Acquired angioedema and Helicobacter pylori infection in a child.
We describe a 10-year-old boy with acquired Helicobacter pylori infection and simultaneous angioedema which is a rare but life-threatening condition. Our patient was hospitalised with generalised angioedema and severe circulatory shock due to extreme loss of fluids and proteins into interstitial tissues (weight gain 10 kg within 2 days, extreme haemoconcentration--haemoglobin 206 g/l, haematocrit 0.570, leucocytosis 18,300 /microl, high lactate 13.8 mmol/l) and simultaneous failure of the complement system (C3 <0.16 g/l, C4 <0.13 g/l, CH50 45 U/ml, i.e. 50% of normal value, C1 inhibitor 0.21 g/l at the lower limit). All possible known causes of angioedema were excluded (infection, allergy, auto-immune disease, NSAIDs, lymphoproliferative disease) except for the simultaneous H. pylori infection which was proven serologically and histologically. Eradication therapy led to a complete remission of the H. pylori infection. An absence of angioedema and the restoration of the complement system was later observed. To the best of our knowledge, no similar case report of a child has yet been published. Helicobacter pylori infection should be considered in the development of angioedema in childhood.


Erythropoietin and granulocyte colony-stimulating factor increase plasminogen activator inhibitor-1 release in HUVEC culture.
Recombinant human erythropoietin (rHuEPO) is considered to be a mitogenic and chemotactic agent in cultured endothelial cells (ECs). The effect of recombinant granulocyte-macrophage (rGM-CSF) and granulocyte (rG-CSF) colony-stimulating factors on the proliferation of human umbilical vein endothelial cells (HUVECs) has been controversial. HUVEC proliferation and the release of endothelial markers in HUVEC culture stimulated by rHuEPO, rGM-CSF and G-CSF were measured. We found the dose-dependent stimulating effect of rHuEPO and rGM-CSF on HUVEC proliferation, but we did not achieve this with rG-CSF. rHuEPO like rG-CSF was an effective agent in stimulating the plasminogen activator inhibitor (PAI)-1 release from HUVECs to a cultured medium, while rGM-CSF failed. We suggest that rHuEPO showed prothrombotic changes in HUVEC culture. Our results support the idea of suspected rHuEPO direct prothrombotic role in haemodialysed patients treated with rHuEPO.


Effects of a novel cardiotonic agent, Org 9731, on force and aequorin light transients in intact ventricular myocardium of the dog: involvement of a cyclic AMP-mediated mechanism and myofibrillar responsiveness to Ca2+ ions.
The action of a novel cardiotonic agent, Org 9731 (4-fluoro-N-hydroxy-5, 6-dimethoxy-benzo[b]thiophene-2-carboximidamide methanesulphonate), on intracellular aequorin light transients and isometric contractions was investigated in ventricular trabeculae isolated from dogs. The positive inotropic effect of Org 9731 at 3 microM and higher (up to 0.1 mM) was associated with an increase in the amplitude of the intracellular Ca2+ transient, but the effect of the compound at 0.3 and 1 mM was accompanied by a decrease of the transient. The maximum inotropic response to Org 9731 was approximately 70% of the maximum response to isoproterenol, while the maximum increase in the amplitude of Ca2+ transients produced by Org 9731 was about 30% of the maximum increase induced by isoproterenol. The duration of isometric contractions was prolonged by Org 9731 at 0.3 and 1 mM, with accompanying prolongation of the duration of light transients. The concentration-response curve for the positive inotropic effect of Org 9731 was markedly shifted by carbachol (3 microM), being moved to the right and downward, and the maximum response to Org 9731 was about 10% of that to isoproterenol in the presence of carbachol. Carbachol abolished the increase in the light transient and the accumulation of adenosine 3',5'-cyclic monophosphate (cyclic AMP) induced by Org 9731. These results indicate that Org 9731 increases cardiac contractility, mainly through the accumulation of cyclic AMP up to a concentration of 0.1 mM and also by increasing the responsiveness of myofibrils to Ca2+ ions at 0.3 mM and higher in association with the attenuation of Ca2+ transients. The structure-activity relationship implies that the introduction of a fluorine atom at position 4 of the benzothiophene ring of Org 30,029 attenuated its Ca(2+)-sensitizing action but markedly increased the activity of mechanisms dependent on cyclic AMP.


KCTD13-mediated ubiquitination and degradation of GluN1 regulates excitatory synaptic transmission and seizure susceptibility.
Temporal lobe epilepsy (TLE) is the most common and severe form of epilepsy in adults; however, its underlying pathomechanisms remain elusive. Dysregulation of ubiquitination is increasingly recognized to contribute to the development and maintenance of epilepsy. Herein, we observed for the first time that potassium channel tetramerization domain containing 13 (KCTD13) protein, a substrate-specific adapter for cullin3-based E3 ubiquitin ligase, was markedly down-regulated in the brain tissue of patients with TLE. In a TLE mouse model, the protein expression of KCTD13 dynamically changed during epileptogenesis. Knockdown of KCTD13 in the mouse hippocampus significantly enhanced seizure susceptibility and severity, whereas overexpression of KCTD13 showed the opposite effect. Mechanistically, GluN1, an obligatory subunit of N-methyl-D-aspartic acid receptors (NMDARs), was identified as a potential substrate protein of KCTD13. Further investigation revealed that KCTD13 facilitates lysine-48-linked polyubiquitination of GluN1 and its degradation through the ubiquitin-proteasome pathway. Besides, the lysine residue 860 of GluN1 is the main ubiquitin site. Importantly, dysregulation of KCTD13 affected membrane expression of glutamate receptors and impaired glutamate synaptic transmission. Systemic administration of the NMDAR inhibitor memantine significantly rescued the epileptic phenotype aggravated by KCTD13 knockdown. In conclusion, our results demonstrated an unrecognized pathway of KCTD13-GluN1 in epilepsy, suggesting KCTD13 as a potential neuroprotective therapeutic target for epilepsy.


L-serine deaminating enzymes in Escherichia coli crude extracts.
(a) The measured L-serine deaminating activity of a crude bacterial extract may originate from L-serine deaminase, from biosynthetic L-threonine deaminase, or from degradative L-serine deaminase. Nevertheless, the contribution of the individual enzymes can be determined.(b) About a half of the L-serine deaminating activity of wild type E. coli bacteria, grown in synthetic minimal medium, originates from L-serine deaminase and about half from biosynthetic L-threonine deaminase.(c) Ninety percent of L-serine deaminating activity of wild type E. coli bacteria, grown in yeast extract-tryptone medium, originates from L-serine deaminase, and the remainging ten percent from the degradative L-threonine deaminase.(d) Conditions have been established in which threonine deaminases are eliminated and the activity of L-serine deaminase alone could be measured, even in crude extracts.


Evaluation and Treatment of Foot Drop Using Nerve Transfer Techniques.
Foot drop represents a complex pathologic condition, requiring a multidisciplinary approach for appropriate evaluation and treatment. Multiple etiologic factors require recognition before considering invasive/operative intervention. When considering surgical management for the treatment of foot drop, it is first and foremost imperative to establish the cause of the condition. Not all causes resulting in clinical foot drop have surgical options. Establishing a cause allows the provider to more appropriately curtail a multidisciplinary approach to working-up, and ultimately, treating the patient. The authors offer an algorithm for evaluating and treating foot drop conditions associated with lumbar spine radiculopathy and peripheral nerve lesions.


Effect of arginine on gastrointestinal immunity during total parenteral nutrition.
It has been well recognized that the prolonged use of total parenteral nutrition (TPN) leads to intestinal immunodeficiency and bacterial translocation (BT). Arginine (ARG) is known to have immunostimulatory effects. But its effects on gut immunity are unknown. This experiment was designed to evaluate the effects of arginine on gut immunity during TPN. Male Sprague Dowley rats were randomized to three groups: group I (chow) was fed rat chow and water ad libitum, group II (TPN) received a standard formula of TPN and group III (TPN-ARG) received the same formula of TPN as group II with the amino acid composition containing 0.5% arginine. With the duration of TPN, the rates of BT increased and interleukin 2 (IL-2) production decreased in TPN group. The results in TPN-ARG group were partly reversed. When TPN was administered for 2 weeks, the rate of BT decreased significantly (P < 0.05) and IL-2 production increased markedly (P < 0.01) in the TPN-ARG group compared with those in the TPN group. Our results suggest that arginine can decrease BT and increase IL-2 production in rats during prolonged TPN.


Assessment of a Novel Urology Resident Simulation-Based Curriculum.
Interactive simulation training during residency is a rapidly growing initiative due to work-hour restrictions, improved simulation model fidelity and an evolving technological field. We designed and implemented a simulation curriculum for urology residents. The objective of this study was to assess its impact on trainee confidence and knowledge. This was a prospective nonblinded case series analyzing the use of simulation education with entrance and exit surveys. We developed and implemented monthly workshops featuring fundamental urological procedures and skills. Residents from a single academic urology residency program received didactic instruction as well as supervised simulation training from an expert faculty member. The majority of residents highly rated all topics and affirmed that they would repeat the simulation topic in the future. Overall, junior residents averaged a 27% gain in base knowledge (p <0.001), and senior residents reported a 15.5% gain in base knowledge (p <0.001). Didactic and mentored simulation portions of the sessions were considered equally valuable (p >0.5). Of the residents 84% felt the sessions better prepared them to be in the operating room and 94% reported that they would recommend the simulation sessions to a peer (p <0.001). Simulation is a valuable tool that prepares residents for operating room experiences. We have developed a robust simulation curriculum that serves as a feasible and valuable model for other training programs, and has led to increased resident confidence and knowledge in urological procedures and skills.


Pterygomaxillary separation in Le Fort I osteotomy UK OMFS consultant questionnaire survey.
Pterygomaxillary osteotomy or leverage alone is commonly used to achieve separation of the posterior maxilla from the pterygoid process in the Le Fort I osteotomy. An osteotomy of the tuberosity is less often used. No published data exist on the extent to which surgeons in the UK have adopted these techniques or on the incidence of technique-related vascular complications. We aimed to investigate techniques that are currently used for pterygomaxillary separation and maxillary mobilisation, and the incidence of serious vascular complications among orthognathic surgeons in the UK in 2004. A questionnaire was sent to 301 oral and maxillofacial (OMFS) consultant surgeons in the UK and 205 were returned (response rate 68%). Most of these surgeons (78%) reported that they use an osteotome or a micro-oscillating saw for pterygomaxillary separation. The others use leverage alone or osteotomy of the tuberosity. Eleven (8%) of the surgeons who use a pterygomaxillary osteotome reported that they had had a serious vascular complication in the past year. There were no vascular complications reported by surgeons who use leverage alone or osteotomy of the tuberosity.


