical spine surgery, carotid artery compression by the retractor can cause hemispheric ischemia and infarction in patients with inadequate collateral circulation. The primary purpose of SSEP monitoring during ACDF surgery is to detect compromise of the dorsal column somatosensory pathways within the cervical spinal cord, but intraoperative SSEP monitoring can also detect hemispheric ischemia. Concurrent recording of cervicomedullary SSEPs can help differentiate cortical SSEP changes due to hemispheric ischemia from those due to compromise of the dorsal column pathways. If there are adverse changes in the cortical SSEPs but no changes in the cervicomedullary SSEPs, the possibility of hemispheric ischemia due to carotid artery compression by the retractor should be considered.


Update of the list of qualified presumption of safety (QPS) recommended microbiological agents intentionally added to food or feed as notified to EFSA 17: suitability of taxonomic units notified to EFSA until September 2022.
The qualified presumption of safety (QPS) approach was developed to provide a regularly updated generic pre-evaluation of the safety of microorganisms, intended for use in the food or feed chains, to support the work of EFSA's Scientific Panels. The QPS approach is based on an assessment of published data for each agent, with respect to its taxonomic identity, the body of relevant knowledge and safety concerns. Safety concerns identified for a taxonomic unit (TU) are, where possible, confirmed at the species/strain or product level and reflected by 'qualifications'. In the period covered by this Statement, new information was found leading to the withdrawal of the qualification 'absence of aminoglycoside production ability' for Bacillus velezensis. The qualification for Bacillus paralicheniformis was changed to 'absence of bacitracin production ability'. For the other TUs, no new information was found that would change the status of previously recommended QPS TUs. Of 52 microorganisms notified to EFSA between April and September 2022 (inclusive), 48 were not evaluated because: 7 were filamentous fungi, 3 were Enterococcus faecium, 2 were Escherichia coli, 1 was Streptomyces spp., and 35 were taxonomic units (TUs) that already have a QPS status. The other four TUs notified within this period, and one notified previously as a different species, which was recently reclassified, were evaluated for the first time for a possible QPS status: Xanthobacter spp. could not be assessed because it was not identified to the species level; Geobacillus thermodenitrificans is recommended for QPS status with the qualification 'absence of toxigenic activity'. Streptoccus oralis is not recommended for QPS status. Ogataea polymorpha is proposed for QPS status with the qualification 'for production purposes only'. Lactiplantibacillus argentoratensis (new species) is included in the QPS list.


Gibberellin delays ripening of tomatoes.
Treatment with gibberellic acid, at concentrations as low as 10(-7)M, of intact tomato fruits, or of pieces in tissue culture, markedly retarded ripening in terms of development of redness. Ethylene stimulations of color development were prevented by treatment with gibberellic acid, but ethylene stimulations of respiration were not. Gibberellin can delay the progress of some components of the ripening of fruit, preventing some of the changes triggered by ethylene.


Comparative genomics and transcriptomics analyses reveal divergent lifestyle features of nematode endoparasitic fungus Hirsutella minnesotensis.
Hirsutella minnesotensis [Ophiocordycipitaceae (Hypocreales, Ascomycota)] is a dominant endoparasitic fungus by using conidia that adhere to and penetrate the secondary stage juveniles of soybean cyst nematode. Its genome was de novo sequenced and compared with five entomopathogenic fungi in the Hypocreales and three nematode-trapping fungi in the Orbiliales (Ascomycota). The genome of H. minnesotensis is 51.4 Mb and encodes 12,702 genes enriched with transposable elements up to 32%. Phylogenomic analysis revealed that H. minnesotensis was diverged from entomopathogenic fungi in Hypocreales. Genome of H. minnesotensis is similar to those of entomopathogenic fungi to have fewer genes encoding lectins for adhesion and glycoside hydrolases for cellulose degradation, but is different from those of nematode-trapping fungi to possess more genes for protein degradation, signal transduction, and secondary metabolism. Those results indicate that H. minnesotensis has evolved different mechanism for nematode endoparasitism compared with nematode-trapping fungi. Transcriptomics analyses for the time-scale parasitism revealed the upregulations of lectins, secreted proteases and the genes for biosynthesis of secondary metabolites that could be putatively involved in host surface adhesion, cuticle degradation, and host manipulation. Genome and transcriptome analyses provided comprehensive understanding of the evolution and lifestyle of nematode endoparasitism.