FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging.
Stress or aging of tissue-specific stem cells is considered central to the decline of tissue homeostasis in the elderly, although little is known of molecular mechanisms underlying hematopoietic stem cell (HSC) aging and stress resistance. Here, we report that mice lacking the transcription factor forkhead box O3a (FoxO3a) develop neutrophilia associated with inhibition of the up-regulation of negative regulator of cell proliferation, Sprouty-related Ena/VASP homology 1 domain-containing proteins 2 (Spred2) and AKT and ERK activation, in HSCs during hematopoietic recovery following myelosuppressive stress conditions. Compared with aged wild-type mice, more severe neutrophilia was also observed in aged Foxo3a-deficient mice. AKT and ERK activation and inhibition of Spred2 were detected in HSCs from aged FoxO3a-deficient mice. Spred2-deficient mice also developed neutrophilia during hematopoietic recovery following myelosuppressive stress, indicating that FoxO3a plays a pivotal role in maintenance, integrity, and stress resistance of HSCs through negative feedback pathways for proliferation. This will provide new insight into the hematopoietic homeostasis in conditions of aging and stress.


Evaluating Comorbidities, Natural History, and Predictors of Early Resolution in a Cohort of Children With Chronic Urticaria.
Chronic urticaria (CU) affects 0.1% to 0.3% of children. Most cases have no identifiable trigger and are classified as chronic spontaneous urticaria (CSU). At least half of patients with CSU may have an autoimmune etiology that can be determined in vitro using the basophil activation test (BAT). While 30% to 55% of CU cases resolve spontaneously within 5 years in adults, the natural history and predictors of resolution in children are not known. To assess the comorbidities, natural history of CU, and its subtypes in children and identify predictors of resolution. We followed a pediatric cohort with chronic urticaria that presented with hives lasting at least 6 weeks between 2013 and 2015 at a single tertiary care referral center. Data were collected on disease activity, comorbidities, physical triggers, BAT results, complete blood cell count, C-reactive protein levels, thyroid-stimulating hormone levels, and thyroid peroxidase antibodies. We assessed the rate of resolution (defined as absence of hives for at least 1 year with no treatment) and the association with clinical and laboratory markers. The cohort comprised 139 children younger than 18 years old. Thirty-one patients (20%) had inducible urticaria, most commonly cold induced. Six children had autoimmune comorbidity, such as thyroiditis and type 1 diabetes. Autoimmune disorders (24 patients [17%]) and CU (17 patients [12%]) were common in family members. Positive BAT results (CD63 levels > 1.8%) were found in 58% of patients. Patients with positive BAT results (CD63 level >1.8%) were twice as likely to resolve after 1 year compared with negative BAT results (hazard ratio [HR], 2.33; 95% CI, 1.08-5.05). In contrast, presence of basophils decreased the likelihood of resolution (HR, 0.40; 95% CI, 0.20-0.99). No correlation with age was found. Chronic urticaria resolved in 43 patients, with a rate of resolution of 10.3% per year. Levels of CD63 higher than 1.8% and absence of basophils were associated with earlier disease resolution. Resolution rate in children with CU is low. The presence of certain biomarkers (positive BAT result and basophil count) may help to predict the likelihood of resolution.


Serum L-arginine and endogenous methylarginine concentrations predict irritable bowel syndrome in adults: A nested case-control study.
BACKGROUND & AIMS: Nitric oxide, a major inhibitory nonadrenergic, noncholinergic neurotransmitter that relaxes smooth muscle, may be implicated in the pathophysiology of visceral hypersensitivity in irritable bowel syndrome (IBS). Impaired bioavailability of the nitric oxide precursor molecule L-arginine and higher concentrations of methylarginines (endogenous inhibitors of nitric oxide synthesis) are known to impair nitric oxide synthesis in numerous gastrointestinal cell types. We therefore examined serum concentrations of L-arginine and the methylarginines in a nested case-control study, to assess whether these factors are associated with adult IBS. Data on clinical characteristics, methylarginines, and L-arginine (measured using LC-MS/MS) were collected from a random population-based cohort of Australian adults (median age = 64 years; IQR = 60-70). Cases of IBS, defined according to Rome III criteria (N = 156), and controls (N = 332) were identified from within the cohort at the 5-year follow-up. In adjusted logistic regression analyses, L-arginine, asymmetric dimethylarginine, symmetric dimethylarginine, L-arginine/asymmetric dimethylarginine ratio, and Kessler-10 psychological distress scores were significantly associated with IBS (p < 0.05). [Correction added on 18 September 2021, after first online publication: In the preceding sentence, the value (p > 0.05) has been changed to (p < 0.05)]. Similar results were found for IBS subtypes. Higher serum L-arginine concentration had the strongest association with IBS diagnosis, with an odds ratio of 9.03 for those with serum L-arginine at the 75th (84 μmol/L) versus 25th (46 μmol/L) percentile (95% CI: 5.99-13.62). L-arginine had the best discriminative ability with a bias-adjusted area under the receiver operator characteristic curve of 0.859. Higher serum concentrations of L-arginine and endogenous methylarginines are strongly associated with IBS in adults.


Family-based association study showing that immunoglobulin A nephropathy is associated with the polymorphisms 2093C and 2180T in the 3' untranslated region of the Megsin gene.
Immunoglobulin A nephropathy (IgAN) is considered to be a multifactorial disease with genetic and environmental factors contributing to its pathogenesis. The genes involved in susceptibility and progression of the disease have not yet been clearly elucidated. Megsin (SERPINB7) is an important candidate gene, predominantly expressed in glomerular mesangium and upregulated in IgAN. To investigate the potential role of this and other genes in IgAN, patients with biopsy-proven IgAN were recruited, as were family members, for a family-based association study. The genotypes of the polymorphisms C2093T and C2180T within the 3' untranslated region of the gene were determined by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing. The results were analyzed by transmission disequilibrium test (TDT) and haplotype relative risk (HRR). TDT analyses revealed that Megsin 2093C and 2180T alleles were significantly more transmitted from heterozygous parents to patients than expected (C2093T: 127 trios, P = 0.034, C2180T: 100 trios, P = 0.002). Extended TDT showed increased cotransmission of the 2093C and 2180T alleles (232 families, P < 0.001). HRR revealed that the 2093C and 2180T alleles were more often transmitted to patients (P = 0.014, <0.001, respectively). Genetic variation in Megsin confers susceptibility to IgAN.


Close to open-Factors that hinder and promote open science in ecology research and education.
The Open Science (OS) movement is rapidly gaining traction among policy-makers, research funders, scientific journals and individual scientists. Despite these tendencies, the pace of implementing OS throughout the scientific process and across the scientific community remains slow. Thus, a better understanding of the conditions that affect OS engagement, and in particular, of how practitioners learn, use, conduct and share research openly can guide those seeking to implement OS more broadly. We surveyed participants at an OS workshop hosted by the Living Norway Ecological Data Network in 2020 to learn how they perceived OS and its importance in their research, supervision and teaching. Further, we wanted to know what OS practices they had encountered in their education and what they saw as hindering or helping their engagement with OS. The survey contained scaled-response and open-ended questions, allowing for a mixed-methods approach. We obtained survey responses from 60 out of 128 workshop participants (47%). Responses indicated that usage and sharing of open data and code, as well as open access publication, were the most frequent OS practices. Only a minority of respondents reported having encountered OS in their formal education. A majority also viewed OS as less important in their teaching than in their research and supervisory roles. The respondents' suggestions for what would facilitate greater OS engagement in the future included knowledge, guidelines, and resources, but also social and structural support. These are aspects that could be strengthened by promoting explicit implementation of OS practices in higher education and by nurturing a more inclusive and equitable OS culture. We argue that incorporating OS in teaching and learning of science can yield substantial benefits to the research community, student learning, and ultimately, to the wider societal objectives of science and higher education.


Fast and memory efficient text image compression with JBIG2.
In this paper, we investigate ways to reduce encoding time, memory consumption and substitution errors for text image compression with JBIG2. We first look at page striping where the encoder splits the input image into horizontal stripes and processes one stripe at a time. We propose dynamic dictionary updating procedures for page striping to reduce the bit rate penalty it incurs. Experiments show that splitting the image into two stripes can save 30% of encoding time and 40% of physical memory with a small coding loss of about 1.5%. Using more stripes brings further savings in time and memory but the return diminishes. We also propose an adaptive way to update the dictionary only when it has become out-of-date. The adaptive updating scheme can resolve the time versus bit rate tradeoff and the memory versus bit rate tradeoff well simultaneously. We then propose three speedup techniques for pattern matching, the most time-consuming encoding activity in JBIG2. When combined together, these speedup techniques can save up to 75% of the total encoding time with at most 1.7% of bit rate penalty. Finally, we look at improving reconstructed image quality for lossy compression. We propose enhanced prescreening and feature monitored shape unifying to significantly reduce substitution errors in the reconstructed images.


UniKP: a unified framework for the prediction of enzyme kinetic parameters.
Prediction of enzyme kinetic parameters is essential for designing and optimizing enzymes for various biotechnological and industrial applications, but the limited performance of current prediction tools on diverse tasks hinders their practical applications. Here, we introduce UniKP, a unified framework based on pretrained language models for the prediction of enzyme kinetic parameters, including enzyme turnover number (kcat), Michaelis constant (Km), and catalytic efficiency (kcat / Km), from protein sequences and substrate structures. A two-layer framework derived from UniKP (EF-UniKP) has also been proposed to allow robust kcat prediction in considering environmental factors, including pH and temperature. In addition, four representative re-weighting methods are systematically explored to successfully reduce the prediction error in high-value prediction tasks. We have demonstrated the application of UniKP and EF-UniKP in several enzyme discovery and directed evolution tasks, leading to the identification of new enzymes and enzyme mutants with higher activity. UniKP is a valuable tool for deciphering the mechanisms of enzyme kinetics and enables novel insights into enzyme engineering and their industrial applications.