Characteristics of hospital inpatient falls across clinical departments.
Hospital inpatient falls are common and may lead to injuries and prolonged hospitalization. Although hospital studies have reported overall fall rates and injuries associated with falls, few have addressed population characteristics and circumstances of falls across clinical departments within a hospital setting. To determine inpatient fall rates in an urban public hospital and to explore associated characteristics across clinical departments. The study was conducted in a 300-bed urban public hospital in Switzerland from 1999 to 2003. Patient data and data from the hospital's standardized fall reporting system on hospital inpatients' first falls, along with associated characteristics, across the departments of internal medicine, geriatrics and surgery, were analyzed. Descriptive statistics and statistical tests: chi(2) and ANOVA tests with multiple comparisons tests (post-hoc analysis) were used. Over this 5-year period, 34,972 patients were hospitalized (female 53.6%; mean age 67.3 +/- 19.3 years; mean length of stay 11.9 +/- 13.2 days) including 2,512 patients (7.5%) who experienced at least one fall during their hospitalization (geriatrics 24.8%; internal medicine 8.8%; surgery 1.9%). The fall rates per 1,000 patient (adjusted for age) days differed significantly between all of the departments (geriatrics 10.7; internal medicine 9.6; surgery: 3.2) (p < 0.001). Overall, 30.1% of the patients who fell experienced minor injuries and 5.1% major injuries. In geriatrics, fall-related circumstances such as transferring were more common (40.4%) than in medicine (33%) or surgery (30.4%) (p < 0.001), whereas falling out of bed was rarer (16.4%) (surgery 27.1%; internal medicine 20.5%) (p < 0.001). In addition, the prevalence of risk factors among patients who fell varied significantly among clinical departments, except for impaired cognition and narcotic use. In the hospital studied, inpatient falls are significantly more common in departments of geriatrics and internal medicine than in surgical departments. Fall rates, related injuries and circumstances of inpatient falls varied significantly among clinical departments, probably due to differences in patient characteristics. When monitoring falls, hospitals should therefore consider differences in characteristics associated with patient falls across clinical departments. High priorities should be allocated in view of identifying patients at risk of falling and implementing fall prevention strategies and interventions.


Fungal bioconversion of 2,4-dichlorophenoxyacetic acid (2,4-D) and 2,4-dichlorophenol (2,4-DCP).
Ninety strains of fungi from the collection of our mycology laboratory were tested in Galzy and Slonimski (GS) synthetic liquid medium for their ability to degrade the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and its by-product, 2,4-dichlorophenol (2,4-DCP) at 100 mg l(-1), each. Evolution of the amounts of each chemical in the culture media was monitored by HPLC. After 5 days of cultivation, the best results were obtained with Aspergillus penicilloides and Mortierella isabellina for 2,4-D and with Chrysosporium pannorum and Mucor genevensis for 2,4-DCP. The data collected seemed to prove, on one hand, that the strains responses varied with the taxonomic groups and the chemicals tested, and, on the other hand, that 2,4-D was less accessible to fungal degradation than 2,4-DCP. In each case, kinetics studies with the two most efficient strains revealed that there was a lag phase of 1 day before the onset of 2,4-D degradation, whereas there was none during 2,4-DCP degradation. Moreover, 2,4-DCP was detected transiently during 2,4-D degradation. Finally, M. isabellina improved its degradation potential in Tartaric Acid (TA) medium relative to GS and Malt Extract (ME) media.


Hygienic practices and acute respiratory illness in family and group day care homes.
To describe hygiene practices in licensed group day care and family day care homes and the association between these practices and the prevalence of respiratory illnesses in the children in attendance. Self-administered surveys were mailed to 137 group and 204 family day care providers. Wearing diapers and being younger than age three were associated with a higher frequency of respiratory illness. Children attending family day care homes had more respiratory illness than children attending group day care homes. Infrequent washing of children's or providers' hands after nose wiping, after diapering, before meals, and before food preparation was significantly associated with a higher frequency of respiratory illness. Use of shared cloth towels instead of individual paper towels and washing of sleeping mats less than once a week were also associated with a higher frequency of respiratory illness. The findings underscore the importance of handwashing and other hygiene practices in reducing the spread of disease in day care settings.


DNA hypermethylation and clinicopathological features in breast cancer: the Western New York Exposures and Breast Cancer (WEB) Study.
Aberrant DNA hypermethylation of gene promoter regions has been increasingly recognized as a common molecular alteration in carcinogenesis. We evaluated the association between major clinicopathological features and hypermethylation of genes in tumors among 803 incidence breast cancer cases from a large population-based case-control study conducted in Western New York State. DNA samples were isolated from archive paraffin embedded tumor tissue and were analyzed for hypermethylation status of the E-cadherin, p16, and RAR-beta(2) genes using real time methylation-specific polymerase chain reaction. The frequencies of hypermethylation were 20.0% for E-cadherin, 25.9% for p16, and 27.5% for RAR-beta(2) genes. For postmenopausal women, hypermethylation of E-cadherin tended to be more likely in progesterone receptor (PR) negative than in PR-positive tumors (odds ratio (OR), 1.41; 95% confidence interval (CI), 0.91-2.18). Hypermethylation of p16 tended to be more frequent among estrogen receptor (ER) negative cases than ER-positive cases (OR, 1.51; 95% CI, 1.01-2.32). Hypermethylation of RAR-beta(2) gene was inversely associated with histological and nuclear grade of breast cancer.


LIPRNAseq: a method to discover lipid interacting RNAs by sequencing.
Current biological research extensively describes the interactions of molecules such as RNA with other nucleic acids or proteins. However, the relatively recent discovery of nuclear phospholipids playing biologically relevant processes outside membranes, as well as, RNA-lipid interactions shows the need for new methods to explore the identity of these RNAs. In this study, we describe the method for LIPID-RNA isolation followed by sequencing and analysis of the RNA that has the ability to interact with the selected lipids. Here we utilized specific phospholipid coated beads for selective RNA binding. We tested RNA from organisms belonging to different realms (human, plant, and yeast), and tested their ability to bind a specific lipid. The results show several RNAs differentially enriched in the pull-down of phosphatidyl Inositol 4,5 bisphosphate coated beads. This method is helpful to screen lipid-binding RNA, which may have relevant biological functions. The method can be used with different lipids and comparison of pull-downs and can narrow the selection of RNAs that interact with a particular lipid for further studies.


Rehabilitative ultrasound imaging of the supraspinatus muscle: Intra- and interrater reliability of thickness and cross-sectional area.
To examine intra- and interrater reliability of thickness and cross-sectional area (CSA) measurements of the supraspinatus muscle using rehabilitative ultrasound imaging (RUSI). Two physical therapists acquired b-mode images of the supraspinatus muscles in twenty-five healthy subjects. Thickness and CSA were measured. Intra- and interrater reliability were examined. Intrarater reliability for thickness was high, (ICC1.1 0.91) for rater 1 and (ICC1.1 0.92) for rater 2. Intrarater reliability for CSA was also high, (ICC1.1 0.90) for rater 1 and (ICC1.1 0.85) for rater 2. Interrater reliability for the thickness was high, (ICC3.1 0.86). For CSA, interrater reliability was moderate, (ICC3.1 0.70). Supraspinatus muscle thickness and CSA can be reliably measured by physical therapists in healthy subjects. These findings confirm that RUSI has an interesting potential for physiotherapy clinical practice, especially to assess morphometric changes in skeletal muscles. Further research is needed in subjects with shoulder disorders.


Calcium uptake into renal brush border membranes in vitamin B6 deficient rats.
The calcium uptake into renal brush border membrane vesicles, which has been purified from normal or vitamin B6 deficient rat renal cortex by calcium precipitation, was investigated. The values of Km and Vmax were determined to be 1.89 mM and 4.26 nmol of Ca2+/mg of protein per 20s in vitamin B6 deficient rats, respectively. This Vmax was lower than that of normal rats. The chemical compositions of renal brush border membranes did not display a difference in normal and vitamin B6 deficient rats. The amount of brush border membranes isolated from 1 gram of renal cortex in vitamin B6 deficient rats was less than in normal rats.


Mechanical properties of rat skeletal muscle after hind limb suspension.
It is clear that there are events which occur in response to neuromuscular activity that are essential to maintain normal muscle properties. Two factors though to influence muscle contractile properties are tension and electrical activity. To study these variables the hind limbs of 10 postpubertal female Sprague-Dawley rats were prevented from supporting the weight of the body for 4 weeks, then in situ isometric properties were determined and compared with 10 age-matched control rats. The soleus (slow plantarflexor), the medial gastrocnemius (fast plantarflexor), and the tibialis anterior (fast dorsiflexor) were studied. The suspended soleus wet weight was 42% lower and the maximum isometric twitch (Pt) and tetanic (P0) tensions were 62 and 69% lower respectively, than in the control rats. The suspended medial gastrocnemius was 18% lower in wet weight and 14 and 9% lower in P0 and Pt than the controls. No differences in wet weight, P0 or Pt were observed in tibialis anterior. Mean contraction time was 22% shorter in the soleus, 9% in the medial gastrocnemius, and unchanged in the tibialis anterior following suspension. Further, the percent of P0 attained during a 330-ms tetanus at 20 Hz was 15% lower in the suspended soleus and unchanged in the other two muscles. The fatigue index (ratio of tension after 2 min of stimulation at 40 Hz for 330 ms once per second to the maximum tension developed during the test) was unaffected by suspension in the soleus and tibialis anterior but was reduced from 49% to 36% in the medial gastrocnemius. The maximum rate of shortening of all three muscles was unaffected by suspension. These results indicate that suspension of the hind limbs selectively affects the mass and force-generating capabilities of the plantarflexors, particularly the predominantly slow soleus. In contrast, the fatigability of only the fast plantarflexor was increased whereas the slow plantarflexor was unaffected. These results, considered in light of collaborative studies, suggest that the chronic force-time levels in a muscle have an important influence on tension- and speed-related properties but not necessarily the fatigability of that muscle. Further, a marked difference in the sensitivity of the contractile elements of slow and fast muscle to this influence was evident.


