Real-life experience of managing vulval erosive lichen planus: a case-based review and U.K. multicentre case note audit.
There is a lack of published evidence for treatment and outcome measures for vulval erosive lichen planus (ELPV). To conduct a multicentre case note review to examine real-life management of ELPV comparing current U.K. practice against an agreed audit standard. Criteria for standards of care for which to evaluate current service provision were set following communication with experts from the British Society for the Study of Vulval Disease. Participants from 10 U.K. centres included nine dermatologists and one gynaecologist who run specialist vulval clinics. Standards examined the documentation of disease severity/impact measures, the use of diagnostic biopsies, treatments used and assessment of treatment response. Audit data were collected from 172 patients. Documentation of symptoms/clinical findings was excellent (99%, 170/172). A schematic diagram was present in the notes of 87% (150/172). Patient-related disease impact measures including Dermatology Life Quality Index (3%, 6/172) or visual analogue scales (1%, 2/172) were less well documented. Biopsies were performed in 78% (135/172); 71% (96/135) showed histological features consistent with erosive lichen planus. Squamous cell carcinoma developed in four patients (two vulval, two oral) and vulval intraepithelial neoplasia in two further patients. Recommended first-line treatment with a very potent topical steroid was used in 75% (129/172) with improvement in 66% (85/129). Significant variation in second-line therapy was seen. Wide variation in U.K. practice demonstrates the absence of standardized guidance for treating ELPV and the need for vulval-specific outcomes. This audit should act as a framework towards improving ELPV management and to plan future research in this area.


Metabolism of mixed human colonic bacteria in a continuous culture mimicking the human cecal contents.
The purpose of this study was to develop an in vitro model of the proximal colon that would permit investigation of the function of colonic bacteria. Five continuous cultures of fecal bacteria were maintained anaerobically in steady state for at least 21 days in a medium simulating ileostomy effluent. The pH was maintained at 6 by the controlled infusion of sodium bicarbonate. Fresh medium (13 ml) was pumped into the culture for 2 min every hour and excess culture was simultaneously removed. The redox potential of all cultures remained below -300 mV, whereas the osmolality was maintained hypertonic compared with the original inoculum or medium. The cultures readily produced volatile fatty acids at a rate of 30.4 +/- 3.6 mmol/day (mean +/- SEM). Acetic acid (10-19 mmol/day) and propionic acid (5-30 mmol/day) were produced in the largest amounts, whereas butyric acid was produced only in small amounts or not at all. Ammonia was produced in each culture in amounts that varied from day to day and between cultures. The osmolality and volatile fatty acid production increased when the carbohydrate input was doubled and decreased when the cultures were deprived of carbohydrate. Thus it is possible to maintain actively fermenting viable cultures in vitro for prolonged periods; such cultures respond to changing conditions and may be useful in investigating the metabolic function of the colon.


Comparative endoluminal visualization of TAXUS crush-stenting at 9 months follow-up by intravascular ultrasound and optical coherence tomography.
We report a case of crush-stenting with Paclitaxel-eluting TAXUS stents in a left anterior descending artery (LAD) bifurcation lesion. In order to obtain precise information on the mid-term neointimal response of the main vessel to this approach, we evaluated the patient angiographically 9 months later, including intravascular visualization with optical coherence tomography (OCT), a new high resolution imaging technique, and IVUS. The evaluation revealed that there was a homogeneous neointimal coverage of the main vessel stents without evidence of significant recurrent lumen renarrowing or malappositions. Compared to IVUS, OCT proved the coverage of the stent struts adjacent to the vessel wall with a superior imaging quality and, in addition, provided new insights into the stent performance at the open bifurcation site.


Biotech boom.
India's thriving biotechnology industry is threatened by a change in the law. Will the current high levels of investment be enough to secure its future?


Preoperative care of infants with nephroblastoma. The International Society of Pediatric Oncology 6 experience.
The International Society of Pediatric Oncology (SIOP) recommends preoperative treatment in the management of eligible patients with Wilms' tumor. Until 1980, children younger than 12 months of age (infants) at diagnosis had been excluded from the SIOP trials. SIOP 6, conducted from 1980 to 1987, was the first SIOP study to include infants older than 6 months of age. This retrospective analysis of 145 infants registered to SIOP 6 demonstrates that in infants older than 6 months and having favorable histology (FH), a two-drug preoperative chemotherapy (CT) regimen of 4 weeks significantly ameliorated stage distribution as determined at delayed surgery but did not affect a good outcome. However, the CT dose utilized in SIOP 6 resulted in an unacceptable toxicity in this age group, and SIOP 9, the new SIOP study of Wilms' tumor, recommends a reduced dose of CT in infants. Preoperative CT is not recommended in infants younger than 6 months of age. Specifically, the high incidence (29%) of mesoblastic nephroma in this age group does not justify such an approach. Histopathologic diagnosis should be obtained in these patients before any treatment.


Author Correction: Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson's disease.
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.


Adjacent cooperation of proteins on DNA are not representative of long-distance interactions.
The cI repressor of bacteriophage lambda is better-fitted to the proximal interactions in which it naturally takes part than to the long-distance cooperative interactions on DNA for which it has become representative. The first observation in support of this statement is the ambiguity of an untypical DNAase I footprint which has become a diagnostic for DNA circularisation (and thus for the capacity of the protein to control expression at a distance). However, it was also observed without effective DNA looping when lac repressor binds to nearly contiguous sites. Additionally, the surface of interaction between the two dimers seems to be more important than the one commonly admitted (via some contacts between the flexible arms), the biological function of the repressor is lost when the sites are separated and loops have not been observed for large separation of the sites. In fact, naturally distant interactions can conform to shorter distances, as an intrinsic property of DNA looping. On the contrary, interactions which are naturally optimised for contiguity are generally constrained to proximity. Alternative protein-protein contacts are generally responsible for this situation (cf. CRP versus NRI in Escherichia coli).