Losing my hand. Body ownership attenuation after virtual lesion of the primary motor cortex.
A fundamental component of the self-awareness is the sensation that we are acting with our own body. Thus, a coherent sense of self implies the existence of a tight link between the sense of body ownership and the motor system. Here, we investigated this issue by taking advantage of a well-known experimental manipulation of body ownership, i.e., the rubber hand illusion (RHI), during which the subjects perceive a fake hand as part of their own body. To test the effect of the motor system down-regulation on the RHI susceptibility, we designed a sham-controlled study, where the primary motor cortex (M1) excitability was modulated by off-line low-frequency repetitive transcranial magnetic stimulation (rTMS). After rTMS (real or sham), subjects underwent the RHI either on the right hand, contralateral to the inhibited hemisphere (Experiment 1), or on the left hand, ipsilateral to the inhibited hemisphere (Experiment 2). Only in Experiment 1, the procedure strengthened the illusory experience, as proved by a significant increase, in rTMS compared to Sham, of both subjective (Embodiment/Disembodiment Questionnaires) and objective (Proprioceptive Drift) RHI measures. This evidence demonstrates that, when the M1 activity is down-regulated, the sense of body ownership is attenuated and the subjects become more prone to incorporate an alien body part. This, in turn, supports the existence of a mutual interaction between the sense of body ownership and the motor system, shedding new light on the construction of a coherent sense of self as an acting body.


Evaluation of unique identifiers used as keys to match identical publications in Pure and SciVal - a case study from health science.
Unique identifiers (UID) are seen as an effective key to match identical publications across databases or identify duplicates in a database. The objective of the present study is to investigate how well UIDs work as match keys in the integration between Pure and SciVal, based on a case with publications from the health sciences. We evaluate the matching process based on information about coverage, precision, and characteristics of publications matched versus not matched with UIDs as the match keys. We analyze this information to detect errors, if any, in the matching process. As an example we also briefly discuss how publication sets formed by using UIDs as the match keys may affect the bibliometric indicators number of publications, number of citations, and the average number of citations per publication. The objective is addressed in a literature review and a case study. The literature review shows that only a few studies evaluate how well UIDs work as a match key. From the literature we identify four error types: Duplicate digital object identifiers (DOI), incorrect DOIs in reference lists and databases, DOIs not registered by the database where a bibliometric analysis is performed, and erroneous optical or special character recognition. The case study explores the use of UIDs in the integration between the databases Pure and SciVal. Specifically journal publications in English are matched between the two databases. We find all error types except erroneous optical or special character recognition in our publication sets. In particular the duplicate DOIs constitute a problem for the calculation of bibliometric indicators as both keeping the duplicates to improve the reliability of citation counts and deleting them to improve the reliability of publication counts will distort the calculation of average number of citations per publication. The use of UIDs as a match key in citation linking is implemented in many settings, and the availability of UIDs may become critical for the inclusion of a publication or a database in a bibliometric analysis.


Alteration of the kinetics of type I procollagen synthesis in human osteosarcoma cells by 1,25-dihydroxyvitamin D3.
The kinetics of type I procollagen synthesis in a human osteosarcoma cell line, MG 63, were investigated after treatment with 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3), a hormonal inducer of phenotypic differentiation. Pulse label and chase experiments demonstrated greatly enhanced production and more rapid reduction of intracellular procollagen molecules in the 1,25-(OH)2 D3-treated cells as compared to the nontreated case. After a chase for 1 h, labeled procollagen was reduced by nine-tenths in 1,25-(OH)2 D3-treated cells, while half of the radioactivity still remained in nontreated cells. The expression rate of type I collagen, which was examined by pulse label experiment, was elevated in association with an increase in the mRNA coding for the type I collagen alpha 1 chain by 1,25-(OH)2 D3 treatment. However, the amount of intracellular procollagen present after 4 h continuous labeling was almost the same, independent of the 1,25-(OH)2 D3 treatment. Thus, we conclude that strage of the molecule was not affected. The results therefore suggest an increase in both the synthesis and secretion of type I collagen. The 1,25-(OH)2 D3 treatment was also found to induce the alpha subunit of prolyl 4-hydroxylase and to be associated with an elevated level of hydroxyproline in the procollagen. Moreover, gelatinase B-resistant procollagen molecules, indicative of intracellular procollagen molecules in the stable triple helical form, were detected only in the 1,25-(OH)2 D3-treated cells. These data suggest more efficient proline hydroxylation is involved in rapid secretion of procollagen after hormone administration. The present evidence points to posttranslational control of procollagen synthesis.


Membrane association, localization and topology of rat inositol 1,4,5-trisphosphate 3-kinase B: implications for membrane traffic and Ca2+ homoeostasis.
We previously reported the isolation of a rat cDNA clone encoding a protein with significant sequence homology to the B isoform of human myo-inositol 1,4,5-trisphosphate 3-kinase (IP3 3-kinase B); this protein was thus designated rat IP3 3-kinase B [Thomas, Brake, Luzio, Stanley and Banting (1994) Biochim. Biophys. Acta 1220, 219-222]. However, no IP3 kinase isoform had been shown to generate the physiologically important isoform of inositol tetrakisphosphate, i.e. inositol 1,3,4,5-tetrakisphosphate. We now present direct evidence that the putative rat IP3 3-kinase B is genuinely an IP3 3-kinase. We also show that the enzyme exists both as a peripheral membrane protein tightly associated with the cytosolic face of the extended endoplasmic reticulum network, and as a cytosolic protein. Association of the IP3 3-kinase with membranes is not affected by treatment with brefeldin A, Na2CO3 (pH 11.5), 2 M NaCl, or alteration of [Ca2+]. However, treatment of isolated membranes with 4 M urea leads to dissociation of the kinase from the membrane, implying that membrane association involves specific, conformation-dependent protein-protein interactions. The fact that IP3 3-kinase B is localized exclusively to membranes of Ca2+ stores, is consistent with a model where this kinase plays a role in IP3-dependent Ca2+ release.


Neurodevelopmental Outcome and Health-related Quality of Life in Children With Single-ventricle Heart Disease Before Fontan Procedure.
Neurodevelopmental impairment and impaired quality of life constitute a major source of morbidity among children with complex congenital heart disease, in particular for single-ventricle (SV) morphologies. Risk factors and quality of life determining clinical and neurodevelopmental outcome at 2 years of age are examined. In a 2-center cohort study, 48 patients with SV morphology (26 hypoplastic left heart syndrome and 22 other types of univentricular heart defect) have been examined before Fontan procedure between 2010 and 2015. Patients were assessed with the Bayley Scales of Infant and Toddler Development, Third Version (Bayley-III), and the Preschool Children Quality of Life (TAPQOL) questionnaire. A total of 44 patients underwent hybrid procedure (n = 25), Norwood procedure (n = 7), or shunt or banding procedure (n = 12) as first surgery before subsequent bidirectional cavopulmonary anastomosis (n = 48). Median cognitive, language, and motor composite scores on the Bayley-III were 100 (range 65-120), 97 (68-124), and 97 (55-124), respectively. The language composite score was significantly below the norm (P = 0.025). Risk factors for poorer neurodevelopmental outcome were prolonged mechanical ventilation, longer days of hospital stay, and more reinterventions (all P < 0.05). Parents reported a good quality of life for their children. Children undergoing Fontan procedure show a favorable development and good quality of life. More complicated postoperative course and reinterventions constitute risk factors for impaired neurodevelopment. Improving postoperative management and implementing routine follow-up assessments aremeasures to further improve the neurodevelopmental outcome of this high-risk patient population.


Intensive care of head-injured patients.
The intensive care and monitoring of patients with head injury is essentially the same among patients with mass lesions requiring surgery and those with no mass lesions. The surgical procedure should be looked upon as an adjuvant therapy to lower a rising intracranial pressure due to an expanding hematoma, macerated or infarcted brain. Apart form this all patients will have the same medical management and ICP recording will determine the extent of such therapy.


Perioperative administration of angiotensin converting enzyme inhibitors decreases the severity and duration of pleural effusions following bidirectional cavopulmonary anastomosis.
Pleural effusions after bidirectional cavopulmonary anastomosis remain a significant cause of morbidity. Prolonged effusions in such patients have been associated with persistent elevations in plasma renin and angiotensin II. We conducted a controlled study in 36 patients (median age 8 months) undergoing bidirectional cavopulmonary anastomosis. Enalapril (5 mcg/kg) was administered intravenously within 1 hour of surgery and every 12 hours thereafter in 18 patients; when these patients were tolerating feeds, enalapril was switched to enteral captopril (3 mg/kg/day) every 8 hours. The other 18 patients did not receive perioperative angiotensin converting enzyme inhibitors. Using standardized criteria for discontinuation of chest tubes (< 2 mL/kg/day), volume and duration of pleural drainage were compared between groups. RESULTS. There were no differences between groups in demographic, diagnostic, or hemodynamic factors. There was no difference in cardiopulmonary bypass time between groups and no difference in postoperative pulmonary arterial pressures. The duration of pleural drainage was shorter (2.2+/-1.4 vs 5.9+/-1.4 days, p<0.001) and the volume less during the first 24 hours (4.7+/-1.2 vs 7.7+/-2.1 mL/kg, p<0.001) and overall (10.6+/-2.4 vs 19.6+/-4.5 mL/kg, p<0.001) in patients who received angiotensin converting enzyme inhibitors than those who did not. Readmission for persistent effusions was required in 3 patients who did not receive angiotensin converting enzyme inhibitors and none who did (p=0.11). Perioperative administration of angiotensin converting enzyme inhibitors is associated with decreased severity and duration of pleural effusions following bidirectional cavopulmonary anastomosis.