Combining epidemiological data and whole genome sequencing to understand SARS-CoV-2 transmission dynamics in a large tertiary care hospital during the first COVID-19 wave in The Netherlands focusing on healthcare workers.
Healthcare facilities have been challenged by the risk of SARS-CoV-2 transmission between healthcare workers (HCW) and patients. During the first wave of the COVID-19 pandemic, infections among HCW were observed, questioning infection prevention and control (IPC) measures implemented at that time. This study aimed to identify nosocomial transmission routes of SARS-CoV-2 between HCW and patients in a tertiary care hospital. All SARS-CoV-2 PCR positive HCW and patients identified between 1 March and 19 May 2020, were included in the analysis. Epidemiological data were collected from patient files and HCW contact tracing interviews. Whole genome sequences of SARS-CoV-2 were generated using Nanopore sequencing (WGS). Epidemiological clusters were identified, whereafter WGS and epidemiological data were combined for re-evaluation of epidemiological clusters and identification of potential transmission clusters. HCW infections were further classified into categories based on the likelihood that the infection was acquired via nosocomial transmission. Secondary cases were defined as COVID-19 cases in our hospital, part of a transmission cluster, of which the index case was either a patient or HCW from our hospital. The study population consisted of 293 HCW and 245 patients. Epidemiological data revealed 36 potential epidemiological clusters, with an estimated 222 (75.7%) HCW as secondary cases. WGS results were available for 195 HCW (88.2%) and 20 patients (12.8%) who belonged to an epidemiological cluster. Re-evaluation of the epidemiological clusters, with the available WGS data identified 31 transmission clusters with 65 (29.4%) HCW as secondary cases. Transmission clusters were all part of 18 (50.0%) previously determined epidemiological clusters, demonstrating that several larger outbreaks actually consisted, of several smaller transmission clusters. A total of 21 (7.2%) HCW infections were classified as from confirmed nosocomial, of which 18 were acquired from another HCW and 3 from a patient. The majority of SARS-CoV-2 infections among HCW could be attributed to community-acquired infection. Infections among HCW that could be classified as due to nosocomial transmission, were mainly caused by HCW-to-HCW transmission rather than patient-to-HCW transmission. It is important to recognize the uncertainties of cluster analyses based solely on epidemiological data.


Atomistic insight into 2D COFs as antiviral agents against SARS-CoV-2.
The recent pandemic of COVID-19 has raised global health concerns. Preventing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) activity in the body is a very promising method to overcome the COVID-19 pandemic. One of the prevention methods is constraining the binding process among the human cell receptor-ACE2 and coronavirus spike protein. In the research done, the effect of deformation of the spike protein structure, due to the covalent organic frameworks (COFs), in reducing the interactions of ACE2 and the spike protein by the computational method was investigated. In this regard, atomic analysis of the interactions of ACE2 and the spike protein is provided using a molecular dynamics simulation. First, we investigated the interactions of the three different COFs, including COF-78, DAAQ-TFP, and COF-OEt, with the spike protein by analyzing the bond energies, as well as structural changes of the spike protein. Then, intermolecular interactions of the deformed spike protein along with ACE2 were assessed to clarify the protein's fusion after the deformation. As indicated by the results, although all introduced COFs deformed the spike protein in an effective way, COF-78 showed the best performance in the prevention of spike protein-ACE2 interactions by changing the molecular structure of the protein. Indeed, the interaction analysis of the deformed spike protein by COF-78 with the ACE2 showed that their interactions had the lowest absolute value of energy, along with the least amount of hydrogen bonds, in which the compaction of the protein was lower compared to the other deformed proteins. Moreover, having a high contact area with an aqueous media as well as severe fluctuations during the simulation time confirmed the positive performance of COF-78. In the current study, we aimed to introduce novel materials and COVID-19 prevention methodology that can be used in face masks and for surface disinfection.


Diagnosis and initial management of urological injuries associated with 200 consecutive pelvic fractures.
During 26 months 200 consecutive patients with fracture of the bony pelvis were evaluated and treated for urological injury. There was no correlation between the extent of pelvic injury and degree of hematuria but hematuria was present in all patients with a urological injury. All urological injuries occurred with anterior arch fractures. The over-all incidence of injury was 13.5 per cent (bladder 9 per cent, urethra 3.5 per cent and combined 1 per cent). Limited extraperitoneal bladder ruptures were treated successfully by Foley catheter drainage.


Computation of tactile object properties requires the integrity of praxic skills.
We describe a series of experiments to examine the tactile identification of objects over the course of neurological recovery in a patient with an intracerebral haemorrhage involving the left inferior and superior parietal lobe. Tactile agnosia in this case involved the ipsilesional as well as the contralesional hand, allowing us to observe the effects of dominant parietal lobe damage without the confounding effects of hemiparesis. The findings demonstrate that both apraxia and tactile apperceptive agnosia may result from a unilateral lesion involving the left parietal lobe. The findings further suggest that the computation of macro-geometrical and micro-geometrical tactile object properties is dissociable. Macro-geometrical tactile analysis depends on intact programming of exploratory hand movements, while the role of such movements in micro-geometrical analysis is less clear.


The need for speed: testing acceleration for estimating animal travel rates in terrestrial dead-reckoning systems.
Numerous methods are currently available to track animal movements. However, only one of these, dead-reckoning, has the capacity to provide continuous data for animal movements over fine scales. Dead-reckoning has been applied almost exclusively in the study of marine species, in part due to the difficulty of accurately measuring the speed of terrestrial species. In the present study we evaluate the use of accelerometers and a metric known as overall dynamic body acceleration (ODBA) as a proxy for the measurement of speed for use in dead-reckoning. Data were collated from previous studies, for 10 species locomoting on a treadmill and their ODBA measured by an attached data logger. All species except one showed a highly significant linear relationship between speed and ODBA; however, there was appreciable inter- and intra-specific variance in this relationship. ODBA was then used to estimate speed in a simple trial run of a dead-reckoning track. Estimating distance travelled using speed derived from prior calibration for ODBA resulted in appreciable errors. We describe a method by which these errors can be minimised, by periodic ground-truthing (e.g., by GPS or VHF telemetry) of the dead-reckoned track and adjusting the relationship between speed and ODBA until actual known positions and dead-reckoned positions accord.


Measuring the sense of self in brain-damaged patients: A STROBE-compliant article.
Recently, researchers have focused on the embodied sense of self (ESS), which consists of the minimal and narrative selves. Although a study demonstrated that the ESS is related to brain dysfunction empirically, the subjective aspects of the ESS, and a systematic approach to it, have not yet been examined in brain-damaged patients. To examine this, we measured the ESS of patients with brain tumors before and after awake craniotomy.A self-reported questionnaire called the Embodied Sense of Self Scale (ESSS) was used to measure the ESS in patients with brain tumors before and after surgery. For comparison, age-matched controls also completed the ESSS.The ESSS scores of the patients with brain tumors before surgery were higher than those of the controls and improved after surgery. Before surgery, patients with left hemispheric lesions had a poorer ESSS than those with right hemispheric lesions. Episodic memory disturbance was highly correlated with malfunction of narrative self and ownership.Brain lesions were associated with anomalous ESSS, associated with hemispheric laterality and cognitive dysfunction.


Successful treatment of ongoing intestinal allograft rejection permits recovery of graft structure and function.
Acute rejection episodes often complicate clinical small bowel transplantation, which prompted us to investigate whether such episodes can be reversed and the intestinal graft salvaged. Inbred Lewis rats that received fully allogeneic Brown-Norway small bowel allografts were treated with cyclosporin A (10 mg/kg) for 5 days, and the drug was then discontinued. Clinical and histologic signs of acute rejection developed, and the animals were subsequently treated with FK 506 (2 mg/kg) on days 14, 16, and 18. Survival was significantly prolonged (201.7 +/- 46.8 days) when compared with animals that were not administered FK 506 (16.5 +/- 0.8 days) or allograft recipients that received no immunosuppressive therapy (10.8 +/- 0.7 days). The histologic changes and functional impairment due to rejection that were observed prior to the start of the FK 506-therapy were reversed. However, biopsy specimens of all animals exhibited features of chronic rejection. This study provides evidence that acute rejection of intestinal allografts can be successfully treated with a short course of FK 506.


Distractions, analytical thinking and falling for fake news: A survey of psychological factors.
Analytical thinking safeguards us against believing or spreading fake news. In various forms, this common assumption has been reported, investigated, or implemented in fake news education programs. Some have associated this assumption with the inverse claim, that distractions from analytical thinking may render us vulnerable to believing or spreading fake news. This paper surveys the research done between 2016 and 2022 on psychological factors influencing one's susceptibility to believing or spreading fake news, considers which of the psychological factors are plausible distractors to one's exercise of analytical thinking, and discusses some implications of considering them as distractors to analytical thinking. From these, the paper draws five conclusions: (1) It is not analytical thinking per se, but analytical thinking directed to evaluating the truth that safeguards us from believing or spreading fake news. (2) While psychological factors can distract us from exercising analytical thinking and they can also distract us in exercising analytical thinking. (3) Whether a psychological factor functions as a distractor from analytical thinking or in analytical thinking may depend on contextual factors. (4) Measurements of analytical thinking may not indicate vulnerability to believing or spreading fake news. (5) The relevance of motivated reasoning to our tendency to believe fake news should not yet be dismissed. These findings may be useful to guide future research in the intersection of analytical thinking and susceptibility to believing or spreading fake news.


Placental weights from normal deliveries in Ireland.
The weight of the delivered placenta gives a useful representation of placental function in utero. In the absence of Irish data, many pathologists rely on data from other populations, many of which are now 15 to 30 years old. The development of a population-specific nomogram would aid in the examination of placentas after delivery, allowing pathologists and medical scientists to more easily distinguish between placental physiological changes and pathology. To record placental weights among women having a singleton delivery in Dublin and to establish median placental weights for each gestational age after 37 weeks. Prospective cohort study in a Tertiary level University Hospital. All singleton pregnancies were included; stillbirths, multiple gestations, and cases with obstetric complications involving the placenta were excluded. The placentas were weighed both untrimmed and trimmed with standard scales. Demographic features including birth weight and maternal parity were also recorded. Four hundred thirty placentas were weighed over a 6-week period. A median term placental weight based on gestational age was established, with a range from the tenth to ninetieth centiles. The weight of the placenta is one of several measurements that are easy to acquire, and when recorded in a systematic fashion, provide information not just on an individual, but also on a population basis. Birth weights have increased over the last century, and this study provides national data helping distinction between placental physiology and pathology.