Reproducibility of cardiovascular autonomic tests in diabetics with and without autonomic dysfunction and in normal controls.
The present study evaluates the reproducibility of five cardiovascular reflex tests, deep breathing (DB), Valsalva maneuver (VM), sustained hand-grip (SHG), postural hypotension (PH) and lying to standing (LS) in normal subjects and in insulin dependent (type I) diabetic patients. The study was carried out in 10 normal subjects, in 10 diabetics with autonomic neuropathy and in 10 diabetics without autonomic neuropathy. The five cardiovascular reflex tests were performed five times on five consecutive days by the same investigator and in identical basal conditions. The intraindividual variability of DB, LS and VM was significantly reduced in diabetics with autonomic neuropathy compared with normal controls, but there was no difference between diabetics without neuropathy and normal controls. The intraindividual variability of PH was significantly increased in diabetics with autonomic neuropathy compared with diabetics without autonomic neuropathy and with normal controls. There was no difference among the three groups in the reproducibility of SHG. In normal subjects the intraindividual variability only exceptionally produced a shift from normal to abnormal values or vice versa; in diabetics with autonomic neuropathy this shift was more frequent.


Impact of physician performed point of care ultrasound (POCUS) during first outpatient cardiology consultation on patient management and downstream testing.
Goal directed point of care ultrasound (POCUS) is a bedside tool to assist with clinical diagnosis. We examined the impact of POCUS performed by consulting cardiologist (CC) during initial cardiology consult on clinical management and downstream testing. Sixty-nine study patients (pts) seen in a general cardiology outpatient clinic of a tertiary center by an expert imaging CC were compared to a control group of 65 pts seen by three different CCs without POCUS during the same time-period, in whom the first standard echo (SE) was performed after the initial visit. Baseline characteristics were similar between the two groups for age, cardiac risk factors, and referral diagnoses. Echo findings on POCUS and by SE (mean delay of 17.2 days after visit) in the control group were comparable for RV size and function and for valvular heart disease. More patients with lower LVEF, higher LV filling pressures, new regional wall motion abnormalities, and increased aortic root size were present among POCUS group resulting in greater yield of echo abnormalities. There were more cardiovascular medication changes at the first visit (15.3% vs. 5.7%, p < .01), less referral for noninvasive stress testing (10% vs. 29%, p < .01), more advanced cardiac testing and subspecialty referrals (29% vs. 18% pts, p = .06), in the study compared to the control group after cardiology visit. POCUS at time of consultation detects more abnormal echo findings, results in more medication adjustments, less referral for noninvasive stress testing, earlier referral for advanced cardiac diagnostic imaging, and subspecialty cardiac referrals.


Empathy, defending, and functional connectivity while witnessing social exclusion.
Peers are present for most bullying episodes. Peers who witness bullying can play an important role in either stopping or perpetuating the behavior. Defending can greatly benefit victimized peers. Empathy is strongly associated with defending. Yet, less is known about defenders' neural response to witnessing social distress, and how this response may relate to the link between empathy and defending. Forty-six first-year undergraduate students (Mage = 17.7; 37 women), with varied history of peer defending, underwent fMRI scanning while witnessing a depiction of social exclusion. Functional connectivity analysis was performed across brain regions that are involved in cognitive empathy, empathetic distress, and compassion. History of defending was positively associated with functional connectivity (Exclusion > Inclusion) between the left orbitofrontal cortex (OFC) - medial prefrontal cortex (MPFC), and right OFC - left and right amygdalae. Defending was negatively associated with functional connectivity between the left OFC - anterior cingulate cortex. The relationship between history of defending and empathy (specifically, empathetic perspective taking) was moderated by functional connectivity of the right OFC - left amygdala. These findings suggest that coactivation of brain regions involved in compassionate emotion regulation and empathetic distress play a role in the relationship between empathy and peer defending.


Evaluation of Postoperative Functional Health Status Decline Among Older Adults.
Functional outcomes have value for older adults who undergo surgical procedures. Preventing postoperative functional decline in this patient population necessitates the identification of the factors associated with this outcome and minimizing their implications. To assess the prevalence of functional decline 30 days after a surgical procedure among older adults 80 years or older, examine the risk factors of this decline, and identify ways to minimize this decline by addressing its mutable factors. This retrospective cohort study used patient data from the Geriatric Surgery Pilot Project, a multi-institutional data registry of the American College of Surgeons National Surgical Quality Improvement Program. Inclusion criteria were patients 80 years or older who underwent a surgical procedure that required an inpatient stay at 1 of 23 hospitals enrolled in the Geriatric Surgery Pilot Project from January 1, 2015, to December 31, 2018, and had preoperative and postoperative functional health status data. Data analysis was performed from January 7, 2019, to December 2, 2019. Adults 80 years or older who underwent an inpatient surgical procedure. The primary outcome was 30-day postoperative functional decline defined by a change in functional health status from admission or before the surgical procedure (ie, from independent to partially or totally dependent, or from partially dependent to totally dependent). Functional health status was measured by a patient's ability to perform activities of daily living. Secondary outcomes were hospital readmission and 30-day postoperative living location. Of the 2013 patients analyzed in this study, 1128 were women (56.0%) and the mean (SD) age was 84.9 (3.9) years. Functional decline at 30 days after the surgical procedure was present in 406 patients (20.2%). Prevalence of this outcome increased with age, with 337 of 1751 patients aged 80 to 89 years (19.2%) experiencing decline compared with 69 of 262 patients 90 years or older (26.3%). In a risk-adjusted model, the geriatric-specific risk factors statistically significantly associated with this outcome included preoperative mobility aid use (odds ratio [OR] 1.76; 95% CI, 1.39-2.22; P < .001) and malnutrition (OR, 1.88; 95% CI, 1.04-3.43; P = .04) as well as postoperative delirium (OR, 2.20; 95% CI, 1.60-3.02; P < .001), pressure ulcer (OR, 1.83; 95% CI, 1.02-3.30; P = .04), and mobility aid at discharge (OR, 2.49; 95% CI, 1.72-3.59; P < .001). Among patients with a 30-day functional decline, 106 (26.1%) required hospital readmission and only 219 (53.9%) were living at home compared with 388 patients (95.6%) living at home before the procedure. In this study, 1 in 5 older adults experienced a functional decline that persisted 30 days after a surgical procedure, an outcome that appeared to be associated with several geriatric-specific risk factors. Future trials are needed to evaluate whether the prevention or mitigation of these factors can decrease the rates of postoperative functional decline in this patient population.