Trends in postneonatal aspiration deaths and reclassification of sudden infant death syndrome: impact of the "Back to Sleep" program.
The introduction of the "Back to Sleep" campaign for the prevention of sudden infant death syndrome (SIDS) brought with it concern that there might be an increase in the incidence of aspiration-related deaths. The objective of this analysis was to describe the trends in postneonatal mortality and proportionate mortality ratios for the United States for the years 1991 to 1996 for aspiration-related deaths and other causes to which a SIDS death could conceivably be reclassified. Linked birth and infant death vital statistic files for the United States were used for the years 1991, 1995, and 1996. US Vital Statistic Mortality files for the years 1992, 1993, and 1994 were used because of the absence of linked files for those years. The overall postneonatal mortality rate between 1991 and 1996 declined 21.9%, whereas the SIDS rate declined 38.9%. The proportion of the postneonatal mortality (PNPMR) contributed by SIDS declined from 37.1% in 1991 to 28.8% in 1996. There was no significant increase in the PNPMR for aspiration, asphyxia, or respiratory failure. There was, however, a significant increase in the PNPMR for suffocation in bed or cradle from 0.9 to 1.3. These data show no evidence of an increased risk of death from aspiration as a result of the "Back to Sleep" program. Although there has been an increase in the proportion of postneonatal mortality attributable to suffocation, this represents a very small proportion of postneonatal mortality and thus potentially a very small number of SIDS deaths reclassified as suffocation.


NMR structure of a complex between MDM2 and a small molecule inhibitor.
MDM2 is a regulator of cell growth processes that acts by binding to the tumor suppressor protein p53 and ultimately restraining its activity. While inactivation of p53 by mutation is commonly observed in human cancers, a substantial percentage of tumors express wild type p53. In many of these cases, MDM2 is overexpressed, and it is believed that suppression of MDM2 activity could yield therapeutic benefits. Therefore, we have been focusing on the p53-MDM2 interaction as the basis of a drug discovery program and have been able to develop a series of small molecule inhibitors. We herein report a high resolution NMR structure of a complex between the p53-binding domain of MDM2 and one of these inhibitors. The form of MDM2 utilized was an engineered hybrid between the human and Xenopus sequences, which provided a favorable combination of relevancy and stability. The inhibitor is found to bind in the same site as does a highly potent peptide fragment of p53. The inhibitor is able to successfully mimic the peptide by duplicating interactions in three subpockets normally made by amino acid sidechains, and by utilizing a scaffold that presents substituents with rigidity and spatial orientation comparable to that provided by the alpha helical backbone of the peptide. The structure also suggests opportunities for modifying the inhibitor to increase its potency.


Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain.
Lactate is shuttled between organs, as demonstrated in the Cori cycle. Although the brain releases lactate at rest, during physical exercise there is a cerebral uptake of lactate. Here, we evaluated the cerebral lactate uptake and release in hypoxia, during exercise and when the two interventions were combined. We measured cerebral lactate turnover via a tracer dilution method ([1-(13)C]lactate), using arterial to right internal jugular venous differences in 9 healthy individuals (5 males and 4 females), at rest and during 30 min of submaximal exercise in normoxia and hypoxia (F(i)o(2) 10%, arterial oxygen saturation 72 ± 10%, mean ± sd). Whole-body lactate turnover increased 3.5-fold and 9-fold at two workloads in normoxia and 18-fold during exercise in hypoxia. Although middle cerebral artery mean flow velocity increased during exercise in hypoxia, calculated cerebral mitochondrial oxygen tension decreased by 13 mmHg (P<0.001). At the same time, cerebral lactate release increased from 0.15 ± 0.1 to 0.8 ± 0.6 mmol min(-1) (P<0.05), corresponding to ∼10% of cerebral energy consumption. Concurrently, cerebral lactate uptake was 1.0 ± 0.9 mmol min(-1) (P<0.05), of which 57 ± 9% was oxidized, demonstrating that lactate oxidation may account for up to ∼33% of the energy substrate used by the brain. These results support the existence of a cell-cell lactate shuttle that may involve neurons and astrocytes.


Autologous Breast Reconstruction With a Delay Procedure of the Deep Inferior Epigastric Artery Perforator Flap Because of Venous Congestion of the Flap on Pedicle: A Case Series.
The deep inferior epigastric artery perforator (DIEP) flap is one of the most used free flaps for the reconstruction of the breast after a mastectomy. Despite careful selection of the patients and preoperative imaging, difficulties in vascularization of the flap can occur in some cases. Although multiple vascular connections (bipedicled, turbocharged, or stacked) can be made in selected cases, there can still be venous congestion before the flap is transferred.Between 2016 and 2018, 4 cases in our series of 281 patients experienced such problems. Three of 4 patients had undergone preoperative imaging of the perforators by a magnetic resonance angiography or computed tomography angiography, in which a good perforator was seen. All 4 patients had a venous problem of blood circulation in the flap intraoperatively. The flaps were left to rest to decide on its venous status. Without improvement after this period of 20 to 30 minutes, the surgeons decided to withhold the translocation of the flap to the chest wall and sutured the flap back into the donor side. The final anastomosis of the DIEP flap occurred on average 8 days after the prefabrication. The translocation of the DIEP flap to the chest in this second operation went uncomplicated in all cases. Postoperatively, all patients had adequate arterial inflow and venous outflow of the flap. There were no postoperative complications.In case a DIEP flap shows venous problems before translocation, a delay procedure can be applied. In this way, the vascularization of the flap can be improved, and the translocation of the DIEP flap in a second operation can be successfully performed.


Corticospinal tract degeneration associated with TDP-43 type C pathology and semantic dementia.
Four subtypes of frontotemporal lobar degeneration with TDP-43 immunoreactive inclusions have been described (types A-D). Of these four subtypes, motor neuron disease is more commonly associated with type B pathology, but has also been reported with type A pathology. We have noted, however, the unusual occurrence of cases of type C pathology having corticospinal tract degeneration. We aimed to assess the severity of corticospinal tract degeneration in a large cohort of cases with type C (n = 31). Pathological analysis included semi-quantitation of myelin loss of fibres of the corticospinal tract and associated macrophage burden, as well as axonal loss, at the level of the medullary pyramids. We also assessed for motor cortex degeneration and fibre loss of the medial lemniscus/olivocerebellar tract. All cases were subdivided into three groups based on the degree of corticospinal tract degeneration: (i) no corticospinal tract degeneration; (ii) equivocal corticospinal tract degeneration; and (iii) moderate to very severe corticospinal tract degeneration. Clinical, genetic, pathological and imaging comparisons were performed across groups. Eight cases had no corticospinal tract degeneration, and 14 cases had equivocal to mild corticospinal tract degeneration. Nine cases, however, had moderate to very severe corticospinal tract degeneration with myelin and axonal loss. In these nine cases, there was degeneration of the motor cortex without lower motor neuron degeneration or involvement of other brainstem tracts. These cases most commonly presented as semantic dementia, and they had longer disease duration (mean: 15.3 years) compared with the other two groups (10.8 and 9.9 years; P = 0.03). After adjusting for disease duration, severity of corticospinal tract degeneration remained significantly different across groups. Only one case, without corticospinal tract degeneration, was found to have a hexanucleotide repeat expansion in the C9ORF72 gene. All three groups were associated with anterior temporal lobe atrophy on MRI; however, the cases with moderate to severe corticospinal tract degeneration showed right-sided temporal lobe asymmetry and greater involvement of the right temporal lobe and superior motor cortices than the other groups. In contrast, the cases with no or equivocal corticospinal tract degeneration were more likely to show left-sided temporal lobe asymmetry. For comparison, the corticospinal tract was assessed in 86 type A and B cases, and only two cases showed evidence of corticospinal tract degeneration without lower motor neuron degeneration. These findings confirm that there exists a unique association between frontotemporal lobar degeneration with type C pathology and corticospinal tract degeneration, with this entity showing a predilection to involve the right temporal lobe.


A study of long-term potentiation in transgenic mice over-expressing mutant forms of both amyloid precursor protein and presenilin-1.
Synaptic transmission and long-term potentiation (LTP) in the CA1 region of hippocampal slices have been studied during ageing of a double transgenic mouse strain relevant to early-onset familial Alzheimer's disease (AD). This strain, which over-expresses both the 695 amino acid isoform of human amyloid precursor protein (APP) with K670N and M671L mutations and presenilin 1 with the A246E mutation, has accelerated amyloidosis and plaque formation. There was a decrease in synaptic transmission in both wildtype and transgenic mice between 2 and 9 months of age. However, preparing slices from 14 month old animals in kynurenic acid (1 mM) counteracted this age-related deficit. Basal transmission and paired-pulse facilitation was similar between the two groups at all ages (2, 6, 9 and 14 months) tested. Similarly, at all ages LTP, induced either by theta burst stimulation or by multiple tetani, was normal. These data show that a prolonged, substantially elevated level of Abeta are not sufficient to cause deficits in the induction or expression of LTP in the CA1 hippocampal region.


Curcumin and Nanocurcumin Oral Supplementation Improve Muscle Healing in a Rat Model of Surgical Muscle Laceration.
To compare the effects of curcumin and nanocurcumin oral supplementation on the muscle healing rate of an animal model of surgical muscle laceration. Thirty-two male adult rats were randomly divided into sham, control, curcumin, and nanocurcumin groups. Partial transection of the gastrocnemius muscle was made in the right limb of the control and treatment groups. The sham and control groups received normal saline, curcumin group received 500 mg/kg of curcumin and nanocurcumin group received 100 mg curcumin-loaded nanomicelles orally every day. They euthanized two weeks later and the specimens were stained by hematoxylin-eosin (H&E) and Masson's trichrome methods. Aspartate transaminase (AST) and creatine phosphokinase (CPK) were measured in blood samples. The percentage of collagen fibers in the nanocurcumin group was significantly lesser than the control and curcumin groups (p<0.001). Muscle fiber regeneration in the treatment groups was significantly higher than the control group (p<0.001). The blood vessels of the nanocurcumin group were significantly more than other groups (p<0.001). Plasma AST had a significant difference in the control group compared to the sham and nanocurcumin groups (p=0.026). The plasma CPK level of the control group was also significantly higher than other groups (p<0.001). In conclusion, although oral curcumin supplementation has little effects because of its poor bioavailability, embedding it in nanoparticles could enhance its systemic effects in promoting the muscle healing process.