Growth and spread of squamous cell carcinoma of the floor of the mouth.
Forty-eight specimens of carcinoma of the floor of the mouth were analyzed histologically by step serial sections. Five tumors were so-called superficial spreading carcinomas with large fields of cancerous mucosa, while 43 specimens showed advanced vertical growth into adjacent structures. Three different routes of invasion could be defined. The region of the sublingual gland was the main pathway in 23 cases. The space between the intrinsic muscles of the tongue and the genioglossus muscle was the main direction of infiltration for 14 tumors. Only 6 specimens showed direct invasion into the intrinsic tongue muscles. There was a good correlation between tumor thickness and the occurrence of metastases. Twenty-six patients (54%) showed metastases in regional lymph nodes and 13 patients with submandibular metastases already had developed metastases along the jugular vein. Unilateral or bilateral functional neck dissections remained the standard treatment procedure for all cases with depths of invasion over 5 mm. To avoid local tumor recurrences, patterns of invasion have to be considered. Soft tissue structures like the sublingual gland, intrinsic tongue muscles, genioglossus muscle and geniohyoid muscle have to be resected routinely. Management of the mandible should be conservative if radiological and clinical investigations are negative.


Transcriptomic analysis of epigenetic modification genes in the termite Reticulitermes speratus.
Eusocial insects display a caste system in which different castes are morphologically and physiologically specialized for different tasks. Recent studies have revealed that epigenetic modifications, including DNA methylation and histone modification, mediate caste determination and differentiation, longevity, and polyethism in eusocial insects. Although there has been a growing interest in the relationship between epigenetic mechanisms and phenotypic plasticity in termites, there is little information about differential expression levels among castes and expression sites for these genes in termites. Here we show royal-tissue-specific expression of epigenetic modification genes in the termite Reticulitermes speratus. Using RNA-seq, we identified 74 genes, including three DNA methyltransferases, seven sirtuins, 48 Trithorax group proteins, and 16 Polycomb group proteins. Among these genes, 15 showed king-specific expression, and 52 showed age-dependent differential expression in kings and queens. Quantitative real-time PCR revealed that DNA methyltransferase 3 is expressed specifically in the king's testis and fat body, whereas some histone modification genes are remarkably expressed in the king's testis and queen's ovary. These findings imply that epigenetic modification plays important roles in the gamete production process in termite kings and queens.


Physical activity and physical fitness in lymphoma patients before, during, and after chemotherapy: a prospective longitudinal study.
Fatigue is a common and distressing symptom in cancer patients, especially in lymphoma patients. One hypothesized mechanism in the etiology of fatigue is a vicious circle between fatigue, physical inactivity, and deconditioning. However, the natural evolution of physical activity and physical fitness over the course of treatment is unknown. Therefore, the aim of this longitudinal study was to assess fatigue, physical activity, and physical fitness in lymphoma patients before, during, and after treatment. Fatigue was measured with the EORTC-QLQ-C30, physical activity with an accelerometer, and physical fitness with a maximal incremental cycle ergometer test, 6-min walking distance test, and muscle strength measurements. Differences between the three measurement moments and baseline differences between Hodgkin lymphoma and non-Hodgkin lymphoma, early and advanced disease, were analyzed. Twenty-nine patients were included. Functional exercise capacity and quadriceps force were impaired before the start of treatment (86 ± 15 and 82 ± 16 % of predicted value, respectively). Over the course of treatment, significant declines were found in hemoglobin, quadriceps force, handgrip force, and maximal oxygen uptake, while patients reported more fatigue (p values < 0.016). Fatigue was significantly correlated with hemoglobin (r = -0.49), physical activity (r = 0.81), and physical functioning (r = -0.44). Large interindividual variations were found. The present study partially confirmed the hypothesized vicious circle between fatigue, physical inactivity, and deconditioning. Further research with larger samples and longer follow-up is needed to identify factors associated with individual variation in the evolution of fatigue, physical activity, and physical fitness.


Herring gull eggs as bioindicators for chlorinated hydrocarbons (contribution to the German Federal Environmental Specimen Bank).
From its position in the marine food chain, the herring gull (Larus argentatus) is a suitable indicator for the level of contamination of its habitats with lipophilic chemicals, especially the chlorinated hydrocarbons. The gull's utility as an indicator is demonstrated by investigations performed at Trischen island in the Elbe estuary and Alte Mellum island situated in the Weser estuary, when judged by their ability to reflect variations in pollution levels. The use of the analysis technique developed and standardized for the German Environmental Specimen Bank gives comparable results for both temporal and spatial variations for contamination levels on the different islands in the Wadden Sea area (North Sea coast) of Germany.


"I never really thought that a virtual ride would be that good!": Experiences of participants with disabilities in online leisure-time physical activity during COVID-19.
The COVID-19 pandemic has exacerbated the sedentary behavior and inactivity of people, including individuals with disability, who were already less active than their able-bodied counterparts. Therefore, it is particularly important to think about how to maintain and increase their leisure-time physical activity (LTPA). Online adaptive programs may represent a useful tool to do so. However, there is a little research focused on the health impacts of online LTPA. This mixed-methods study aimed to explore the experiences of people with disabilities who participated in online adaptive LTPA along with the factors contributing to or limiting participation. First, semi-structured interviews were conducted with 10 individuals participating in online adaptive LTPA offered by a community organization. Based on these interviews, a survey was developed and completed by 104 participants. The results of the study suggested that people with disabilities can get a variety of physical and emotional health benefits when participating in adaptive online LTPA, including a strong social benefit. Staff attitude and knowledge as well as the staff's ability to adapt to participant needs played important roles in facilitating participation. Greater access to equipment was needed. This study offers insights into how online LTPA could support the health-promoting behavior of people with disabilities during the pandemic and beyond.


Elevated Urbanization-Driven Plant Accumulation of Metal(loid)s Including Arsenic Species and Assessment of the Kłodnica River Sediment Contamination.
The impact of water and bottom sediment pollution of a river subjected to a strong industrial anthropogenic pressure of metal(loid) (including arsenic and its species) accumulation in riverbank plants such as Solidago virgaurea L., Phragmites L. and Urtica dioica L. was investigated. The high-performance liquid chromatography-inductively coupled plasma-mass spectrometry (HPLC-ICP-MS) technique was used to study organic and inorganic arsenic species in selected plants and their response to heavy metal and arsenic contamination. The modified BCR extraction results showed that arsenic was mainly bound to the mobile reducible and organic-sulfide fractions in the Kłodnica River bottom sediments. Research has shown that the bottom sediments of the Kłodnica River are contaminated with metals, including Pb, Zn, Ni, As, and among arsenic species, the As(V) form dominated quantitatively, with its highest concentration being 49.3 mg kg-1 and the organic species occurred extremely rarely. The highest concentration of arsenic, among the tested plants, occurred in Phragmites communis L. The evaluation of the bottom sediment pollution was performed using Sb/As factor, geoaccumulation index (Igeo), enrichment factor (EF) and pollution load index (PLI). The ability of the plant to assimilate metals from the substrate was studied by calculation of the bioaccumulation factor (BAF). Values of the Igeo change in a wide range from class 1 (uncontaminated to moderately polluted for Cu and Zn) at the first sampling point, to 5 (highly to extremely polluted for Ba and Fe) at the K4 sampling point. The Igeo results show an increase in the contamination with elements toward the runoff of the Kłodnica River.


Leiomyoma of the tunica albuginea in a horse.
A leiomyoma of the left testicle was found in a 7-year-old Arabian stallion at routine castration. The neoplasm consisted of interlacing bundles of well-differentiated, haphazardly arranged, smooth muscle cells attached superficially to the tunica albuginea.


Bacterial contamination of saline nasal irrigations in children: An original research.
Microbiologic analysis of nasal saline irrigations (NSIs) used in hospitalized children was performed. Of 253 collected samples, 24.9% were positive, and the number of positive samples significantly increased over time (P < .001). Staphylococcus aureus was the most frequently detected bacterium (28.6%). None of the 118 patients who received NSIs developed a nasosinusal infection. Colonization by cutaneous and environmental germs is frequent and develops early. Hygienic measures should be advocated to reduce contamination.


No evidence of hematopoietic stem cell mobilization in patients submitted to hepatectomy or in patients with acute on chronic liver failure.
Liver regeneration is a heterogeneous phenomenon involving the proliferation of different cell lineages in response to injury. Under a strong positive selection pressure bone marrow derived stem cells may be involved in this process, by making a contribution to both parenchymal restoration and endothelial cell replacement. We investigate bone marrow stem cell migration to the liver in patients undergoing hepatectomy or with acute on chronic liver failure. We enrolled 6 patients submitted to hepatectomy, 6 patients to cholecystectomy and 8 patients with acute decompensation of liver cirrhosis. Mobilization of CD34+ cells was evaluated by cytofluorimetry on peripheral blood samples at different time points; baseline, 1, 3, 7, 15 and 30 days after surgery and at admission, 1, 7 and discharge among patients with acute on chronic liver failure. 10 healthy subjects undergoing blood donation were also enrolled to evaluated the basal value of CD34+ cells. White blood cell counts remained in the normal range (4.1-9.8 x 10(9)/L) in all groups throughout the follow-up. In all patients of Groups 1, 2 and 3, circulating CD34+ failed to show statistically significant differences both as the absolute number and as the percentage at any time point compared to healthy controls. Bone marrow derived cell mobilization can not be detected after hepatectomy or during an acute decompensation on a cirrhotic liver. Under these circumstances liver regeneration can probably call upon mature hepatocytes and endogenous progenitor cells. The involvement of extrahepatic progenitors if any, is a rare and limited phenomenon.