The lord of the ring: mandatory role of the kidney in drug therapy of hypertension.
Strong evidence supports the idea that total peripheral resistance (TPR) is increased in all forms of human and experimental hypertension. Although the etiological participation of TPR in the origin and long-term maintenance of hypertension has been extensively debated, it now seems clear that the renal, nonadaptive, infinite gain-working, pressure-sensitive natriuresis and diuresis is the main mechanism of blood pressure control in the long term. The tissue, cellular, biochemical, and genetic sensors and executors of this process have not been fully identified yet, but the role of the renal medulla has gained growing attention as the physiopathological scenario in which the key regulatory elements reside. Specifically, the functionality of the renomedullary vasculature seems to be highly responsible for blood pressure control. The vasculature of the renal medulla becomes a new and more specific target for the therapeutic intervention of hypertension. Recent data on the effect of baroreceptor-controlled renal sympathetic activity on the long-term regulation of blood pressure are integrated. The renomedullary effects of the main antihypertensive drugs are discussed, and new perspectives for the therapeutic intervention of hypertension are outlined. Comparison of the genetic program of the renal medulla before and after the development of hypertension in spontaneously hypertensive and experimentally induced animal models might provide a mechanism for identifying the key genes that become activated or suppressed in the development of high blood pressure. These genes, their encoded proteins, or other elements related to their signalling and genetic pathways might serve as new and more specific targets for the pharmacological treatment of abnormally elevated blood pressure. Besides, proteins specifically located to the luminal side of the renomedullary vascular endothelium may serve as potential targets for site-directed drug and gene therapy.


Reduction of NOx in Fe-EDTA and Fe-NTA solutions by an enriched bacterial population.
An enriched biomass was developed from municipal sewage sludge consisting of three dominant bacteria, representing the genera of Enterobacter, Citrobacter and Streptomyces. The biomass was used in a series of batch experiments in order to determine kinetic constants associated with biomass growth and NOx reduction in aqueous Ferrous EDTA/NTA solutions and Ferric EDTA/NTA solutions using ethanol as organic electron donor. The maximum specific reduction rates of NOx in Ferrous EDTA and Ferrous NTA solutions were 0.037 and 0.047mMolesL(-1)d(-1)mg(-1) biomass, respectively while in Ferric EDTA and Ferric NTA solutions were 0.022 and 0.024mMolesL(-1)d(-1)mg(-1) biomass, respectively. In case of Ferric EDTA/NTA solution, the kinetic constants associated with reduction of Ferric EDTA/NTA to Ferrous EDTA/NTA were also evaluated simultaneously. The maximum specific reduction rates of Ferric EDTA and Ferric NTA were 0.0021 and 0.0026mMolesL(-1)d(-1)mg(-1) biomass. The significance of these observations are presented and discussed in this paper.


Rise from the ashes - the reconstruction of charcoal fossil flowers.
The fossil record provides a unique opportunity to study the evolutionary history and past diversity of life. Without making use of palaeontological data, a comprehensive understanding of the phylogeny and present diversity of life would remain elusive. Angiosperms (flowering plants) are the largest and most diverse group of land plants. Our understanding of their evolution has in recent years profited immensely from the discovery and study of three-dimensionally preserved fossil flowers. Descriptions of such fossil flowers are in many respects equivalent to those of extant plants. Here, I provide background information about this type of angiosperm fossils and give special attention to the techniques used to reconstruct their three-dimensional shape and organization.


Longitudinal monitoring of fetal behavior in twins when one is anencephalic.
To our knowledge, there has been no report on longitudinal monitoring of fetal behavior in the anencephalic fetus. A 30-year-old woman was diagnosed with a twin pregnancy at 8 weeks' gestation; at week 20, one of the twins was identified as anencephalic. From 25-36 weeks' gestation, the behavioral patterns of each fetus were recorded weekly on videotape for 60 minutes, then compared with morphologic findings after birth. Our data comparing normal and anencephalic fetuses indicate that the development of the central nervous system above the medulla oblongata plays an important role in the elimination of fetal movements, such as startle, jumping, and writhing, and in the commencement of breathing movements.


Glue embolization for gastroduodenal ulcer bleeding: contribution to hemodynamics and healing process.
Although the morbidity of bowel ischemic events after glue embolization has been suggested, a causal relationship between glue and ischemia has not been clearly established. To evaluate the efficiency and safety of transcatheter arterial embolization with n-butyl cyanoacrylate (NBCA-TAE) for upper gastrointestinal hemorrhage (GIH). Between October 2006 and October 2012, 21 patients with upper GIH underwent NBCA-TAE, and endoscopic data were obtained within 30 days of follow-up. Shock index prior to and immediately after NBCA-TAE were compared to determine changes in hemodynamics. Days to Forrest type III, as assessed by follow-up endoscopy, was used as an indicator of the healing process. Other clinical outcomes included days for starting ingestion and for hospital discharge. Sixteen gastric and five duodenal ulcers, classified into Forrest type I, were treated. Immediate hemostasis was achieved in all the patients, and no re-bleeding occurred within the follow-up period. Shock index significantly (P < 0.001) improved from before (0.99 ± 0.076) to immediately after NBCA-TAE (0.67 ± 0.038). Sequential mucosal healing processes were observed in all the patients, and the number of days to Forrest type III was 9.6 ± 7.1. The number of days for starting ingestion and hospital discharge was 9.0 ± 4.5 and 15 ± 7.7 days, respectively. NBCA-TAE is an effective and safe method for the control of nonvariceal upper GIH, in terms of contribution to hemodynamics and healing process of the gastroduodenal mucosa.


Brain monitoring in hospitals needs to be strengthened.
Careful brain monitoring saves lives and is beneficial to patients' health. Nevertheless, Norway lacks guidelines for brain monitoring in hospitals.


Phenotypic variation in the molt characteristics of a seasonal coat color-changing species reveals limited resilience to climate change.
The snowshoe hare (Lepus americanus) possesses a broad suite of adaptations to winter, including a seasonal coat color molt. Recently, climate change has been implicated in the range contraction of snowshoe hares along the southern range boundary. With shortening snow season duration, snowshoe hares are experiencing increased camouflage mismatch with their environment reducing survival. Phenological variation of hare molt at regional scales could facilitate local adaptation in the face of climate change, but the level of variation, especially along the southern range boundary, is unknown. Using a network of trail cameras and historical museum specimens, we (1) developed contemporary and historical molt phenology curves in the Upper Great Lakes region, USA, (2) calculated molt rate and variability in and among populations, and (3) quantified the relationship of molt characteristics to environmental conditions for snowshoe hares across North America. We found that snowshoe hares across the region exhibited similar fall and spring molt phenologies, rates and variation. Yet, an insular island population of hares on Isle Royale National Park, MI, completed their molt a week earlier in the fall and initiated molt almost 2 weeks later in the spring as well as exhibited slower rates of molting in the fall season compared to the mainland. Over the last 100 years, snowshoe hares across the region have not shifted in fall molt timing; though contemporary spring molt appears to have advanced by 17 days (~ 4 days per decade) compared to historical molt phenology. Our research indicates that some variation in molt phenology exists for snowshoe hares in the Upper Great Lakes region, but whether this variation is enough to offset the consequences of climate change remains to be seen.