Identifying Persuasive Design Principles and Behavior Change Techniques Supporting End User Values and Needs in eHealth Interventions for Long-Term Weight Loss Maintenance: Qualitative Study.
An increasing number of eHealth interventions aim to support healthy behaviors that facilitate weight loss. However, there is limited evidence of the effectiveness of the interventions and little focus on weight loss maintenance. Knowledge about end user values and needs is essential to create meaningful and effective eHealth interventions, and to identify persuasive system design (PSD) principles and behavior change techniques (BCTs) that may contribute to the behavior change required for successful long-term weight loss maintenance. This study aimed to provide insight into the design of eHealth interventions supporting behavior change for long-term weight maintenance. The study sought to identify the values and needs of people with obesity aiming to maintain weight after weight loss, and to identify PSD principles, BCTs, and design requirements that potentially enable an eHealth intervention to meet end user values and needs. This study presents the concept of integrating PSD principles and BCTs into the design process of eHealth interventions to meet user values and needs. In this study, individual interviews and focus groups were conducted with people with obesity (n=23) and other key stakeholders (n=27) to explore end user values and needs related to weight loss maintenance. Design thinking methods were applied during the focus group sessions to identify design elements and to explore how eHealth solutions can support the needs to achieve sustainable weight loss maintenance. The PSD model and behavior change taxonomy by Michie were used to identify PSD principles and BCT clusters to meet end user values and needs. A total of 8 key end user values were identified, reflecting user needs for weight loss maintenance support: self-management, personalized care, autonomy, feel supported, positive self-image, motivation, happiness, and health. Goals and planning, feedback and monitoring, repetition and substitution, shaping knowledge, social support, identity, and self-belief were some of the BCT clusters identified to address these concepts, together with PSD principles such as personalization, tailoring, self-monitoring, praise, and suggestions. The process of translating end user values and needs into design elements or features of eHealth technologies is an important part of the design process. To our knowledge, this is the first study to explore how PSD principles and BCTs can be integrated when designing eHealth self-management interventions for long-term weight loss maintenance. End users and other key stakeholders highlighted important factors to be considered in the design of eHealth interventions supporting sustained behavior change. The PSD principles and BCTs identified provide insights and suggestions about design elements and features to include for supporting weight loss maintenance. The findings indicate that a combination of BCTs and PSD principles may be needed in evidence-based eHealth interventions to stimulate motivation and adherence to support healthy behaviors and sustained weight loss maintenance. ClinicalTrials.gov NCT04537988; https://clinicaltrials.gov/ct2/show/NCT04537988.


Office spirometry significantly improves early detection of COPD in general practice: the DIDASCO Study.
To determine if spirometry is essential for the early detection of COPD in general practice, compared to the screening value of a short questionnaire. A prospective survey of the population aged 35 to 70 years visiting their general practitioner (GP) during a 12-week period, using a questionnaire on symptoms of obstructive lung disease (OLD). Spirometry was performed in all participants with positive answers and in a 10% random sample from the group without complaints. Twenty GPs were provided with a hand-held spirometer, and received training in performance and interpretation of lung function tests. All 35- to 70-year-old patients (n = 3,408) were screened for current use of bronchodilators. The subgroup receiving bronchodilators (n = 250, 7%) was assumed to have OLD, and was excluded. Airflow obstruction was defined according to the European Respiratory Society standards. The positive predictive power of the questionnaire was low (sensitivity, 58%; specificity, 78%; likelihood ratio, 2.6). One hundred twenty-six cases of formerly unknown OLD were detected in the group of patients with complaints, vs an extrapolated number of 90 in the group without complaints. Despite a negative predictive value of 95% for the questionnaire used, 42% of the newly diagnosed cases of OLD would not have been detected without spirometry. The use of a spirometer is mandatory if early stages of OLD are to be detected in general practice. Screening for airflow obstruction almost doubles the number of known patients with OLD.


Alternative definitions of chronic bronchitis and their correlation with CT parameters.
Phenotyping of chronic bronchitis (CB) using COPD assessment tool (CAT) scores and St George's Respiratory Questionnaire (SGRQ) has rarely been attempted. The present study defined CB using CAT 1 and 2 scores and the questions on the severity of cough and sputum from the SGRQ. Furthermore, the predictability of CT parameters was also assessed for each CB definition. Patients enrolled in the Korean Obstructive Lung Disease study from June 2005 to October 2015 were evaluated for this study. The patients were spirometrically diagnosed with COPD and had a smoking history of >10 pack-years. Volumetric CT scans were performed for each patient upon enrollment in the cohort. Two definitions of CB using CAT 1/2 scores and SGRQ questions were used to phenotype CB among the study patients. Receiver operating characteristic curve analysis was performed to estimate the predictability of CT parameters for the CB phenotypes. Using CAT 1/2 scores, 57 of 279 (20.4%) patients had CB, and 178 of 573 (31.1%) had CB when the SGRQ questions were used to phenotype it. Total CAT and SGRQ scores were significantly higher in the CB group than those in the non-CB group for both definitions of CB. Forced expiratory volume in 1 second was lower for both CAT-defined and SGRQ-defined CB than that in the non-CB group. Mean wall thickness was significantly higher for both CB groups than in the non-CB group. Expiratory lung volume was higher and mean lung density was significantly lower for the SGRQ-defined CB group than non-CB group. The 2 CB definitions using CAT scores and the SGRQ questions correlated with associated CT airway parameters. SGRQ-defined CB better reflected the accompaniment of small airway obstruction when compared with CAT-defined CB.


Prediction of thermostability from amino acid attributes by combination of clustering with attribute weighting: a new vista in engineering enzymes.
The engineering of thermostable enzymes is receiving increased attention. The paper, detergent, and biofuel industries, in particular, seek to use environmentally friendly enzymes instead of toxic chlorine chemicals. Enzymes typically function at temperatures below 60°C and denature if exposed to higher temperatures. In contrast, a small portion of enzymes can withstand higher temperatures as a result of various structural adaptations. Understanding the protein attributes that are involved in this adaptation is the first step toward engineering thermostable enzymes. We employed various supervised and unsupervised machine learning algorithms as well as attribute weighting approaches to find amino acid composition attributes that contribute to enzyme thermostability. Specifically, we compared two groups of enzymes: mesostable and thermostable enzymes. Furthermore, a combination of attribute weighting with supervised and unsupervised clustering algorithms was used for prediction and modelling of protein thermostability from amino acid composition properties. Mining a large number of protein sequences (2090) through a variety of machine learning algorithms, which were based on the analysis of more than 800 amino acid attributes, increased the accuracy of this study. Moreover, these models were successful in predicting thermostability from the primary structure of proteins. The results showed that expectation maximization clustering in combination with uncertainly and correlation attribute weighting algorithms can effectively (100%) classify thermostable and mesostable proteins. Seventy per cent of the weighting methods selected Gln content and frequency of hydrophilic residues as the most important protein attributes. On the dipeptide level, the frequency of Asn-Glu was the key factor in distinguishing mesostable from thermostable enzymes. This study demonstrates the feasibility of predicting thermostability irrespective of sequence similarity and will serve as a basis for engineering thermostable enzymes in the laboratory.


Differential effects of RNAi treatments on field populations of the western corn rootworm.
RNA interference (RNAi) mediated crop protection against insect pests is a technology that is greatly anticipated by the academic and industrial pest control communities. Prior to commercialization, factors influencing the potential for evolution of insect resistance to RNAi should be evaluated. While mutations in genes encoding the RNAi machinery or the sequences targeted for interference may serve as a prominent mechanism of resistance evolution, differential effects of RNAi on target pests may also facilitate such evolution. However, to date, little is known about how variation of field insect populations could influence the effectiveness of RNAi treatments. To approach this question, we evaluated the effects of RNAi treatments on adults of three western corn rootworm (WCR; Diabrotica virgifera virgifera LeConte) populations exhibiting different levels of gut cysteine protease activity, tolerance of soybean herbivory, and immune gene expression; two populations were collected from crop rotation-resistant (RR) problem areas and one from a location where RR was not observed (wild type; WT). Our results demonstrated that RNAi targeting DvRS5 (a highly expressed cysteine protease gene) reduced gut cysteine protease activity in all three WCR populations. However, the proportion of the cysteine protease activity that was inhibited varied across populations. When WCR adults were treated with double-stranded RNA of an immune gene att1, different changes in survival among WT and RR populations on soybean diets occurred. Notably, for both genes, the sequences targeted for RNAi were the same across all populations examined. These findings indicate that the effectiveness of RNAi treatments could vary among field populations depending on their physiological and genetic backgrounds and that the consistency of an RNAi trait's effectiveness on phenotypically different populations should be considered or tested prior to wide deployment. Also, genes that are potentially subjected to differential selection in the field should be avoided for RNAi-based pest control.