Indwelling double-pigtail plastic stents for treating disconnected pancreatic duct syndrome-associated peripancreatic fluid collections: long-term safety and efficacy.
Long-term transmural double-pigtail stent (DPS) placement is recommended for patients with disconnected pancreatic duct syndrome (DPDS) and peripancreatic fluid collections (peri-PFCs). The long-term safety and efficacy of indwelling DPSs were evaluated. Medical files of patients treated with DPS for DPDS-associated peri-PFC and with a follow-up ≥ 48 months were reviewed. Early ( < 30 days) and late complications of DPS placement were evaluated and the primary endpoint, i. e., incidence of late complications per 100 patient-years of follow-up, was calculated. Short- and long-term success rates of endoscopic treatment and rate of peri-PFC recurrence were among secondary endpoints. From 2002 to 2014 we identified 116 patients, with mean (SD) follow-up of 80.6 (34.4) months. Among early complications (n = 20), 6 occurred peri-interventionally. Late complications (n = 17) were mainly pain due to DPS-induced ulcer or erosion (n = 10) and 14 of these were treated conservatively or by stent removal; 2 gastro-pancreatico-colo-cutaneous fistulas and 1 persisting bleed required surgical intervention. No DPS-related deaths were recorded. The incidence rate (95 %CI) of late complications was 2.18 (1.27-3.49) per 100 patient-years of follow-up. Short- and long-term success rates (with 95 %CI) of endoscopic treatment were 97.4 % (94.5 %-100 %) and 94 % (89.6 %-98.3 %), respectively. The peri-PFC recurrence rate was 28 % (20.1 %-35.9 %), and 92.3 % of these occurred within the first 2 years. Stent migration, chronic pancreatitis, and length of stent (> 6 cm) were independently associated with higher rates of peri-PFC recurrence. Long-term transmural drainage with DPS is a safe and effective treatment for DPDS-associated peri-PFCs. However, about one quarter of peri-PFCs will recur.


The new enhancement technologies and the place of vulnerability in our lives.
What is the place of vulnerability in our lives? The current debate about the ethics of enhancement technologies provides a context in which to think about this question. In my view, the current debate is likely to be fruitless, largely because we bring the wrong ethical resources to bear on its questions. In this article, I recall an important, but currently neglected, role that moral concepts play in our thinking, a role they should especially play in relation to the introduction of new technologies. I call this the 'contemplative role of moral concepts'. I then contrast two approaches to the contemplative role of moral concepts which are found in the current literature, and show why it is important to keep in mind both of these approaches when thinking about human vulnerability.


Identification of histidine residues at the active site of Megalobatrachus japonicus alkaline phosphatase by chemical modification.
Alkaline phosphatase from Megalobatrachus japonicus was inactivated by diethyl pyrocarbonate (DEP). The inactivation followed pseudo-first-order kinetics with a second-order rate constant of 176 M(-1) x min(-1) at pH 6.2 and 25 degrees C. The loss of enzyme activity was accompanied with an increase in absorbance at 242 nm and the inactivated enzyme was re-activated by hydroxylamine, indicating the modification of histidine residues. This conclusion was also confirmed by the pH profiles of inactivation, which showed the involvement of a residue with pK(a) of 6.6. The presence of glycerol 3-phosphate, AMP and phosphate protected the enzyme against inactivation. The results revealed that the histidine residues modified by DEP were located at the active site. Spectrophotometric quantification of modified residues showed that modification of two histidine residues per active site led to complete inactivation, but kinetic stoichiometry indicated that one molecule of modifier reacted with one active site during inactivation, probably suggesting that two essential histidine residues per active site are necessary for complete activity whereas modification of a single histidine residue per active site is enough to result in inactivation.


Electrochemical sensor for sensitive nitrite and sulfite detection in milk based on acid-treated Fe3O4@SiO2 nanoparticles.
In this work, a simple electrochemical sensing platform based on acid-treated Fe3O4@SiO2 nanoparticles was successfully prepared for nitrite and sulfite detection. Fe3O4@SiO2 nanoparticles were synthesized through the sol-gel and hydrothermal methods. Fe3O4@SiO2 presented positive charges after acid treatment, which could enhance the electrostatic attraction between Fe3O4@SiO2 and nitrite and sulfite. The Fe3O4@SiO2(acid-treated) modified magnetic glassy carbon electrode (MGCE) was applied to detect nitrite and sulfite using differential pulse voltammetry and cyclic voltammetry. Under optimized conditions, the developed electrochemical sensor presented good analytical properties for nitrite and sulfite detection with detection limits of 3.33 μmol/L and 31.57 μmol/L, respectively. The good recoveries varied from 85.18% to 111.02%, with a relative standard deviation of 0.23-4.80%. Furthermore, the Fe3O4@SiO2(acid-treated) modified MGCE showed better selectivity, reproducibility, and repeatability in nitrite and sulfite detection. Therefore, this proposed electrochemical sensor provides a new method for developing a nitrite and sulfite detection sensor.


Double Columellar Strut: A New Method for Tip Surgery-A Study of 642 Cases with a 15-Year Follow-up.
Of the first nasal tip modeling procedures performed, the Anderson tripod concept is the most well known, and many anatomy-related studies have analyzed the components involved in tip surgery. The main goals of nasal tip surgery are to stabilize the tip complex, which largely affects the shape, projection and rotation of the nasal tip. The present study describes a new, original method, the double columellar strut and its main advantages compared to conventional techniques used for structural rhinoplasty. The study involved 642 patients (496 women and 146 men, with an average age of 38.67 years) who underwent surgery between 2004 and 2018 by two operators. The patients were re-examined to evaluate the outcomes at least 1 year after surgery, and long-term results (15 years) were recorded for the oldest patients in regard to esthetics (projection, shape, rotation) and breathing function. Of the 642 patients, 34 required a surgical revision for minor defects of the tip due to asymmetry, and the natural appearance after the first surgery was not affected. For the primary rhinoplasties, there were no breathing disorders that required revision surgery due to systematic restoration or preservation of the middle third. The double columellar strut could be performed in the same conditions that the others conventional structural grafts. As a polyvalent alternative, it can be used with closed or open approaches and involves the use of only a limited amount of cartilaginous material. This anatomical approach yields natural results, acting as a foundation for controlling the shape, projection and rotation of the nasal tip. In addition, with or without complementary techniques such as the "tongue-in-groove" technique or tip grafts, the double columellar strut can be considered a "multifunction pocket knife" for tip surgery. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .


[Depression common among young people with somatic disorders. Fatigue, lack of emotional engagement, increased need of sleep are some of the warning signals].
During Depression Screening Day in Uppsala, Sweden, 127 adolescents, 23 boys and 104 girls, in the ages 13-20 years were investigated. We found that 44 (34.6%) fulfilled the criteria for a major depression according to DSM-IV criteria and 42 (40.4%) of the girls and 2 (9.5%) of the boys had an ongoing depression. All depressive symptoms, except increased appetite, were significantly more common in the depressed as compared to the non-depressed adolescents. The most common symptoms were fatigue, decreased interest and concentration difficulties. When the adolescents with major depression were compared to adults with major depression, rated by means of self-rating with the Montgomery Asberg Depression Rating Scale, depressions among adolescents and adults were very similar. However, sleep disturbances and decreased initiative were less frequent among the adolescents while decreased appetite was more common. Many of the patients with major depression found had mild symptoms but 21 (44.7%) were regarded being in need for medical treatment.


Comprehensive characterization of the patient-derived xenograft and the paralleled primary hepatocellular carcinoma cell line.
Hepatocellular carcinoma (HCC) is an aggressive cancer with high mortality and morbidity worldwide. The limited clinically relevant model has impeded the development of effective HCC treatment strategy. Patient-derived xenograft (PDX) models retain most of the characteristics of original tumors and were shown to be highly predictive for clinical outcomes. Notably, primary cell line models allow in-depth molecular characterization and high-throughput analysis. Combined usage of the two models would provide an excellent tool for systematic study of therapeutic strategies. Here, we comprehensively characterized the novel PDX and the paralleled primary HCC cell line model. Tumor tissues were collected from HCC surgical specimens. HCC cells were sorted for in vivo PDX and in vitro cell line establishment by the expression of hepatic cancer stem cell marker to enhance cell viability and the rate of success on subsequent culture. The PDX and its matching primary cell line were authenticated and characterized in vitro and in vivo. Among the successful cases for generating PDXs and primary cells, HCC40 is capable for both PDX and primary cell line establishment, which were then further characterized. The novel HCC40-PDX and HCC40-CL exhibited consistent phenotypic characteristics as the original tumor in terms of HBV protein and AFP expressions. In common with HCC40-PDX, HCC40-CL was tumorigenic in immunocompromised mice. The migration ability in vitro and metastatic properties in vivo echoed the clinical feature of venous infiltration. Genetic profiling by short tandem repeat analysis and p53 mutation pattern consolidated that both the HCC40-PDX and HCC40-CL models were derived from the HCC40 clinical specimen. The paralleled establishment of PDX and primary cell line would serve as useful models in comprehensive studies for HCC pathogenesis and therapeutics development for personalized treatment.


Freeze-fracture analysis of structural reorganization during meiotic maturation in oocytes of Xenopus laevis.
During meiotic maturation, the cortex of oocytes of Xenopus laevis undergoes structural reorganization, visualized in this study by freeze-fracture electron microscopy. In the full-grown but immature oocyte, annulate lamellae are dispersed throughout the subcortex of the egg, 5 to 20 micron from the plasma membrane. The annulate lamellae consist of well-organized stacks of membrane with visible pores. Stimulation of meiotic maturation by progesterone leads to disruption of the annulate lamellae and formation of an elaborate cortical endoplasmic reticulum which surrounds the cortical granules and intertwines throughout the cortex of the mature egg. Pore-like structures similar to those previously observed in the subcortical annulate lamellae are observed in the mature cortical endoplasmic reticulum. The cortical endoplasmic reticulum is often in close apposition with the plasma membrane and with membranes of cortical granules, but no junctions are visualized. This study provides further evidence that the cortical endoplasmic reticulum develops during progesterone-stimulated meiotic maturation in vitro, and that the annulate lamellae are precursors to the cortical endoplasmic reticulum.