Reconstitution of nuclear import in permeabilized cells.
The trafficking of protein and RNA cargoes between the cytoplasm and the nucleus of eukaryotic cells, which is a major pathway involved in cell regulation, is mediated by nuclear transport sequences in the cargoes and by shuttling transport factors. The latter include receptors (karyopherins) that recognize the cargoes and carry them across the nuclear pore complex (NPC), and the small GTPase Ran, which modulates karyopherin-cargo binding. Nuclear import can be studied in vitro using digitonin-permeabilized cells, which are depleted of shuttling transport factors. Nuclear import can be reconstituted in the permeabilized cells with exogenous cytosol or with purified recombinant transport factors, and can be quantified by light microscopy of fluorescently labeled cargoes or by immunofluorescence staining. Here we describe procedures for in vitro nuclear import in permeabilized mammalian cells, and for the preparation of recombinant transport factors (importin alpha, importin beta, importin 7, transportin, Ran, NTF2) and other reagents commonly used in the assay. This assay provides means to characterize the molecular mechanisms of nuclear import and to study the import requirements of specific cargoes.


Antibiotic Stewardship for Older Adults in Ambulatory Care Settings: Addressing an Unmet Challenge.
Inappropriate antibiotic use is common in older adults (aged >65 y), and they are particularly vulnerable to serious antibiotic-associated adverse effects such as cardiac arrhythmias, delirium, aortic dissection, drug-drug interactions, and Clostridioides difficile. Antibiotic prescribing improvement efforts in older adults have been primarily focused on inpatient and long-term care settings. However, the ambulatory care setting is where the vast majority of antibiotic prescribing to older adults occurs. To help improve the clinical care of older adults, we review drivers of antibiotic prescribing in this population, explore systems aspects of ambulatory care that can create barriers to optimal antibiotic use, discuss existing stewardship interventions, and provide guidance on priority areas for future inquiry. J Am Geriatr Soc 68:244-249, 2020.


Male infanticide and paternity analyses in a socially natural herd of Przewalski's horses: sexual selection?
The sexual selection hypothesis explains infanticide by males in many mammals. In our 11-year study, we investigated this hypothesis in a herd of Przewalski's horses where we had witnessed infanticidal attacks. Infanticide was highly conditional and not simply linked to takeovers. Attacks occurred in only five of 39 cases following a takeover, and DNA paternity revealed that, although infanticidal stallions were not the genetic fathers in four cases out of five, stallions present at birth did not significantly attempt to kill unrelated foals. Infanticide did not reduce birth intervals; only in one case out of five was the infanticidal stallion, the father of the next foal; mothers whose foals were attacked subsequently avoided associating with infanticidal stallions. Therefore, evidence for the sexual selection hypothesis was weak. The "human disturbance" hypothesis received some support, as only zoo bred stallions which grew up in unnatural social groups attacked foals of mares which were pregnant during takeovers.


Ultrasonography assessment of vocal cords mobility in children after cardiac surgery.
Upper airway obstruction after pediatric cardiac surgery is not uncommon. In the cardiac surgical population, an important etiology is vocal cord paresis or paralysis following extubation. In this study, we aimed to evaluate the feasibility and accuracy of ultrasonography (US) assessment of the vocal cords mobility and compare it to fiber-optic laryngoscope (FL). A prospective pilot study has been conducted in Pediatric Cardiac ICU (PCICU) at King Abdulaziz Cardiac Center (KACC) from the 1st of June 2009 till the end of July 2010. Patients who had cardiac surgery manifested with significant signs of upper airway obstruction were included. Each procedure was performed by different operators who were blinded to each other report. Results of invasive (FL) and non-invasive ultrasonography (US) investigations were compared. Ten patients developed persistent significant upper airway obstruction after cardiac surgery were included in the study. Their mean ± SEM of weight and age were 4.6 ± 0.4 kg and 126.4 ± 51.4 days, respectively. All patients were referred to bedside US screening for vocal cord mobility. The results of US were compared subsequently with FL findings. Results were identical in nine (90%) patients and partially different in one (10%). Six patients showed abnormal glottal movement while the other four patients demonstrated normal vocal cords mobility by FL. Sensitivity of US was 100% and specificity of 80%. US assessment of vocal cord is simple, non-invasive and reliable tool to assess vocal cords mobility in the critical care settings. This screening tool requires skills that can be easily obtained.


An improved blood hemorrhaging treatment using diatoms frustules, by alternating Ca and light levels in cultures.
Hemorrhage control requires hemostatic materials that are both effective and biocompatible. Among these, diatom biosilica (DBs) could significantly improve hemorrhage control, but it induces hemolysis (the hemolysis rate > 5%). Thus, the purpose of this study was to explore the influence of Ca2+ biomineralization on DBs for developing fast hemostatic materials with a low hemolysis rate. Here, CaCl2 was added to the diatom medium under high light (cool white, fluorescent lamps, 67.5 µmol m-2 s-1), producing Ca-DBs-3 with a particle size of 40-50 μm and a Ca2+ content of Ca-DBs-3 obtained from the higher concentration CaCl2 group (6.7 mmol L-1) of 0.16%. The liquid absorption capacity of Ca-DBs-3 was 30.43 ± 0.57 times its dry weight; the in vitro clotting time was comparable to QuikClot® zeolite; the hemostatic time and blood loss using the rat tail amputation model were 36.40 ± 2.52 s and 0.39 ± 0.12 g, which were 40.72% and 19.50% of QuikClot® zeolite, respectively. Ca-DBs-3 showed no apparent toxicity to L929 cells (cell viability > 80%) and was non-hemolysis (the hemolysis rate < 2%). This study prepared Ca-DBs-3 with a rapid hemostatic effect and good biocompatibility, providing a path to develop diatom biosilica hemostatic materials. The online version contains supplementary material available at 10.1007/s42995-023-00180-3.