Role of Silymarin in Cancer Treatment: Facts, Hypotheses, and Questions.
The flavonoid silymarin extracted from the seeds of Sylibum marianum is a mixture of 6 flavolignan isomers. The 3 more important isomers are silybin (or silibinin), silydianin, and silychristin. Silybin is functionally the most active of these compounds. This group of flavonoids has been extensively studied and they have been used as hepato-protective substances for the mushroom Amanita phalloides intoxication and mainly chronic liver diseases such as alcoholic cirrhosis and nonalcoholic fatty liver. Hepatitis C progression is not, or slightly, modified by silymarin. Recently, it has also been proposed for SARS COVID-19 infection therapy. The biochemical and molecular mechanisms of action of these substances in cancer are subjects of ongoing research. Paradoxically, many of its identified actions such as antioxidant, promoter of ribosomal synthesis, and mitochondrial membrane stabilization, may seem protumoral at first sight, however, silymarin compounds have clear anticancer effects. Some of them are: decreasing migration through multiple targeting, decreasing hypoxia inducible factor-1α expression, inducing apoptosis in some malignant cells, and inhibiting promitotic signaling among others. Interestingly, the antitumoral activity of silymarin compounds is limited to malignant cells while the nonmalignant cells seem not to be affected. Furthermore, there is a long history of silymarin use in human diseases without toxicity after prolonged administration. The ample distribution and easy accessibility to milk thistle-the source of silymarin compounds, its over the counter availability, the fact that it is a weed, some controversial issues regarding bioavailability, and being a nutraceutical rather than a drug, has somehow led medical professionals to view its anticancer effects with skepticism. This is a fundamental reason why it never achieved bedside status in cancer treatment. However, in spite of all the antitumoral effects, silymarin actually has dual effects and in some cases such as pancreatic cancer it can promote stemness. This review deals with recent investigations to elucidate the molecular actions of this flavonoid in cancer, and to consider the possibility of repurposing it. Particular attention is dedicated to silymarin's dual role in cancer and to some controversies of its real effectiveness.


[Results of application of platelet-enriched autogenous plasma for the treatment of patients after middle ear surgery].
A total of 39 patients presenting with chronic suppurative otitis media were examined and treated based at the Department of Otorhinolaringology, Kursk Regional Clinical Hospital. The results of the study indicate that a group of patients treated with the use of platelet-enriched autogenous plasma simultaneously with sanation surgery and tympanoplasty underwent accelerated healing of the postoperative cavity and restoration of hearing compared with the patients who received the traditional treatment.


Crohn's disease associated adenocarcinoma of ileocaecal region: a miscalculated approach.
Adenocarcinoma of the bowel is a dreadful sequelae of inflammatory bowel disease that can be difficult to diagnose and has been shown to have poor prognosis. The diagnosis is often made on histopathological examination of the resected specimen for what is suspected to be an exacerbation of the underlying intestinal Crohn's. A 39-year-old woman who was being treated for small bowel Crohn's disease for 4 years presented with features of intermittent intestinal obstruction that was refractory to medical therapy. A contrast CT of the abdomen was suggestive of ileocaecal Crohn's disease, and colonoscopy revealed a stricture at proximal transverse colon with multiple superficial ulcers. She underwent a mesentery sparing right hemicolectomy and had an uneventful recovery. The biopsy, however, was reported to be moderately differentiated adenocarcinoma stage T3N0 with a harvest of four pericolic nodes. Adjuvant chemotherapy was advised, which she deferred. Ten months later, she presented to the emergency room with features of intestinal obstruction. Contrast CT of the abdomen showed thickening at the anastomotic site with intestinal obstruction. On exploratory laparotomy, tumour recurrence was noted at the site of the anastomosis and diffuse peritoneal metastasis. A palliative diversion ileostomy was done due to inoperable obstructing disease. She was then given palliative therapy and subsequently succumbed to the illness. The inclusion of mesentery with the resected specimen in Crohn's disease has been a debate over many years. Since the preoperative diagnosis of carcinoma of the bowel in Crohn's disease is challenging, all ileocolic resections should be radical as done in oncological resections. This would yield better oncological safety and may improve survival rates.


Osteogenic differentiation regulated by Rho-kinase in periodontal ligament cells.
The periodontal ligament is a multifunctional soft connective tissue, which functions not only as a cushion supporting the teeth against occlusal force, but is also a source of osteogenic cells that can regenerate neighboring hard tissues. Periodontal ligament cells (PDL cells) contain heterogeneous cell populations, including osteogenic cell progenitors. However, the precise mechanism underlying the differentiation process remains elusive. Cell differentiation is regulated by the local biochemical and mechanical microenvironment that can modulate gene expression and cell morphology by altering actin cytoskeletal organization mediated by Rho-associated, coiled-coil containing protein kinase (ROCK). To determine its role in PDL cell differentiation, we examined the effects of ROCK on cytoskeletal changes and kinetics of gene expression during osteogenic differentiation. PDL cells were isolated from human periodontal ligament on extracted teeth and cultured in osteogenic medium for 14 days. Y-27632 was used for ROCK inhibition assay. Osteogenic phenotype was determined by monitoring alkaline phosphatase (ALP) activity and calcium deposition by Alizarin Red staining. ROCK-induced cytoskeletal changes were examined by immunofluorescence analysis of F-actin and myosin light chain 2 (MLC2) expression. Real-time PCR was performed to examine the kinetics of osteogenic gene expression. F-actin and phospho-MLC2 were markedly induced during osteogenic differentiation, which coincided with upregulation of ALP activity and mineralization. Subsequent inhibition assay indicated that Y-27632 significantly inhibited F-actin and phospho-MLC2 expression in a dose-dependent manner with concomitant partial reversal of the PDL cell osteogenic phenotype. PCR array analysis of osteogenic gene expression indicated that extracellular matrix genes, such as fibronectin 1, collagen type I and III, and biglycan, were significantly downregulated by Y27632. These findings indicated crucial effects of ROCK in cytoskeletal reorganization and differentiation of PDL cells toward osteogenic cells. ROCK contributes to induction of osteogenic differentiation by synergistic increases in extracellular matrix gene expression in PDL cells.


Parental Divorce and Trajectories of Alcohol Consumption in Men: A Genetically Informative Perspective.
Much of what is known about parental divorce and adult alcohol outcomes comes from cross-sectional comparisons of those who did and did not experience parental divorce. In contrast, far less is known about whether and how parental divorce is associated with alcohol consumption trajectories. We used a longitudinal perspective to investigate the associations between parental divorce and men's alcohol consumption trajectories as well as a genetically informative approach to evaluate whether the pattern of genetic and environmental influences on these trajectories differed for men who did and did not experience parental divorce. The sample included 1,614 adult men from a population-based twin registry in Virginia. Measures of parental divorce (before age 16) and alcohol consumption (between ages 10 and 40) came from interviews and life history calendars. Data were analyzed with growth curve and longitudinal biometric variance component models. In total, 11% of the sample experienced parental divorce. Parental divorce was associated with higher alcohol consumption intercepts that were sustained over time but was not associated with the linear slope or quadratic curvature of men's alcohol consumption trajectories. Longitudinal biometric variance components modeling indicated that genetic influences on alcohol consumption were higher in adolescence and young adulthood among those who experienced parental divorce compared with those who did not. Parental divorce is associated with the shape and relative influence of genetic and environmental factors on men's alcohol consumption trajectories from adolescence through adulthood.


The shifting engines of medicalization.
Social scientists and other analysts have written about medicalization since at least the 1970s. Most of these studies depict the medical profession, interprofessional or organizational contests, or social movements and interest groups as the prime movers toward medicalization. This article contends that changes in medicine in the past two decades are altering the medicalization process. Using several case examples, I argue that three major changes in medical knowledge and organization have engendered an important shift in the engines that drive medicalization: biotechnology (especially the pharmaceutical industry and genetics), consumers, and managed care. Doctors are still gatekeepers for medical treatment, but their role has become more subordinate in the expansion or contraction of medicalization. Medicalization is now more driven by commercial and market interests than by professional claims-makers. The definitional center of medicalization remains constant, but the availability of new pharmaceutical and potential genetic treatments are increasingly drivers for new medical categories. This requires a shift in the sociological focus examining medicalization for the twenty-first century.


Primary brain tumor patients admitted to a US intensive care unit: a descriptive analysis.
Purpose: To describe our population of primary brain tumor (PBT) patients, a subgroup of cancer patients whose intensive care unit (ICU) outcomes are understudied. Methods: Retrospective analysis of PBT patients admitted to an ICU between 2013 to 2018 for an unplanned need. Using descriptive analyses, we characterized our population and their outcomes. Results: Fifty-nine PBT patients were analyzed. ICU mortality was 19% (11/59). The most common indication for admission was seizures (n = 16, 27%). Conclusion: Our ICU mortality of PBT patients was comparable to other solid tumor patients and the general ICU population and better than patients with hematological malignancies. Further study of a larger population would inform guidelines for triaging PBT patients who would most benefit from ICU-level care.


Anaesthetic implications and management of a giant ovarian cyst.
With improvement in health care, improved access to hospitals and better imaging modalities, huge abdominal tumours are rarely seen in modern day surgical practice. They present many challenges to anaesthesiologists. Difficult intubations, life threatening cardiovascular and pulmonary complications, are commonly encountered. Management of such cases is associated with significant mortality and morbidity. The consequences of surgery are mainly attributable to the size of the mass rather than to its distinctive pathology. We hereby report a very rare case of a giant ovarian cyst weighing 57kg, which was successfully managed by a careful pre-operative evaluation, maintenance of intraoperative haemodynamic and fluid management.


[Building skills for the nurse's educational actions in primary health care].
This is a study to review the methodological process developed to built a profile of competencies required for nurse's educational actions. It was a qualitative research, in the historical and dialectical materialism, that used competence as the conceptual category, anchored in the conceptions of work in health and operating knowledge. The subjects were teachers and students of the School of Nursing of University of Sao Paulo (USP), Brazil; nurses, managers and patients of health services connected to USP. The speech analysis technique was used to analyze the speeches. All groups addressed contained similarities related to knowledge, skills and attitudes required to the development of more dialogical and participative educational practices. The methodological approach described enable the construction of a profile of competencies related to nurse's educational actions, in a collective perspective, closer to the population's health needs.