Autoantibodies with beta-adrenergic activity from chronic chagasic patients induce cardiac arrhythmias and early afterdepolarization in a drug-induced LQT2 rabbit hearts.
Cardiac arrhythmias are one of the main causes of death in ChCP and other dilated cardiomyopathies. Previous studies demonstrated that ventricular arrhythmias are associated with the presence of autoantibodies with beta-adrenergic activity, Ab-β. The aim of this study was to investigate whether Ab-β, present in chronic chagasic patients (ChCP), induce cardiac arrhythmias in the pharmacological type-2 long QT syndrome model (LQTS-2). The LQTS2 was established by perfusion of Tyrode saline solution with a potassium channel blocker E-4031 (5μM) in isolated rabbit hearts or in rabbit cardiac strips, in order to record ECG or action potential, respectively. Autoantibodies from ChCP activating (Ab-β) or not (Ab-NR) cardiac beta 1-adrenergic receptors were used. Ab-β, but not Ab-NR, were able to significantly shorten QT, QTc and increase Tpeak-Tend interval in the LQTS-2. A positive correlation between higher QTc and Tpeak-Tend was found after Ab-β perfusion in the same model. In addition, in the LQTS-2 model, in almost 75% (11/15) of the hearts perfused with Ab-β, ventricular and atrio-ventricular electrical disturbances were observed. Atenolol abolished all Ab-β-induced arrhythmias. Ab-β, when perfused in a cellular LQTS-2, drastically reduced the action potential duration and evoked early afterdepolarization (EAD's), while Ab-NR did not modulate the AP properties in the LQTS-2. The results indicate that Ab-β were able to induce cardiac arrhythmias and EAD's. This phenomenon can explain, at least in part, the cellular mechanism of Ab-β-induced arrhythmias. Furthermore, atenolol is effective for the treatment of Ab-β-induced arrhythmias.


Transduction mechanism involving the presynaptic adenosine receptor at mouse motor nerve terminals.
The inhibitory effect of 2-chloroadenosine on spontaneous quantal release of transmitter at the mouse neuromuscular junction was abolished after pretreating tissues either with pertussis toxin (PTX), or with H7, a protein kinase inhibitor. H7 alone caused a fall in miniature endplate potential (MEPP) frequency, but PTX did not. The results are consistent with the hypothesis that rates of neurotransmitter release are directly related to intraterminal cyclic AMP levels, and that these can be reduced by A1 adenosine receptor agonists through the mediation of a Gi protein.


Vascular remodeling and its role in the pathogenesis of ascites in fast growing commercial broilers.
This study examined the putative role of blood vessel pathology in the development of ascites in broilers. Major blood vessels (aorta, brachiocephalic arteries, pulmonary arteries, and vena cava) from normal commercial male broiler chickens, and broilers that developed congestive heart failure (CHF) with or without ascites were subjected to gross and microscopic examination. On cross-section, grossly, the arteries from normal broilers and those showing dilated cardiomyopathy without ascites appeared circular, with firm wall tone characteristic of the normal artery. In contrast, the arteries from ascitic broilers appeared flaccid and lacked elasticity, which was evidenced by collapsing, ellipsoid cross-sectional arterial lumen owing to the structural weakness of the arterial walls. Microscopically, ascitic broilers showed thinning or occasionally total loss of elastic elements in the arterial wall, and reduced network density of the structural matrix of the vascular wall, as well as increased thickness of fibers in vena cava. The structural changes seen in the major arteries from ascitic broilers are maladaptive, and as such would definitively impose an increased hemodynamic burden on the already failing heart pump. The changes in veins are indicative of pathological remodeling conducive to increased permeability of the vascular wall, particularly in the situation when a poorly distensible structure is further subjected to wall stress associated with increased pressure and volume overload. Taken together, increased hemodynamic burden and reduced structural density of the venous wall constitute conditions conducive for seepage and accumulation of ascitic fluid.


Genetic characterization of Trypanosoma brucei circulating in domestic animals of the Fontem sleeping sickness of Cameroon.
To improve our knowledge on the transmission dynamics of trypanosomes, Trypanosoma brucei was identified in domestic animals of the Fontem sleeping sickness focus of Cameroon and their genetic characterizations were performed using seven polymorphic microsatellite markers. About 397 domestic animals including 225 pigs, 87 goats, 65 sheep and 20 dogs were sampled. The card agglutination test for trypanosomiasis was positive for 254 (63.98%) animals while the parasitological examinations (thin blood film and capillary tube centrifugation) revealed 86 (21.66%) trypanosome infections. The PCR based method revealed 140 (35.26%) infections of trypanosomes of the subgenus Trypanozoon. The genetic characterization of these 140 positive samples revealed 89 different alleles: 82 in pigs, 72 in goat, 60 in sheep and 48 in dog. Whatever the microsatellite marker used, most of positive samples were amplified. However, the sensitivity (percentage of samples amplified for each marker) of these markers varies significantly between them (χ(2) = 120.32; P < 0.0001). This study showed a high level (80.00%) of mixed genotypes as well as a wide range of T. brucei genotypes circulating in domestic animals of the Fontem sleeping sickness focus of Cameroon. This indicates that several T. brucei genotypes can naturally be transmitted simultaneously to tsetse flies during a single blood meal.


Comparing the efficacy and tolerability of biologic therapies in psoriasis: an updated network meta-analysis.
The rapid expansion of psoriasis biologics has led to an urgent need to understand their relative efficacy and tolerability to inform treatment decisions better and, specifically, to inform guideline development. To update a 2017 meta-analysis on the comparative efficacy and tolerability of biologic treatments for psoriasis. We searched the MEDLINE, PubMed, Embase and Cochrane databases for randomized controlled trials (RCTs), published up to 7 September 2018, of 11 licensed, NICE-approved biologics targeting tumour necrosis factor (adalimumab, etanercept, infliximab, certolizumab pegol), interleukin (IL)-12/IL-23p40 (ustekinumab), IL-17A (secukinumab, ixekizumab), IL-17RA (brodalumab) and IL-23p19 (guselkumab, tildrakizumab, risankizumab). A frequentist network meta-analysis ascertained direct or indirect evidence comparing biologics with one another, methotrexate or placebo. This was combined with hierarchical cluster analyses to consider efficacy (≥ 90% improvement in Psoriasis Area and Severity Index (PASI 90) or Physician's Global Assessment 0 or 1; PASI 75; Dermatology Life Quality Index improvement) and tolerability (drug withdrawal due to adverse events) outcomes at 10-16 weeks, followed by assessments of study quality, heterogeneity and inconsistency. We identified 62 RCTs presenting data on direct comparisons (31 899 participants). All biologics were efficacious compared with placebo or methotrexate at 10-16 weeks. Hierarchical cluster analyses revealed that adalimumab, brodalumab, certolizumab pegol, guselkumab, risankizumab, secukinumab, tildrakizumab and ustekinumab were comparable with respect to high short-term efficacy and tolerability. Infliximab and ixekizumab clustered together, with high short-term efficacy but relatively lower tolerability than the other agents, although the number of drug withdrawal events across the network was low, so these findings should be treated with caution. Using our methodology we found that most biologics cluster together with respect to short-term efficacy and tolerability, and we did not identify any single agent as 'best'. These data need to be interpreted in the context of longer-term efficacy, effectiveness data, safety, posology and drug acquisition costs when making treatment decisions.


Prenatal development in greater mouse-eared bat, Myotis myotis (Borkhausen, 1797) (Chiroptera, Vespertilionidae).
Order Chiroptera is the second largest mammal group after rodents. An understanding of the development of the bats, which is a very special mammal group in terms of their lifestyles, morphology and their ability to fly, is very important because most of the adult anatomical differences characterizing species occur during organogenesis. In this study, developmental stages were determined for Myotis myotis species based on external morphological characteristics from embryos obtained from wild-caught pregnant females. The developmental stages of M. myotis were comparable with those of other bat species.


Emotional enhancement of perceptual priming is preserved in aging and early-stage Alzheimer's disease.
Perceptual priming for emotionally-negative and neutral scenes was tested in early-stage Alzheimer's disease (AD) patients and healthy younger, middle-aged and older adults. In the study phase, participants rated the scenes for their arousal properties. In the test phase, studied and novel scenes were initially presented subliminally, and the exposure duration was gradually increased until a valence categorization was made. The difference in exposure duration required to categorize novel versus studied items was the dependent measure of priming. Aversive content increased the magnitude of priming, an effect that was preserved in healthy aging and AD. Results from an immediate recognition memory test showed that the priming effects could not be attributable to enhanced explicit memory for the aversive scenes. These findings implicate a dissociation between the modulatory effect of emotion across implicit and explicit forms of memory in aging and early-stage AD.


Treatment for School-Age Children Who Stutter: A Systematic Review of Japanese Literature.
This systematic review identified and synthesized published research articles, written in Japanese, on the clinical effectiveness of a broad range of nonpharmacological interventions for school-age children who stutter. A systematic review of Japanese literature published between January 1, 1980, and July 7, 2020, reporting interventions for school-age children who stutter, was carried out through a search of two databases (CiNii Article database and Japan Medical Abstract Society database) using the key words "stuttering" and "school-age" or "child" or "primary school students" or "children" or "school child" in Japanese. To be included in the review, the articles must report studies where data were subjectively reported by clinicians, where school-age participants were treated for developmental stuttering, where participants received interventions conducted by clinicians, and where quantitative outcomes (pre- and/or posttreatment) were measured; and they must be published in Japanese. Forty articles met all the inclusion criteria. Most articles adopted a case series or single-case study design. A total of 179 intervention programs were identified from all the articles and broadly classified into speech therapy, psychological therapy, interventions for modifying the child's environment, and others. Our systematic review provided a broad overview of the treatments used for school-age children who stutter in Japan. Future research should focus on gathering more reliable, systematic, and rigorous evidence to establish the effectiveness of stuttering treatments for school-age children and thereby develop evidence-based practices.


Urethra-inspired biomimetic scaffold: A therapeutic strategy to promote angiogenesis for urethral regeneration in a rabbit model.
Limited angiogenesis and epithelialization make urethral regeneration using conventional tissue-engineered grafts a great challenge. Consequently, inspired from the native urethra, bacterial cellulose (BC) and bladder acellular matrix (BAM) were combined to design a three dimensional (3D) biomimetic scaffold. The developed BC/BAM scaffold was engineered for accelerating urethral regeneration by enhancing angiogenesis and epithelialization. The BC/BAM scaffold reveals the closest mimic of native urethra in terms of the 3D porous nanofibrous structure and component including collagen, glycosaminoglycans, and intrinsic vascular endothelial growth factor (VEGF). In vitro studies showed that the bioinspired BC/BAM scaffold promoted in vitro angiogenesis by facilitating human umbilical vein endothelial cells (HUVECs) growth, expression of endothelial function related proteins and capillary-like tube formation. Effect of the BC/BAM scaffold on angiogenesis and epithelialization was studied by its implantation in a rabbit urethral defect model for 1 and 3 months. Results demonstrated that the improved blood vessels formation in the urethra-inspired BC/BAM scaffold significantly promoted epithelialization and accelerated urethral regeneration. The urethra-inspired BC/BAM scaffold provides us a new design approach to construct grafts for urethral regeneration. STATEMENT OF SIGNIFICANCE: Findings in urethral regeneration demonstrate that an ideal tissue-engineered urethra should have adequate angiogenesis to support epithelialization for urethral regeneration in vivo. In this study, inspired from the native urethra, a bioinspired bacterial cellulose/bladder acellular matrix (BC/BAM) scaffold was developed to promote angiogenesis and epithelialization. The designed scaffold showed the closest physical structure and component to natural urethra, which is beneficial to angiogenesis and regeneration of urethral epithelium. This is the first time to utilize BC and dissolved BAM to develop biomimetic scaffold in urethral tissue engineering. Our biomimetic strategy on urethra graft design provided enhanced angiogenesis and epithelialization to achieve an accelerated and successful rabbit urethral repair. We believe that our urethra-inspired biomimetic scaffold would provide new insights into the design of urethral tissue engineering grafts.