Diagnostic evaluation of fatal Balamuthia mandrillaris meningoencephalitis in a captive Bornean orangutan (Pongo pygmaeus) with identification of potential environmental source and evidence of chronic exposure.
A female Bornean orangutan (Pongo pygmaeus) aged 11 years and 6 months was examined by veterinarians after caretakers observed lethargy and facial grimacing. Within 72 h the primate had left-sided hemiparesis that worsened over the next week. An MRI revealed a focal right-sided cerebral mass suspected to be a neoplasm. Ten days after onset of clinical signs, the orangutan died. On postmortem exam, the medial right parietal lobe was replaced by a 7 × 4 × 3.5 cm focus of neuromalacia and hemorrhage that displaced the lateral ventricle and abutted the corpus callosum. Histopathology of the cerebral lesion revealed pyogranulomatous meningoencephalitis with intralesional amoeba trophozoites and rare cysts. Fresh parietal lobe was submitted to the Centers for Disease Control and Prevention lab for multiplex free-living amoebae real-time PCR and detected Balamuthia mandrillaris DNA at a high burden. Mitochondrial DNA was sequenced, and a 760-bp locus 19443F/20251R was compared to several human infections of B. mandrillaris and shown to be identical to the isolates from four human cases of encephalitis: 1998 in Australia, 1999 in California, 2000 in New York, and 2010 in Arizona. Indirect immunofluorescent antibody testing of stored serum samples indicated exposure to B. mandrillaris for at least 2 years prior to death. Within 1 week of the orangutan's death, water from the exhibit was analyzed and identified the presence of B. mandrillaris DNA, elucidating a possible source of exposure. B. mandrillaris, first reported in a mandrill in 1986, has since occurred in humans and animals and is now considered an important emerging pathogen.


Rationale and design of the Chinese Atrial Fibrillation Registry Study.
Robust data on the contemporary management of atrial fibrillation (AF) patients in China are limited. Importantly current practice in AF management has changing dramatically in recent years. Data from a large registry study will enable us to evaluate the uptake and outcomes with different therapies in a large Chinese AF population. The Chinese Atrial Fibrillation Registry study (CAFR) aims to enroll 20,000 consecutive atrial fibrillation (AF) patients from 32 tertiary and non-tertiary hospitals in Beijing, China, and follow up these patients every 6 months until 2020. Key data collected includes basic sociodemographic information, symptoms and signs, medical history, results of physical examination and laboratory test, details of treatments and personal insurance status. For patients who consent, 5 ml of blood sample will be stored at -80 °C for future analyses of biomarkers. At each 6 month follow up visit, data relating to clinical outcomes will be collected. Data from a randomly selected 10 % of patients will be internally validated with their raw source data. Ischemic stroke events will be adjudicated by an independent endpoint committee. CAFR will be one of the largest registries of Asian AF patients (and the largest in Chinese AF patients), as well as providing the longest follow up. This study would provide a valuable opportunity for 'real world' clinical epidemiology with insights into the uptake (and outcomes) of contemporary AF management. Chinese Clinical Trial Registry ChiCTR-OCH-13003729 . Registered 22 October 2013.


A high-throughput atomic emission analyzer for simultaneous field detection of dissolved inorganic and organic carbon in seawater and lake water.
Dissolved inorganic carbon (DIC) and dissolved organic carbon (DOC) are two important indicators of global carbon cycle. However, there are no portable analyzers available to simultaneously accomplish high-throughput field detection of them in the same sample. Herein, a simple analyzer comprising a dual-mode reactor to accomplish both chemical vapor generation and headspace sampling, and a miniature point discharge optical emission spectrometer (μPD-OES) was developed for simultaneous and high-throughput detection of DIC and DOC in seawater and lake water. Phosphoric acid and persulfate were successively injected into sample solutions to convert DIC and DOC to CO2 under the conditions of magnetic stirring and UV irradiation, respectively. Subsequently, the generated CO2 was swept into the μPD-OES for quantitation of DIC and DOC via monitoring carbon atomic emission at 193.0 nm. Under optimal conditions, limits of detection for DIC and DOC (as C) were both 0.01 mg L-1 with relative standard deviations (n = 20) better than 5% and sample throughput of 80 samples per hour. Compared to conventional analyzers, the proposed instrument provides the advantages of high throughput, compactness, low energy consumption and eliminates expensive instruments. The accuracy of the system was validated by simultaneous determination of DIC and DOC in various water samples in laboratory and field environments.


Access flow reduction for cardiac failure.
High-flow in hemodialysis arteriovenous angioaccesses is frequent. It may result in high-output cardiac failure, which should be prevented by fistula flow reduction. The most frequently reported flow reduction procedure is banding but immediate and long-term results are questionable. Alternative techniques are related here with personal results. Juxta-anastomosis "Proximal Radial Artery Ligation" (PRAL) is a very simple and effective reduction technique for side-to-end radio-cephalic fistulas (82 patients; reduction rate [RR]: 54% ± 19%). For brachial artery-based fistulas flow reduction two variants of Revision Using Distal Inflow (RUDI) procedures are used: 1) RUDI-1 using a polytetrafluoroethylene (PTFE) graft or a greater saphenous vein, which we first described in 1989 as "Distal Report of the Arterial Inflow" (35 patients; RR: 53% ± 18%), 2) RUDI-2 procedure, "Transposition of the Radial Artery", which we described in 2009 (47 patients; RR: 66% ± 14%).


Timelapse viability assay to detect division and death of primary multiple myeloma cells in response to drug treatments with single cell resolution.
Heterogeneity among cancer cells and in the tumor microenvironment (TME) is thought to be a significant contributor to the heterogeneity of clinical therapy response observed between patients and can evolve over time. A primary example of this is multiple myeloma (MM), a generally incurable cancer where such heterogeneity contributes to the persistent evolution of drug resistance. However, there is a paucity of functional assays for studying this heterogeneity in patient samples or for assessing the influence of the patient TME on therapy response. Indeed, the population-averaged data provided by traditional drug response assays and the large number of cells required for screening remain significant hurdles to advancement. To address these hurdles, we developed a suite of accessible technologies for quantifying functional drug response to a panel of therapies in ex vivo three-dimensional culture using small quantities of a patient's own cancer and TME components. This suite includes tools for label-free single-cell identification and quantification of both cell division and death events with a standard brightfield microscope, an open-source software package for objective image analysis and feasible data management of multi-day timelapse experiments, and a new approach to fluorescent detection of cell death that is compatible with long-term imaging of primary cells. These new tools and capabilities are used to enable sensitive, objective, functional characterization of primary MM cell therapy response in the presence of TME components, laying the foundation for future studies and efforts to enable predictive assessment drug efficacy for individual patients.