Oncocytic change in adult rhabdomyoma.
An adult rhabdomyoma was studied with the light and electron microscopes. The source of eosinophilia of the cytoplasm on light microscopy can be attributed to two components: a filamentous and a granular components. Ultrastructural studies displayed numerous banded myofilaments and mitochondria exhibiting varying degrees of abnormalities. These mitochondrial alterations were similar to those described in oncocytes and oncocytomas. The latter morphologic findings suggest that the mitochondrial abnormalities in adult rhabdomyomas represent an oncocytic change and that they are an integral part of the neoplastic process. Though primarily affecting epithelial cells, oncocytic change, may, under unusual circumstances, involve mesenchymal cells.


1-[5-(2-Fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel and potent potassium-competitive acid blocker for the treatment of acid-related diseases.
Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 μM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. TAK-438, at a dose of 4 mg/kg (as the free base) orally, completely inhibited basal and 2-deoxy-d-glucose-stimulated gastric acid secretion in rats, and its effect on both was stronger than that of lansoprazole. TAK-438 increased the pH of gastric perfusate to a higher value than did lansoprazole or SCH28080, and the effect of TAK-438 was sustained longer than that of lansoprazole or SCH28080. These results indicate that TAK-438 exerts a more potent and longer-lasting inhibitory action on gastric acid secretion than either lansoprazole or SCH28080. TAK-438 is a novel antisecretory drug that may provide a new option for the patients with acid-related disease that is refractory to, or inadequately controlled by, treatment with PPIs.


Congestive Adenopathy: A Mediastinal Sequela of Volume Overload.
Endosonography has improved our ability to reach thoracic lymph nodes and to diagnose pathologic conditions with nodal involvement and has lowered the threshold for biopsy. The purpose of this study was to avoid unnecessary procedures, it is important to recognize benign adenopathy. Congestive heart failure (CHF) is both common and a common cause of adenopathy. The purpose of this study was to study the association between CHF and adenopathy and to describe the typical presentation of congestive adenopathy. We performed a retrospective correlation of computed tomographic (CT) and laboratory findings for patients admitted to hospital with a diagnosis of CHF. Of 500 patients admitted with a diagnosis of CHF, 215 appeared to have CT scans of the chest, and not to have a potentially confounding etiology of adenopathy. The incidence of adenopathy in this study group was 68%. Pulmonary edema on CT and pleural effusion were both significantly associated with adenopathy (P<0.01 for both). The pattern of congestive adenopathy was one of enlargement of several mediastinal nodes and less likely to involve hilar nodes and single stations in isolation. Congestive adenopathy is common in patients with evidence for acute volume overload. The pattern of presentation should allow clinicians to recognize congestive adenopathy and to separate it from other adenopathy for which biopsy might be appropriate.


Spin label studies in chlamydomonas.
When spin label is added to Chlamydomonas the organism is apparently unaffected, but the paramagnetic resonance signal of the spin label decreases. Irradiation with visible light greatly accelerates this decrease, which is partially reversible. If the cells are grown in the presence of the spin label and washed well, no spin label signal is detectable. However, such cells can no longer catalyze the destruction of added spin label in the light. This finding sug- gests that the molecule is bound to a specific site, which undergoes a change in conformation with illumination.


MDR and PRP: a comparison of methods for high-order genotype-phenotype associations.
Complex diseases such as cardiovascular disease are likely due to the effects of high-order interactions among multiple genes and demographic factors. Therefore, in order to understand their underlying biological mechanisms, we need to consider simultaneously the effects of genotypes across multiple loci. Statistical methods such as multifactor dimensionality reduction (MDR), the combinatorial partitioning method (CPM), recursive partitioning (RP), and patterning and recursive partitioning (PRP) are designed to uncover complex relationships without relying on a specific model for the interaction, and are therefore well-suited to this data setting. However, the theoretical overlap among these methods and their relative merits have not been well characterized. In this paper we demonstrate mathematically that MDR is a special case of RP in which (1) patterns are used as predictors (PRP), (2) tree growth is restricted to a single split, and (3) misclassification error is used as the measure of impurity. Both approaches are applied to a case-control study assessing the effect of eleven single nucleotide polymorphisms on coronary artery calcification in people at risk for cardiovascular disease.


Chicken vigilin gene: a distinctive pattern of hypersensitive sites is characteristic for its transcriptional activity.
Vigilin, a multidomain hn-ribonucleo-K-homologous protein, is part of a ribonucleoprotein complex with cognate tRNA and is found in both the nucleus and the cytoplasm. In an approach to identify genomic regions involved in regulation of the chicken vigilin gene, we carried out transfection studies with a reporter gene in suitable chicken cells. After including a distantly positioned 5'-sequence in the construct, we observed a 10.5-fold increase in luciferase (EC 1. 13.12.7) expression compared with basal promoter activity. Accordingly, chromatin analysis of freshly isolated embryonic tendon fibroblasts with high levels of vigilin mRNA expression shows a DNase-I-hypersensitive site (DHS1) localized 2.2 kb upstream of the transcriptional start site. Similarly, phytohaemagglutinin-stimulated lymphocytes with a 4-fold elevated expression of vigilin mRNA compared with resting lymphocytes also exhibited this unique DHS, having switched from that found at 3.3 kb (DHS2) in resting lymphocytes. Furthermore, using gel-retardation experiments with DNA representing either DHS1 or DHS2, a specific interaction with chicken nuclear extracts was seen.


How can NHS trusts in England optimise strategies to improve the mental health and well-being of hospital doctors? The Care Under Pressure 3 (CUP3) realist evaluation study protocol.
The growing incidence of mental ill health in doctors was a major issue in the UK and internationally, even prior to the COVID-19 pandemic. It has significant and far-reaching implications, including poor quality or inconsistent patient care, absenteeism, workforce attrition and retention issues, presenteeism, and increased risk of suicide. Existing approaches to workplace support do not take into account the individual, organisational and social factors contributing to mental ill health in doctors, nor how interventions/programmes might interact with each other within the workplace. The aim of this study is to work collaboratively with eight purposively selected National Health Service (NHS) trusts within England to develop an evidence-based implementation toolkit for all NHS trusts to reduce doctors' mental ill health and its impacts on the workforce. The project will incorporate three phases. Phase 1 develops a typology of interventions to reduce doctors' mental ill health. Phase 2 is a realist evaluation of the existing combinations of strategies being used by acute English healthcare trusts to reduce doctors' mental ill health (including preventative promotion of well-being), based on 160 interviews with key stakeholders. Phase 3 synthesises the insights gained through phases 1 and 2, to create an implementation toolkit that all UK healthcare trusts can use to optimise their strategies to reduce doctors' mental ill health and its impact on the workforce and patient care. Ethical approval has been granted for phase 2 of the project from the NHS Research Ethics Committee (REC reference number 22/WA/0352). As part of the conditions for our ethics approval, the sites included in our study will remain anonymous. To ensure the relevance of the study's outputs, we have planned a wide range of dissemination strategies: an implementation toolkit for healthcare leaders, service managers and doctors; conventional academic outputs such as journal manuscripts and conference presentations; plain English summaries; cartoons and animations; and a media engagement campaign.


Pindex: Private multi-linked index for encrypted document retrieval.
Cryptographic cloud storage is used to make optimal use of the cloud storage infrastructure to outsource sensitive and mission-critical data. The continuous growth of encrypted data outsourced to cloud storage requires continuous updating. Attacks like file-injection are reported to compromise confidentiality of the user as a consequence of information leakage during update. It is required that dynamic schemes provide forward privacy guarantees. Updates should not leak information to the untrusted server regarding the previously issued queries. Therefore, the challenge is to design an efficient searchable encryption scheme with dynamic updates and forward privacy guarantees. In this paper, a novel private multi-linked dynamic index for encrypted document retrieval namely Pindex is proposed. The multi-linked dynamic index is constructed using probabilistic homomorphic encryption mechanism and secret orthogonal vectors. Full security proofs for correctness and forward privacy in the random oracle model is provided. Experiments on real world Enron dataset demonstrates that our construction is practical and efficient. The security and performance analysis of Pindex shows that the dynamic multi-linked index guarantees forward privacy without significant loss of efficiency.


A Customized System to Test Pelvic Floor Muscles Contraction: A Proof of Concept.
Studies show that there is a high prevalence of pelvic floor dysfunctions which negatively affect the quality of life of people who suffer from them. The few sensory mechanisms that pelvic floor muscles have to inform the brain of their situation can make it difficult to perform voluntary contractions or identify risk factors. Currently, there is no consensus to improve this proprioception. This work introduces the development of a novel intravaginal device that is connected to a mobile data acquisition system and able to discern the correct contraction of the pelvic floor muscles versus contraction of adjacent muscles or abdominal thrust efforts. A cross-sectional pilot clinical study has been carried out to validate this end with healthy adult nulliparous woman with good pelvic floor muscles contraction capability in supine position.Clinical relevance- The proposed system allows a personalized and real-time assessment of the contractile capability of the pelvic floor muscles (PFM), distinguishing between muscular plans (deep/superficial PFM), between sides (right/left PFM), and between pressures from the PFM and intra-abdominal muscles (IAP). The development of an intravaginal device which is able to simultaneously measure all these features is an important advancement in this field since it can provide information in real time on the contraction capability of all the PFM as well as on the influence of the IAP during different PFM exercises.