An observational study of once-daily modified-release methylphenidate in ADHD: the effect of previous treatment on ADHD symptoms, other externalising symptoms and quality-of-life outcomes.
Methylphenidate (MPH) is the most commonly prescribed stimulant for children with ADHD. Data on the effects of different MPH formulations in real-life settings are scarce, and the role of previous therapy on treatment outcome when switching medications has not been well studied. OBSEER was an observational study designed to evaluate the effectiveness and safety of Equasym XL(®) in routine care. This study assessed whether the improvements reported with Equasym XL(®) are influenced by the degree of symptom control achieved with the previous medication. Patients enrolled in OBSEER were stratified by prior treatment (none, MPH-immediate release [IR] once daily [o.d.] [MPH-IR o.d.], MPH-IR repeated [MPH-IR >o.d.] and MPH-MR [modified release] excluding Equasym XL(®)), and changes in ADHD and other externalising symptoms (CGI-S, FBB-ADHD and DAYAS) and quality of life (QoL, KINDL) were evaluated during treatment with Equasym XL(®). A total of 782 patients were analysed. Significant group-by-time interactions were found for all symptom variables analysed, indicating that effects varied by previous medication. For CGI-S and FBB-ADHD total scores, the greatest reductions in ADHD symptoms were observed in the treatment-naïve subgroup, followed (in order) by MPH-IR o.d., MPH-IR >o.d. and MPH-MR. A similar profile was seen for DAYAS ratings for all periods of the day except the evening, when there were no significant differences between subgroups. Similarly, the treatment-naïve and MPH-IR o.d. subgroups showed the greatest improvements in KINDL ratings. Although effects were greatest for treatment-naïve patients, improvements were also observed in the prior treatment subgroups for symptoms and QoL. This suggests that a change to Equasym XL(®) may be beneficial in patients with suboptimal effects on prior medication.


Electronic origin of disorder and diffusion at a molecule-metal interface: self-assembled monolayers of CH3S on Cu111.
The relationship between structure, interfacial electrostatics, bonding, and dynamics of organic molecules on metals is studied using a self-assembled monolayer of methylthiolate, CH3S, on Cu(111). The flat adsorption energy landscape of CH(3)S/Cu(111) results from metal-to-molecule charge redistribution which allows for a high mobility of CH3S. This contributes a nonuniform diffuse background to Bragg scattering, which needs to be considered in diffraction analyses. Ramifications on the interpretation of experimental data and the potential impact on the design of metal-organic interfaces are discussed.


Urology Patients and the Internet: Socioeconomic Status and Language Skills Significantly Impact Use.
Patient Internet use and resources are likely multifactorial. We assess how socioeconomic factors and language skills affect Internet use by patients. We prospectively surveyed 116 patients with a bilingual questionnaire before they underwent urological surgery from July to September 2013. We obtained institutional review board approval for this study. Patients were surveyed for demographic data, English abilities, Internet use, anxiety level and understanding of the surgery. Patients with low English abilities were significantly more likely to have lower incomes and education (p <0.05). In addition, patients with low English abilities were significantly more likely neither to have Internet access nor to have used it to research their surgery. On multivariate analysis those with low confidence in English were 2.8 times more likely not to have used the Internet to research their surgery when controlling for age. Increased age remained statistically associated with a lower likelihood of using the Internet even when controlling for all demographic data. Lastly, patients with low confidence in English were significantly less likely to report increased anxiety before surgery (OR 0.147) when controlling for all demographic data including ethnicity. In our community those patients with low confidence in their English abilities are less likely to have access to, and use, the Internet before undergoing surgery. Older patients also use the Internet less often. Urologists should be aware of this potential language and age gap. Those with low English skills should likely be provided with additional counseling.


Corticotomy facilitated orthodontics: Review of a technique.
Corticotomy found to be effective in accelerating orthodontic treatment. The most important factors in the success of this technique is proper case selection and careful surgical and orthodontic treatment. Corticotomy facilitated orthodontics advocated for comprehensive fixed orthodontic appliances in conjunction with full thickness flaps and labial and lingual corticotomies around teeth to be moved. Bone graft should be applied directly over the bone cuts and the flap sutured in place. Tooth movement should be initiated two weeks after the surgery, and every two weeks thereafter by activation of the orthodontic appliance. Orthodontic treatment time with this technique will be reduced to one-third the time of conventional orthodontics. Alveolar augmentation of labial and lingual cortical plates were used in an effort to enhance and strengthen the periodontium, reasoning that the addition of bone to alveolar housing of the teeth, using modern bone grafting techniques, ensures root coverage as the dental arch expanded. Corticotomy facilitated orthodontics is promising procedure but only few cases were reported in the literature. Controlled clinical and histological studies are needed to understand the biology of tooth movement with this procedure, the effect on teeth and bone, post-retention stability, measuring the volume of mature bone formation, and determining the status of the periodontium and roots after treatment.


Current genetic strategies to investigate gene functions in Trichoderma reesei.
The filamentous fungus Trichoderma reesei (teleomorph Hypocrea jecorina, Ascomycota) is a well-known lignocellulolytic enzymes-producing strain in industry. To increase the fermentation titer of lignocellulolytic enzymes, random mutagenesis and rational genetic engineering in T. reesei were carried out since it was initially found in the Solomon Islands during the Second World War. Especially the continuous exploration of the underlying regulatory network during (hemi)cellulase gene expression in the post-genome era provided various strategies to develop an efficient fungal cell factory for these enzymes' production. Meanwhile, T. reesei emerges competitiveness potential as a filamentous fungal chassis to produce proteins from other species (e.g., human albumin and interferon α-2b, SARS-CoV-2 N antigen) in virtue of the excellent expression and secretion system acquired during the studies about (hemi)cellulase production. However, all the achievements in high yield of (hemi)cellulases are impossible to finish without high-efficiency genetic strategies to analyze the proper functions of those genes involved in (hemi)cellulase gene expression or secretion. Here, we in detail summarize the current strategies employed to investigate gene functions in T. reesei. These strategies are supposed to be beneficial for extending the potential of T. reesei in prospective strain engineering.


Selection of patient for cardiac resynchronization therapy: role of QT corrected dispersion.
About 30 to 50% of patients undergoing cardiac resynchronization therapy (CRT) may not show clinical or echocardiographic improvement, despite fulfilling guidelines recommendations for CRT. For this reason, we need a more accurate method to assess CRT eligibility. The aims of this study were to verify, on a 12-month follow-up, the usefulness of QT corrected dispersion (QTcD) in a patient's selection for CRT. We stratified 53 patients who underwent CRT, into two groups based on the estimation of QTcD, that is, QTcD > 60 ms and QTcD ≤ 60 ms. In all patients were performed New York Heart Association (NYHA) class determination, six-minute walking test, QtcD, and QRS measurements, and complete echocardiographic assessment at 1, 3, 6, and 12 months after implantation. At baseline, there were no significant differences in clinical, echocardiographic, and electrocardiographic parameters duration between two groups. At 12-month follow-up between the two groups, there were significant differences in NYHA (1.2 ± 0.4 vs 2 ± 0.6; P < 0.01), six-minute walking distance (422 ± 68 vs 364 ± 68; P < 0.01), left ventricular (LV) ejection fraction (34 ± 7% vs 28 ± 6%; P < 0.01), LV end-diastolic diameter (57 ± 7 vs 63 ± 8; P < 0.01), and LV intraventricular dyssynchrony (24 ± 14 vs 39 ± 23; P < 0.01). This study suggests that QTc dispersion in addition to QRS duration could improve the sensitivity of electrocardiogram in a patient's selection for CRT.


KUS121, a VCP modulator, attenuates ischemic retinal cell death via suppressing endoplasmic reticulum stress.
Ischemic neural damages cause several devastating diseases, including brain stroke and ischemic retinopathies, and endoplasmic reticulum (ER) stress has been proposed to be the underlying mechanism of the neuronal cell death of these conditions. We previously synthesized Kyoto University substances (KUSs) as modulators of valosin-containing protein (VCP); KUSs inhibit VCP ATPase activity and protect cells from different cell death-inducing insults. Here, we examined the efficacy of KUS121 in a rat model of retinal ischemic injury. Systemic administration of KUS121 to rats with ischemic retinal injury significantly suppressed inner retinal thinning and death of retinal ganglion and amacrine cells, with a significant functional maintenance of visual functions, as judged by electroretinography. Furthermore, intravitreal injection of KUS121, which is the clinically preferred route of drug administration for retinal diseases, appeared to show an equal or better neuroprotective efficacy in the ischemic retina compared with systemic administration. Indeed, induction of the ER stress marker C/EBP homologous protein (CHOP) after the ischemic insult was significantly suppressed by KUS121 administration. Our study suggests VCP modulation by KUS as a promising novel therapeutic strategy for ischemic neuronal diseases.