Economic evaluation of an occupational health care guideline for prevention of weight gain among employees.
To determine the cost-effectiveness and the financial return of a guideline for occupational physicians (OPs), aimed at the prevention of weight gain among employees. The guideline consisted of a company-environment scan and up to five individual sessions with an OP. Sixteen OPs randomized to the guideline (n = 7) or usual care group (n = 9) recruited 275 and 249 employees. Costs were collected by using 3-monthly retrospective questionnaires. Quality-adjusted life-years gained were determined with 6-monthly administered EuroQol-5D. Waist circumference and body weight were measured at baseline and 18 months. Unfavorable differences were found on waist circumference (+1.6 cm; 95% confidence interval [CI], 0.27 to 2.90) and weight (+1.1 kg; 95% CI, 0.01 to 2.15). Probabilities of cost-effectiveness were consistently less than 55%. Net employer loss was &OV0556;-158 (95% CI, -2865 to 2672). The occupational health care guideline was not cost-effective and no financial return was shown.


Enzymatic synthesis of 2'-O-acyl prodrugs of 1-(beta-D-arabinofuranosyl)-5(E)-(2-bromovinyl)uracil and of 2'-O-acyl-araU, -araC and -araA.
Pig liver esterase (EC 22.214.171.124) catalysed regioselective hydrolysis of 1-(2,3,5-tri-O-acyl-beta-D-arabinofuranosyl)uracil, -cytosine and -adenine to give the corresponding 2'-monoesters effectively and in high yield. This methodology enabled the preparation of 1-(2-O-acyl-beta-D-arabinofuranosyl)-5-[(E)-(2-bromovinyl)]uracil prodrugs which, although slightly less active than the parent 1-(beta-D-arabinofuranosyl)-5-(E)-(2 bromovinyl)uracil (sorivudine; BV-araU), were strongly active in vitro against varicella-zoster virus (ED50 2.4-45 ng/ml). The retarded rates of enzymatic hydrolysis of the 2'-esters imply that they might function as lipophilic prodrugs, leading to increased plasma and cellular concentrations. In view of the marked in vitro activity, they represent an interesting approach to arabinofuranosyl nucleoside prodrugs with improved pharmacokinetics and enzymatic stability.


The cGAS-STING-YY1 axis accelerates progression of neurodegeneration in a mouse model of Parkinson's disease via LCN2-dependent astrocyte senescence.
Recent studies provide clues that astrocyte senescence is correlated with Parkinson's disease (PD) progression, while little is known about the molecular basis for astrocyte senescence in PD. Here, we found that cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) was upregulated in senescent astrocytes of PD and aged mice. Strikingly, deletion of astrocytic cGAS significantly prevented senescence of astrocytes and neurodegeneration. Furthermore, we identified LCN2 as the effector of cGAS-STING signal by RNA-Seq analysis. Genetic manipulation of LCN2 expression proved the regulation of cGAS-STING-LCN2 axis in astrocyte senescence. Additionally, YY1 was discovered as the transcription factor of LCN2 by chromatin immunoprecipitation. Binding of STING to YY1 impedes nuclear translocation of YY1. Herein, we determine the involvement of the cGAS-STING-YY1-LCN2 signaling cascade in the control of astrocyte senescence and PD progression. Together, this work fills the gap in our understanding of astrocyte senescence, and provides potential targets for delaying PD progression.


Automated registration of hip and spine for longitudinal QCT studies: integration with 3D densitometric and structural analysis.
To eliminate user interaction in longitudinal quantitative computed tomography (QCT) measurements of bone mineral density (BMD) and geometry, we have developed and optimized an automated registration algorithm for QCT images of the hip and spine and integrated it with a previously developed 3D densitometric and structural analysis program. With registration, the follow-up images are automatically aligned with respect to the baseline scans, and the bone quantification of the aligned follow-up scan is initiated based on the bone morphometric features defined on the baseline scan. To validate the algorithm, we analyzed 20 pairs of repeat QCT images (10 hip pairs and 10 spine pairs) acquired on a modern multi-slice CT scanner, with repositioning between each scan pair to simulate repeat visits. Bone measurements obtained with automatic registration achieved comparable or improved precision errors compared to those obtained by careful manual analysis of the follow-up scans. The algorithm we have developed was based on the mutual information approach, with simplex optimization under a multi-resolution scheme. The average registration time was 2.3 min for a hip pair and 1.1 min for a vertebra pair using a standard desktop computer. Based on the reduced user interaction, high degree of precision, and short execution time, this is a promising technique for monitoring therapy in patients and clinical trials.


Photon versus proton whole ventricular radiotherapy for non-germinomatous germ cell tumors: A report from the Children's Oncology Group.
To determine if proton therapy reduces doses to cranial organs at risk (OARs) as compared to photon therapy in children with non-germinomatous germ cell tumors (NGGCT) receiving whole ventricular radiotherapy (WVRT). Dosimetric data for patients with NGGCT prospectively enrolled in stratum 1 of the Children's Oncology Group study ACNS1123 who received 30.6 Gy WVRT were compared. Target segmentation was standardized using a contouring atlas. Doses to cranial OARs were compared between proton and photon treatments. Clinically relevant dose-volume parameters that were analyzed included mean dose and dose to 40% of the OAR volume (D40). Mean and D40 doses to the supratentorial brain, cerebellum, and bilateral temporal, parietal, and frontal lobes were statistically significantly lower amongst proton-treated patients, as compared to photon-treated patients. In a subgroup analysis of patients uniformly treated with a 3-mm planning target volume, patients who received proton therapy continued to have statistically significantly lower doses to brain OARs. Children treated with proton therapy for WVRT had lower doses to normal brain structures, when compared to those treated with photon therapy. Proton therapy should be considered for patients receiving WVRT for NGGCT.