HIV-1 drug resistance emergence among breastfeeding infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral prophylaxis for prevention of mother-to-child transmission: a secondary analysis.
Nevirapine and lamivudine given to mothers are transmitted to infants via breastfeeding in quantities sufficient to have biologic effects on the virus; this may lead to an increased risk of a breastfed infant's development of resistance to maternal antiretrovirals. The Kisumu Breastfeeding Study (KiBS), a single-arm open-label prevention of mother-to-child HIV transmission (PMTCT) trial, assessed the safety and efficacy of zidovudine, lamivudine, and either nevirapine or nelfinavir given to HIV-infected women from 34 wk gestation through 6 mo of breastfeeding. Here, we present findings from a KiBS trial secondary analysis that evaluated the emergence of maternal ARV-associated resistance among 32 HIV-infected breastfed infants. All infants in the cohort were tested for HIV infection using DNA PCR at multiple study visits during the 24 mo of the study, and plasma RNA viral load for all HIV-PCR-positive infants was evaluated retrospectively. Specimens from mothers and infants with viral load >1,000 copies/ml were tested for HIV drug resistance mutations. Overall, 32 infants were HIV infected by 24 mo of age, and of this group, 24 (75%) infants were HIV infected by 6 mo of age. Of the 24 infants infected by 6 mo, nine were born to mothers on a nelfinavir-based regimen, whereas the remaining 15 were born to mothers on a nevirapine-based regimen. All infants were also given single-dose nevirapine within 48 hours of birth. We detected genotypic resistance mutations in none of eight infants who were HIV-PCR positive by 2 wk of age (specimens from six infants were not amplifiable), for 30% (6/20) at 6 wk, 63% (14/22) positive at 14 wk, and 67% (16/24) at 6 mo post partum. Among the 16 infants with resistance mutations by 6 mo post partum, the common mutations were M184V and K103N, conferring resistance to lamivudine and nevirapine, respectively. Genotypic resistance was detected among 9/9 (100%) and 7/15 (47%) infected infants whose mothers were on nelfinavir and nevirapine, respectively. No mutations were detected among the eight infants infected after the breastfeeding period (age 6 mo). Emergence of HIV drug resistance mutations in HIV-infected infants occurred between 2 wk and 6 mo post partum, most likely because of exposure to maternal ARV drugs through breast milk. Our findings may impact the choice of regimen for ARV treatment of HIV-infected breastfeeding mothers and their infected infants.


Effect of oral administration of excessive iron in adult ponies.
To evaluate the potential of excess dietary iron to cause hepatic lesions similar to those described in horses with suspected iron toxicosis or hemochromatosis. Prospective study. 6 adult male ponies. 4 ponies received 50 mg of iron/kg (22.7 mg/lb) of body weight each day by oral administration of ferrous sulfate, which contained 20% elemental iron; 2 ponies received only the carrier (applesauce). Complete blood counts, serum biochemical analyses, and hepatic tissue biopsies were performed, and serum iron concentrations were measured. Blood and tissue samples were obtained at days 0 and 2, and at the end of weeks 1, 3, 6, and 8 after administration of iron was initiated. Treatment was discontinued after 8 weeks, and hepatic iron concentrations were measured at 28 weeks. Hepatic iron concentrations, serum iron concentrations, percentage saturation of transferrin, and serum ferritin concentrations were increased, compared with baseline and control concentrations, by week 8. Adverse clinical signs or histologic lesions in the liver were not detected in any ponies. At 28 weeks, hepatic iron concentrations had decreased. Histologic lesions were not seen in the hepatic biopsy specimens obtained from the ponies treated with ferrous sulfate. It was concluded that it would be unlikely for iron toxicosis to develop in adult ponies or horses during a period of < 8 weeks when food or water contained increased amounts of iron. It is suspected that previous reports of hepatopathies in animals with hemosiderin accumulation may represent a primary hepatopathy with secondary hemosiderin accumulation, especially if the only source of iron is via oral consumption.


The role of solvent structure in the absorption spectrum of solvated electrons: mixed quantum/classical simulations in tetrahydrofuran.
In polar fluids such as water and methanol, the peak of the solvated electron's absorption spectrum in the red has been assigned as a sum of transitions between an s-like ground state and three nearly degenerate p-like excited states bound in a quasispherical cavity. In contrast, in weakly polar solvents such as tetrahydrofuran (THF), the solvated electron has an absorption spectrum that peaks in the mid-infrared, but no definitive assignment has been offered about the origins of the spectrum or the underlying structure. In this paper, we present the results of adiabatic mixed quantum/classical molecular dynamic simulations of the solvated electron in THF, and provide a detailed explanation of the THF-solvated electron's absorption spectrum and electronic structure. Using a classical solvent model and a fully quantum mechanical excess electron, our simulations show that although the ground and first excited states are bound in a quasispherical cavity, a multitude of other, nearby solvent cavities support numerous, nearly degenerate, bound excited states that have little Franck-Condon overlap with the ground state. We show that these solvent cavities, which are partially polarized so that they act as electron trapping sites, are an inherent property of the way THF molecules pack in the liquid. The absorption spectrum is thus assigned to a sum of bound-to-bound transitions between a localized ground state and multiple disjoint excited states scattered throughout the fluid. Furthermore, we find that the usual spherical harmonic labels (e.g., s-like, p-like) are not good descriptors of the excited-state wave functions of the solvated electron in THF. Our observation of multiple disjoint excited states is consistent with femtosecond pump-probe experiments in the literature that suggest that photoexcitation of solvated electrons in THF causes them to relocalize into solvent cavities far from where they originated.


[Somatosensory evoked spikes and epileptiform activity in "normal" children].
Little is known about somatosensory evoked spikes (SES) in the EEG of normal children. We studied the occurrence of SES and spontaneous epileptiform activity (SEA) in 173 normal children ageg 7 to 11 years. During the EEG ten taps were applied to both hands and feet. The occurrence of high voltage potentials evoked by each stimulation of one or both heels or hands (SES) and the occurrence of SEA were evaluated. SEA was observed in four children (2.3 %): central/parietal spikes in two cases, generalized spike-and-wave in one, and parietal/midtemporal spikes in one case. A ten years old girl (0,58%) had SES on median parietal region by tapping the left foot. This EEG was otherwise normal. Our findings of SEA are similar to those obtained in other normal populations. SES can be observed in normal children. These SES suggest that we are dealing with an age-related functional phenomenon.


MicroRNAs: non coding pleiotropic factors in development, cancer prevention and treatment.
One of the most important advance obtained from transcriptome analysis in recent years is the discovery of a series of noncoding RNA (ncRNA) families, with regulatory roles in several biological processes, that are actively transcribed from the genome of many organisms. Among them microRNAs (miRNAs) are small regulatory, single-stranded, RNA molecules (19-25 nucleotides in length) that are generated from hairpin primary transcripts [1]. In the cytoplasm, the mature miRNA molecule, through a limited base-pairing complementary sequences interaction, destabilizes or blocks the translation of their phylogenetically conserved target mRNAs transcripts [2]. Following the identification of a functional miRNAs pathway in C. elegans, miRNAs contribution to development, cell fate determination and physiological tissue homeostasis in mammals has rapidly emerged [3]. MiRNAs exhibit a developmental stage- and tissue-specific expression pattern and are present in complex regulatory circuits to regulate stem cells function, tissue differentiation and maintenance of cell identity during embryogenesis and adult life [4]. Recently, the deregulation of miRNAs expression and activity has been correlated with the pathogenesis of various human diseases and cancer. In cancer, the loss of tumour suppressive miRNAs enhances the expression of target oncogenes, whereas increased expression of oncogenic miRNAs can repress target tumour suppressor genes [5, 6]. This new wealth of knowledge points to miRNAs as being novel cancer genes and biomarkers relevant to the pathogenesis, diagnosis and prognosis of disease that may be useful in the management of human cancer. Moreover, the localization of non-random chromosomal abnormalities and other types of genetic alterations at miRNA genomic regions observed in several types of cancer cells underline the contribution of the deregulation of miRNAs expression to malignancy processes [7]. Advances in expression technologies have facilitated the high-throughput analysis of small RNAs, identifying novel miRNAs and showing that these genes may be aberrantly expressed in various human tumors [8]. Hence, a new molecular taxonomy of human cancers based on miRNAs expression profiling has been proposed. Indeed, it was recently found that miRNAs profiles are more informative than messenger RNA profiles and could classify poorly differentiated tumors since they better reflect the developmental lineage and differentiation state of cancer. Different wide screening approaches performed to establish miRNAs expression profiles showed a unique miRNAs signature, relevant to the pathogenesis, diagnosis and prognosis of disease that may be useful in the management of human cancer. Summarizing, miRNAs expression and regulation are emerging in several normal and pathological processes ranging from the control of embryonic stem cell commitment to the deregulation of cell fate determination and the molecular pathogenesis of human cancer. The aim of this issue is to review the functional roles of microRNA pathways in the establishment and progression of human diseases with a particular attention to the identification of miRNAs signatures as innovative cancer biomarkers for the management and prevention of human cancers.


2016 revision of the WHO classification of lymphoid neoplasms.
The 2016 revision of the World Health Organization (WHO) classification of lymphoid neoplasms have been published in "Blood" as a review form. A major revision is being published that will be an update of the current fourth edition and not a truly new fifth edition. Because it is considered a part of the fourth edition, while some provisional entities will be promoted to definite entities and a small number of new provisional entities added, there will be no new definite entities. As with the 2001 and 2008 classifications, an all-important Clinical Advisory Committee meeting was held to obtain the advice and consent of clinical hematologists/oncologists and other physicians critical to the revision. The classification maintains the goals of helping to identify homogeneous groups of well-defined entities and facilitating the recognition of uncommon diseases that require further clarification. Some provisional or variant entities; EBV-positive large B-cell lymphoma, elderly and Pediatric follicular lymphoma focused on the age of onset, in situ lesions, and gray zone lymphomas, recognized in the 2008 WHO classification, were revised. This will review the major areas in mature B-cell lymphoid and mature T/NK-cell lymphoid neoplasms and Hodgkin lymphoma where changes from the 2008 WHO classification.