[Congenital heart disease in adulthood].
While a few decades ago only a minority of patients, particularly of those with complex congenital heart disease, could reach adulthood, progress of pediatric cardiology and cardiac surgery allows now the survival of the majority. Thus, adult cardiology is faced with a new challenging patient population. Since only a few congenital heart defects can be cured, regular follow-up during adult life is of major importance. Residual as well as consequently developed lesions must be recognized. Optimal timing of surgery or catheter intervention is necessary to provide the best long-term outcome. Despite optimal treatment part of the patients will develop long-term complications such as arrhythmias, pulmonary hypertension and, eventually, heart failure. Acute complications such as arrhythmias, aortic dissection or rupture, endocarditis, cerebral events due to embolism, bleeding or abscesses, and pulmonary embolism or bleeding must be recognized early and treated appropriately. Management of noncardiac surgery, pregnancy and delivery can be challenging. Another task is counseling regarding exercise and sports, choice of profession, driving and insurance issues. Finally, psychosocial issues must be taken into account for appropriate care of this special patient group.


Ocular vestibular evoked myogenic potentials (OVEMPs) produced by impulsive transmastoid accelerations.
Recent work has demonstrated the existence of ocular vestibular evoked myogenic potentials (OVEMPs), which likely reflect projections underlying the translational vestibular ocular reflex (TVOR). We examined extraocular muscle activity associated with impulsive acceleration of the head in the transmastoid plane. Accelerometry was measured in 4 subjects in response to acceleration impulses produced by a gamma function delivered with a Minishaker (4810, Bruel & Kjaer). This stimulus produced peak head accelerations of 0.13-0.14 g occurring at between 3.1 and 4.0 ms at the mastoids for both right and left head movement. OVEMPs were recorded in 10 normal subjects with 5 directions of gaze, using electrode pairs placed lateral to, above and below the eyes. OVEMPs occurred at short latency, with initial peaks between 10.3 ms (p10) and 15.3 ms (n15). For a given recording site and gaze direction, the responses were determined solely by the direction of imposed acceleration. We propose that, given the transtemporal nature of the stimuli, utricular afferents are likely to be powerfully activated. The OVEMPs evoked may be generated by the lateral recti and oblique muscles. Sudden lateral accelerations of the head evoke the translational VOR and ocular counter rolling reflex and the pattern of muscle activations indicated by the OVEMPs appear to be a manifestation of these reflexes.


Implication of advanced glycation end products (Ages) and their receptor (Rage) on myocardial contractile and mitochondrial functions.
Advanced glycation end products (AGEs) play an important role for the development and/or progression of cardiovascular diseases, mainly through induction of oxidative stress and inflammation. AGEs are a heterogeneous group of molecules formed by non-enzymatic reaction of reducing sugars with amino acids of proteins, lipids and nucleic acids. AGEs are mainly formed endogenously, while recent studies suggest that diet constitutes an important exogenous source of AGEs. The presence and accumulation of AGEs in various cardiac cell types affect extracellular and intracellular structure and function. AGEs contribute to a variety of microvascular and macrovascular complications through the formation of cross-links between molecules in the basement membrane of the extracellular matrix and by engaging the receptor for advanced glycation end products (RAGE). Activation of RAGE by AGEs causes up regulation of the transcription factor nuclear factor-κB and its target genes. of the RAGE engagement stimulates oxidative stress, evokes inflammatory and fibrotic reactions, which all contribute to the development and progression of devastating cardiovascular disorders. This review discusses potential targets of glycation in cardiac cells, and underlying mechanisms that lead to heart failure with special interest on AGE-induced mitochondrial dysfunction in the myocardium.


Bone-marrow origin of endometrial granulocytes in the early human placental bed.
A large number of cells in the first trimester human placenta have been shown to express leucocyte-common antigen by the use of a monoclonal antibody in an immunoperoxidase technique. The distribution of endometrial granulocytes in the decidua of early pregnancy indicates that a large proportion of these cells bear the leucocyte-common antigen and are thus bone-marrow derived.


Activation of the first component of complement, C1: comparison of the effect of sixteen different enzymes on serum C1.
In this study, the effect of sixteen different enzymes on serum C1 and its subcomponents was investigated. The sixteen enzymes could be divided into three groups. First, enzymes which activate native C1: trypsin (optimal concentration 2.4 x 10(-4) mM); alpha-chymotrypsin (2.3 x 10(3) mM); thrombin (1.0 x 10(-5) mM); plasmin (1.9 x 10(-5) mM); elastase (5.8 x 10(-5) mM); pronase (3.0 x 10(-6) mM). All these enzymes are serine esterase and activate native serum C1 bound to EAC4 at the given concentration within 10 min at 30 degrees C. Furthermore, native C1 inhibited by a pentosanpolysulfoester, Sp54, is unable to undergo the internal activation but can be externally activated by the serine esterases. Second, enzymes which do not activate native C1 but result in a dose and time-dependent loss of C1 activity: collagenase; pepsin; carboxypeptidase B. Third, enzymes which have no effect on C1 and C1: Lysozyme; neuraminidase; beta-galactosidase; L-amino acid oxidase; arginase; streptokinase, and acetylcholinesterase.


Targeting angiogenesis with a conjugate of HPMA copolymer and TNP-470.
Angiogenesis is crucial for tumor growth. Angiogenesis inhibitors, such as O-(chloracetyl-carbamoyl) fumagillol (TNP-470), are thus emerging as a new class of anticancer drugs. In clinical trials, TNP-470 slowed tumor growth in patients with metastatic cancer. However, at higher doses necessary for tumor regression, many patients experienced neurotoxicity. We therefore synthesized and characterized a water-soluble conjugate of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer, Gly-Phe-Leu-Gly linker and TNP-470. This conjugate accumulated selectively in tumor vessels because of the enhanced permeability and retention (EPR) effect. HPMA copolymer-TNP-470 substantially enhanced and prolonged the activity of TNP-470 in vivo in tumor and hepatectomy models. Polymer conjugation prevented TNP-470 from crossing the blood-brain barrier (BBB) and decreased its accumulation in normal organs, thereby avoiding drug-related toxicities. Treatment with TNP-470 caused weight loss and neurotoxic effects in mice, whereas treatment with the conjugate did not. This new approach for targeting angiogenesis inhibitors specifically to the tumor vasculature may provide a new strategy for the rational design of cancer therapies.


Mosaic patterns of selection in genomic regions associated with diverse human traits.
Natural selection shapes the genetic architecture of many human traits. However, the prevalence of different modes of selection on genomic regions associated with variation in traits remains poorly understood. To address this, we developed an efficient computational framework to calculate positive and negative enrichment of different evolutionary measures among regions associated with complex traits. We applied the framework to summary statistics from >900 genome-wide association studies (GWASs) and 11 evolutionary measures of sequence constraint, population differentiation, and allele age while accounting for linkage disequilibrium, allele frequency, and other potential confounders. We demonstrate that this framework yields consistent results across GWASs with variable sample sizes, numbers of trait-associated SNPs, and analytical approaches. The resulting evolutionary atlas maps diverse signatures of selection on genomic regions associated with complex human traits on an unprecedented scale. We detected positive enrichment for sequence conservation among trait-associated regions for the majority of traits (>77% of 290 high power GWASs), which included reproductive traits. Many traits also exhibited substantial positive enrichment for population differentiation, especially among hair, skin, and pigmentation traits. In contrast, we detected widespread negative enrichment for signatures of balancing selection (51% of GWASs) and absence of enrichment for evolutionary signals in regions associated with late-onset Alzheimer's disease. These results support a pervasive role for negative selection on regions of the human genome that contribute to variation in complex traits, but also demonstrate that diverse modes of evolution are likely to have shaped trait-associated loci. This atlas of evolutionary signatures across the diversity of available GWASs will enable exploration of the relationship between the genetic architecture and evolutionary processes in the human genome.


Does the brain actively maintain itself?
All living systems have special mechanisms for combatting entropy; however, the brain has dimensions of organized complexity beyong those manifest in the anatomical structure and physiology of the rest of the body. Reasons are given in support of the notion that the brain therefore must have a special, intrinsic "homeostatic" system for its information bearing structures, and, further, that slow electroencephalographic activity has properties which might make it useful for such an order-maintaining function. Recovery from brain damage is hypothesized to be a byproduct of this process, which may involve a cruder sort of information processing than occurs with such functions as perception and learning. Synchronized EEG activity may be adequate to handle this sort of information processing. Speculations are offered about possible mechanics, on the neuronal level, of slow wave participation in plasticity; for example, one such suggestion is based on findings that electrical fields can influence cellular orientation. The methodology of discovering the distribution within the brain of the hypothetical maintenance system is discussed briefly.


Molecular and environmental determinants of biomolecular condensate formation.
Biomolecular condensate formation has been implicated in a host of biological processes and has found relevance in biology and disease. Understanding the physical principles and underlying characteristics of how these macromolecular assemblies form and are regulated has become a central focus of the field. In this Review, we introduce features of phase-separating biomolecules from a general physical viewpoint and highlight how molecular features, including affinity, valence and a competition between inter- and intramolecular contacts, affect phase separation. We then discuss sequence properties of proteins that serve to mediate intermolecular interactions. Finally, we review how the intracellular environment can affect structural and sequence determinants of proteins and modulate physical parameters of their phase transitions. The works reviewed highlight that a complex interplay exists between structure, sequence and environmental determinants in the formation of biomolecular condensates.


Deep Learning-Based Differential Diagnosis of Follicular Thyroid Tumors Using Histopathological Images.
Deep learning systems (DLSs) have been developed for the histopathological assessment of various types of tumors, but none are suitable for differential diagnosis between follicular thyroid carcinoma (FTC) and follicular adenoma (FA). Furthermore, whether DLSs can identify the malignant characteristics of thyroid tumors based only on random views of tumor tissue histology has not been evaluated. In this study, we developed DLSs able to differentiate between FTC and FA based on 3 types of convolutional neural network architecture: EfficientNet, VGG16, and ResNet50. The performance of all 3 DLSs was excellent (area under the receiver operating characteristic curve = 0.91 ± 0.04; F1 score = 0.82 ± 0.06). Visual explanations using gradient-weighted class activation mapping suggested that the diagnosis of both FTC and FA was largely dependent on nuclear features. The DLSs were then trained with FTC images and linked information (presence or absence of recurrence within 10 years, vascular invasion, and wide capsular invasion). The ability of the DLSs to diagnose these characteristics was then determined. The results showed that, based on the random views of histology, the DLSs could predict the risk of FTC recurrence, vascular invasion, and wide capsular invasion with a certain level of accuracy (area under the receiver operating characteristic curve = 0.67 ± 0.13, 0.62 ± 0.11, and 0.65 ± 0.09, respectively). Further improvement of our DLSs could lead to the establishment of automated differential diagnosis systems requiring only biopsy specimens.