C-reactive protein in atherosclerotic lesions: its origin and pathophysiological significance.
C-reactive protein (CRP) is frequently deposited in the lesions of the arterial intima; however, the origin and pathological significance of CRP in these lesions are not completely understood. In this study, we measured CRP levels in the plasma of hypercholesterolemic rabbits and investigated CRP expression at both the mRNA and protein levels using rabbit and human atherosclerotic specimens. CRP levels were significantly elevated in both cholesterol-fed and Watanabe heritable hyperlipidemic rabbits, and CRP levels were clearly correlated with aortic atherosclerotic lesion size. Immunohistochemical staining coupled with Western blotting analysis revealed that CRP-immunoreactive proteins were found at all stages of atherosclerosis from the early to advanced lesions. CRP was present extracellularly and co-localized with apolipoprotein B but was rarely associated with the cytoplasm of macrophages and foam cells. Real-time reverse transcriptase-polymerase chain reaction analysis revealed that CRP mRNA in atherosclerotic lesions was barely detectable, and isolated macrophages did not express CRP mRNA, suggesting that CRP proteins found in the lesions were essentially derived from the circulation rather than synthesized de novo by vascular cells. These results suggest that there is a link between plasma CRP and the degree of atherosclerosis and that inhibition of plasma CRP may represent a therapeutic modality for the treatment of cardiovascular disease.


Synthesis of N4-substituted CTP by mammalian CTP synthetase.
Highly purified CTP synthetase from Ehrlich ascites tumor cells catalyzes the formation of N4-substituted CTP from UTP and hydroxylamine and its derivatives. The products with hydroxylamine and O-methylhydroxylamine were identified as N4-hydroxyCTP and N4-methoxyCTP by absorption spectra and chromatographic behavior on Dowex column, respectively. The weak nucleophilic amines such as methylamine, ethylamine or diethylamine and a less nucleophilic amine, sulfamic acid, did not react with UTP. These results suggest that the nucleophilicity and basicity of amines are important in the enzymic reaction with UTP.


Stereotactic radiotherapy (SRT) for differentiated thyroid cancer (DTC) oligometastases: an AIRO (Italian association of radiotherapy and clinical oncology) systematic review.
The aim of this systematic review was to examine efficacy of stereotactic radiotherapy (SRT) in patients with oligometastatic thyroid cancer. A systematic search was conducted by means of PubMed, Scopus, and Cochrane library. gov was searched for ongoing or recently completed trials, and PROSPERO was searched for ongoing or recently completed systematic reviews. We analyzed only clinical studies as full text carried out on patients with oligometastatic thyroid cancer treated with SRT. Conference papers, surveys, letters, editorials, book chapters, and reviews were excluded. Time of publication was restricted to the years 1990-2021. The number of evaluated patients was 146 (267 lesions), and the median age was 58 years. The median 1-year local control (LC) was 82% (range 67.0%-97.1%); the median disease-free survival (DFS) was 12 months (range 4-53); the median 1-year overall survival was 72% (range 66.6%-85.0%); the 3-year cancer-specific survival was 75.0%; and the 4-year cancer-specific survival was 37.5%. No grade 3-5 acute toxicity was reported. No late effects were recorded. SRT for oligometastases from thyroid cancer as salvage therapy is well tolerated and yields high rates of LC and prolonged DFS.


Adenocarcinoma in the anal canal after ileal pouch-anal anastomosis for familial adenomatous polyposis using a double-stapled technique: report of two cases.
Restorative proctocolectomy with an ileal pouch-anal anastomosis is thought to abolish the risk of colorectal adenoma development in patients suffering from familial adenomatous polyposis. Both after mucosectomy with a handsewn anastomosis and after a double-stapled anastomosis, rectal mucosa is left behind at the anastomotic site. This carries the potential for the development of polyps and a subsequent malignancy. In our clinic, two patients recently developed an adenocarcinoma at the anastomotic site, despite a yearly follow-up endoscopy.A 40-year-old female underwent an ileal pouch-anal anastomosis with a double-stapled anastomosis in 1991. She refrained from follow-up for several years, but returned eight years postoperatively with a fistula at the anastomotic site. Biopsies revealed an adenocarcinoma infiltrating in the fistula tract T2N0M0. The patient was treated with preoperative radiotherapy (60 Gy), abdominoperineal resection, and a permanent ileostomy.A 27-year-old male underwent an ileal pouch-anal anastomosis with a double-stapled anastomosis in 1990. Because of his profession, endoscopy was performed only once every two years. Endoscopic biopsies ten years postoperatively revealed adenocarcinoma T4N0M0. The patient underwent an abdominoperineal resection with partial resection of the prostate, and a permanent ileostomy was constructed.


Benzimidazole-based fXa inhibitors with improved thrombin and trypsin selectivity.
Optimization of the benzimidazole-based fXa inhibitors for selectivity versus thrombin and trypsin was achieved by substitution on the benzimidazole ring and replacement of the naphthylamidine group. Substitution of a nitro group at the 4-position on the benzimidazole improves both potency against fXa and selectivity versus thrombin. Alternatively, replacement of the naphthylamidine with either a biphenylamidine or propenylbenzamidine not only improves fXa potency and selectivity versus thrombin, but selectivity versus trypsin as well.


Phase I clinical trial of recombinant human tumor necrosis factor.
A phase I and pharmacokinetic study of recombinant tumor necrosis factor (rH-TNF Asahi) was carried out in 29 patients, who received a total of 72 courses with doses ranging from 1 to 48 X 10(4) units/m2. Drug was given as 1-h i.v. infusions. Acute toxicities, taking the form of fever, chills, tachycardia, hypertension, peripheral cyanosis, nausea and vomiting, headache, chest tightness, low back pain, diarrhea and shortness of breath were seen, but were not dose-limiting or dose-related. Some early rise in SGOT, without any change in serum bilirubin, was noted at the highest doses. Eosinophilia, monocytosis, mild hypocalcemia and an increase in fibrin degradation products were seen in a few patients. The dose-limiting toxicity was hypotension, which occurred after the end of the drug infusion and was seen in all 5 patients treated at the highest dose. There was no mortality or long-term morbidity. There were no responses. Pharmacokinetic studies indicated a rapid plasma clearance and a short plasma half-life, generally less than 0.5 h.


Anesthetic Isoflurane or Desflurane Plus Surgery Differently Affects Cognitive Function in Alzheimer's Disease Transgenic Mice.
Anesthesia/surgery could be associated with cognitive impairment and Alzheimer's disease neuropathogenesis. However, whether surgery under different anesthetics has different effects on cognitive function remains largely unknown. We therefore set out to compare effects of anesthetic isoflurane or desflurane plus surgery on cognitive function and hippocampus levels of synaptic marker (postsynaptic density-95 and synaptophysin) and ATP. Five-month-old AD Transgenic (Tg) (FAD5X) and wild-type male mice received isoflurane or desflurane plus abdominal surgery. We assessed cognitive function in Barnes maze and measured hippocampus levels of postsynaptic density-95, synaptophysin, and ATP in the mice. We determined whether vitamin K2 could mitigate these anesthesia/surgery-induced changes. Isoflurane, but not desflurane, plus surgery increased escape latency and escape distance in Barnes maze probe test and reduced postsynaptic density-95, synaptophysin, and ATP levels as compared to control condition in AD Tg mice. Vitamin K2 attenuated the anesthesia/surgery-induced changes in the AD Tg mice. These findings suggest that isoflurane, but not desflurane, plus surgery might induce cognitive impairment via causing brain energy deficits. Pending confirmative studies in both animals and humans suggest desflurane could be a better choice for AD patients when surgery is needed. Moreover, vitamin K2 could treat cognitive deficiency associated with anesthesia and surgery.