Efficacy and Safety of Escitalopram Oral Drops to Treat Major Depressive Disorder and Generalized Anxiety Disorder in Adolescent, Adult and Geriatric Patients: A Prospective Multicenter Observational Study in Pakistan.
Background Escitalopram is widely used for the management of the major depressive disorder and generalized anxiety disorder, but there is no to very limited data available regarding efficacy and safety in Pakistani patients. This study was conducted to evaluate the efficacy and safety of escitalopram oral drops to manage the major depressive disorder and generalized anxiety disorder in a local cluster within Pakistan. Methods This prospective multicenter observational study was conducted in the department of psychiatry from August 2018 - August 2019. Eighty-five patients meeting the selection criteria were included in the study. Adolescent, adult, and geriatric patients of either gender with generalized anxiety disorder having Hamilton Anxiety Rating Scale (HAM-A) rate ≥ 10 and major depressive disorder having Montgomery-Asberg Depression Rating Scale (MADRS) rate ≥ 7 or patients with co-morbid generalized anxiety disorder (GAD), major depressive disorder (MDD) were selected for the study. We are reporting patients' improvement from baseline, response rate, and remission rate. Data analysis is performed by using SPSS version 21 (IBM Inc, Armonk, USA). Results Among enrolled patients, 42 were adolescents, 22 were adults, and 21 were geriatric. The mean age of an adolescent, adult, and geriatric patients was 14.92 ± 2.04, 44.54 ± 12.08, and 64.61 ± 3.16 years, respectively. Among enrolled patients, the mean change in a total score of HAM-A for anxiety and MADRS for depression were -10.04 ± 4.32 and -17.67 ± 14.42, respectively. At the end of the study, the remission rate and response rate for depression were 82 % and 75%, respectively. Similarly, the remission rate and the response for anxiety were 76% and 81%, respectively. Mean HAM-A and MADRS scores were significantly improved for adolescent, adult, and geriatric patients. Adverse events were reported in eight (9.41%) patients with six having gastrointestinal (GI) disturbance and two having to worsen anxiety. All reported adverse events were of mild severity. Conclusion Escitalopram oral drops are found effective and tolerable in reducing both anxiety and depression over the duration of study in all age groups, including adolescents, adults, and geriatrics.


No evidence of flowering synchronization upon floral volatiles for a short lived annual plant species: revisiting an appealing hypothesis.
Self-incompatible plants require simultaneous flowering mates for crosspollination and reproduction. Though the presence of flowering conspecifics and pollination agents are important for reproductive success, so far no cues that signal the flowering state of potential mates have been identified. Here, we empirically tested the hypothesis that plant floral volatiles induce flowering synchrony among self-incompatible conspecifics by acceleration of flowering and flower opening rate of non-flowering conspecifics. We exposed Brassica rapa Maarssen, a self-incompatible, in rather dense patches growing annual, to (1) flowering or non-flowering conspecifics or to (2) floral volatiles of conspecifics by isolating plants in separate containers with a directional airflow. In the latter, odors emitted by non-flowering conspecifics were used as control. Date of first bud, duration of first flower bud, date of first flower, maximum number of open flowers and flower opening rate were not affected by the presence of conspecific flowering neighbors nor by floral volatiles directly. This study presents a compelling approach to empirically test the role of flower synchronization by floral volatiles and challenges the premises that are underlying this hypothesis. We argue that the life history of the plant as well as its interaction with pollinators and insect herbivores, as well as the distance over which volatiles may serve as synchronization cue, set constraints on the fitness benefits of synchronized flowering which needs to be taken into account when testing the role of floral volatiles in synchronized flowering.


Landscape movements of migratory birds and bats reveal an expanded scale of stopover.
Many species of birds and bats undertake seasonal migrations between breeding and over-wintering sites. En-route, migrants alternate periods of flight with time spent at stopover--the time and space where individuals rest and refuel for subsequent flights. We assessed the spatial scale of movements made by migrants during stopover by using an array of automated telemetry receivers with multiple antennae to track the daily location of individuals over a geographic area ~20 × 40 km. We tracked the movements of 322 individuals of seven migratory vertebrate species (5 passerines, 1 owl and 1 bat) during spring and fall migratory stopover on and adjacent to a large lake peninsula. Our results show that many individuals leaving their capture site relocate within the same landscape at some point during stopover, moving as much as 30 km distant from their site of initial capture. We show that many apparent nocturnal departures from stopover sites are not a resumption of migration in the strictest sense, but are instead relocations that represent continued stopover at a broader spatial scale.


Disarmed complaints: unpacking satisfaction with end-of-life care.
Difficult health care encounters often do not translate into expressions of dissatisfaction with care. This paper focuses on the 'non-expression' of dissatisfaction with care in the accounts of 12 people in Canada who provided care to a relative or friend who died of breast cancer. The analysis foregrounded in this paper began from the observation that as difficult health care experiences were elaborated, speakers located health professionals' actions in relation to various situational factors, including the fact of a (cancer) death and conditions of constraint in the health system. Set alongside these two realities, expressions of dissatisfaction tended to be disarmed. Results of this study suggest that the cost of articulating dissatisfaction with care is high where the cared-for person has died, and the perceived value of focusing on difficult experiences is low. Further, respondents in this study took the specificity of the situation and the setting into account in formulating beliefs about the care outcomes for which health professionals could be held responsible. When conditions in the health system and the disease process of advanced cancer were positioned in talk as 'ultimate limits' on health professionals' actions, perceived lapses in care were excused.


[Severe falciparum malaria treated with exchange transfusion].
Acute severe malaria can be seen at any Norwegian hospital. The prognosis of this serious disease depends on rapid and effective treatment. Two case reports of patients treated with exchange transfusions are presented. Two young Norwegian women travelled without adequate prophylaxis against malaria in South-East Asia and Central and Southern Africa respectively. A few days after leaving the endemic areas they got high fever, joint and muscular pain, and headache. In one of the patients the symptoms were interpreted as flu symptoms; one week later the patient was admitted to hospital suffering from severe malaria. The other patient was admitted to hospital on the day she returned to Norway, six days after getting febrile. Thin blood films showed Plasmodium falciparum, with 30% and 40-50% parasitaemia respectively. Both patients were icteric with thrombocytopenia and increased creatinine. The first patient had severe renal failure and signs of cerebral affection. She was treated with haemodialysis and exchange transfusions. The other patient was treated with exchange transfusions because of her high parasitaemia. Both patients made a complete recovery and were discharged after three and two weeks. Severe falciparum malaria is a condition with high case-fatality if diagnostics and treatment is not optimal. In especially severe cases, exchange transfusion may be lifesaving.


The peripheral chemoreflex: indefatigable guardian of fetal physiological adaptation to labour.
The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic-ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5-2 min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour.


Site-Specific and Stable Conjugation of the SARS-CoV-2 Receptor-Binding Domain to Liposomes in the Absence of Any Other Adjuvants Elicits Potent Neutralizing Antibodies in BALB/c Mice.
Understanding immune responses toward viral infection will be useful for potential therapeutic intervention and offer insights into the design of prophylactic vaccines. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. To understand the complex immune responses toward SARS-CoV-2 infection, here we developed a method to express and purify the recombinant and engineered viral receptor-binding domain (RBD) to more than 95% purity. We could encapsulate RNA molecules into the interior of a virion-sized liposome. We conjugated the purified RBD proteins onto the surface of the liposome in an orientation-specific manner with defined spatial densities. Both the encapsulation of RNAs and the chemical conjugation of the RBD protein on liposome surfaces were stable under physiologically relevant conditions. In contrast to soluble RBD proteins, a single injection of RBD-conjugated liposomes alone, in the absence of any other adjuvants, elicited RBD-specific B cell responses in BALB/c mice, and the resulting animal sera could potently neutralize HIV-1 pseudovirions that displayed the SARS-CoV-2 spike proteins. These results validate these supramolecular structures as a novel and effective tool to mimic the structure of enveloped viruses, the use of which will allow systematic dissection of the complex B cell responses to SARS-CoV-2 infection.


Distribution and number of gonadotrophic cells in the pituitary gland of prepubertal female rats.
The localization and number of LH- and FSH-containing cells (LH cells and FSH cells) in the pituitary gland of prepubertal female rats aged 5 micron, 10, 20, 25 and 30 days were determined by means of immunocytochemical light microscopy of 5 horizontal sections. Anti-rat LHbeta and anti-rat FSHbeta were used in combination with the unlabelled peroxidase-antiperoxidase method. The gonadotrophic cells were regularly distributed throughout the pars distalis but at 5 and 10 days of age few LH and FSH cells were found in lateral regions. The numbers of LH and FSH cells per pituitary gland increased with age. The number of LH cells per unit volume of pituitary tissue reached a maximum at 20 days; the number of FSH cells reached a maximum at 15 days and then decreased with increasing age. At all ages except 5 days more LH than FSH cells were counted per unit volume. Some cells reacting with both anti-rat LHbeta and anti-rat FSHbeta were detected. Comparison of the data obtained on the dynamics of cell number with data previously obtained on pituitary gonadotrophin content suggests that at successive prepubertal ages LH and FSH cells contain increasing amounts of their respective hormones.


The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration.
Nature exploits cage-like proteins for a variety of biological purposes, from molecular packaging and cargo delivery to catalysis. These cage-like proteins are of immense importance in nanomedicine due to their propensity to self-assemble from simple identical building blocks to highly ordered architecture and the design flexibility afforded by protein engineering. However, delivery of protein nanocages to the renal tubules remains a major challenge because of the glomerular filtration barrier, which effectively excludes conventional size nanocages. Here, we show that DNA-binding protein from starved cells (Dps) - the extremely small archaeal antioxidant nanocage - is able to cross the glomerular filtration barrier and is endocytosed by the renal proximal tubules. Using a model of endotoxemia, we present an example of the way in which proximal tubule-selective Dps nanocages can limit the degree of endotoxin-induced kidney injury. This was accomplished by amplifying the endogenous antioxidant property of Dps with addition of a dinuclear manganese cluster. Dps is the first-in-class protein cage nanoparticle that can be targeted to renal proximal tubules through glomerular filtration. In addition to its therapeutic potential, chemical and genetic engineering of Dps will offer a nanoplatform to advance our understanding of the physiology and pathophysiology of glomerular filtration and tubular endocytosis.