The use of lanthanide luminescence as a reporter in the solid state: Desymmetrization of the prochiral layers of γ-zirconium phosphate/phosphonate and circularly polarized luminescence.
Solid-state CPL measurements were performed for the first time on hybrid, laminar materials based on γ-ZrP pillared with organic diphosphonates. Ad hoc optically pure diphosphonates were synthesized and the luminescence properties of their complexation with Tb(III) were verified in solution. CD and CPL measurements showed that the bistriazolylpyridine chromophores bonded to the metal provided an effective chiral environment that produced significant signals. In the case of the γ-ZrP-derived materials, experimental evidence and simple molecular modeling hinted to the occurrence of supramolecular chirality in the particles, induced by the intrinsic dissymmetry of the organic diphosphonates or by the intercalation of chiral species such as 1-phenethylamine. Chirality at the supramolecular level was revealed in the solid state by the CPL signals measured from reporter Tb(III) ions intercalated in the hybrid matrix.


RID serve as a more appropriate measure than phenol sulfuric acid method for natural water-soluble polysaccharides quantification.
With structural diversity of water-soluble polysaccharides, their precise quantitative analysis by phenol‑sulfuric acid method becomes more difficult and challenging. In this study, the quantification analysis of dextran and glucose in phenol sulfuric acid method was compared in this paper. When the concentration is below 90 μg/mL, the quantification of glucose is close to theoretical value, however, glucose derivatives have significantly different absorption. Later, quantitative factors of water-soluble polysaccharide in RID measurement were investigated. The optimum temperature was 40 °C and linear range was 0.3125-10.0 mg/mL in RID for dextrans (1.0-500 kDa) and glucose derivatives. Method validation studies of the RID method were further performed and compared to conventional phenol sulfuric acid method, which demonstrated that RID measurement is more reliable and satisfactory method. The intervention of water-soluble impurity in RID response should be well control below 6% (w/w). By comparison, the RID measurement could well alleviate drawbacks in phenol‑sulfuric acid method.


A Drosophila model of chemotherapy-related cognitive impairment.
Chemotherapy-related cognitive impairment (CRCI) is a common adverse effect of treatment and is characterized by deficits involving multiple cognitive domains including memory. Despite the significant morbidity of CRCI and the expected increase in cancer survivors over the coming decades, the pathophysiology of CRCI remains incompletely understood, highlighting the need for new model systems to study CRCI. Given the powerful array of genetic approaches and facile high throughput screening ability in Drosophila, our goal was to validate a Drosophila model of CRCI. We administered the chemotherapeutic agents cisplatin, cyclophosphamide, and doxorubicin to adult Drosophila. Neurocognitive deficits were observed with all tested chemotherapies, especially cisplatin. We then performed histologic and immunohistochemical analysis of cisplatin-treated Drosophila tissue, demonstrating neuropathologic evidence of increased neurodegeneration, DNA damage, and oxidative stress. Thus, our Drosophila model of CRCI recapitulates clinical, radiologic, and histologic alterations reported in chemotherapy patients. Our new Drosophila model can be used for mechanistic dissection of pathways contributing to CRCI and pharmacologic screens to identify novel therapies to ameliorate CRCI.


Genomic Mutations of BK Polyomavirus in Patients after Kidney Transplantation: A Cross-Sectional Study in Vietnam.
The purpose of this study was to identify the SNP sites and determine the BKV genotype circulating in kidney-transplant Vietnamese recipients based on the VP1 gene region. 344 samples were collected from post-kidney-transplant recipients at the 103 Vietnam Military Hospital to investigate the number of BKV infections. Positive samples with a sufficient virus concentration were analyzed by nested PCR in the VP1 region, sequencing detected genotyping and single-nucleotide polymorphism. BKV infection was determined in 214 patients (62.2%), of whom 11 (5.1%) were diagnosed with BKV-associated nephropathy. Among the 90 BKV-I strains sequenced, 89 (98.88%) were strains of I/b-1 and 1 (1.12%) was strain I/b-2. The 60 BKV-IV strains had a greater diversity of subgroups, including 40% IV/a-1, 1.66% IV/a-2, 56.68% IV/c-1, and 1.16% IV/c-2. Additionally, of 11 cases diagnosed with BKVN, seven belonged to subgroup I/b-1 (63.6%) and four to subgroup IV/c-1 (36.4%). Moreover, 22 specific SNPs that were genotype I or IV were determined in this Vietnamese population. Specifically, at position 1745, for the Vietnamese BKV-IV strains, the SNP position (A→G) appeared in 57/60 samples (95%). This causes transformation of the amino acid N→S. This SNP site can enable detection of genotype IV in Vietnam. It represents a unique evolution pattern and mutation that has not been found in other international strains. The BKV-I genotype was more common than BKV-IV; however, mutations that occur on the VP1 typing region of BKV-IV strains were more frequent than in BKV-I strains.


The Role of Neuropsychiatric Symptoms in Research Diagnostic Criteria for Neurodegenerative Diseases.
Neuropsychiatric syndromes and symptoms play increasingly important roles in research diagnostic criteria for neurodegenerative disorders. Diagnostic criteria were reviewed including those for dementia, Alzheimer's disease, mild cognitive impairment, mild behavioral impairment, prodromal Alzheimer's disease, dementia with Lewy bodies, prodromal dementia with Lewy bodies, Parkinson's disease, multiple system atrophy, frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy, corticobasal degeneration, traumatic encephalopathy syndrome, Huntington' disease, amyotrophic lateral sclerorsis. All contemporary research diagnostic criteria for neurodegenerative disorders expect those for Parkinson's disease, primary progressive aphasia, multisystem atrophy and amyotrophic lateral sclerosis include neuropsychiatric phenomena as core diagnostic criteria. There are no disease-specific neuropsychiatric symptoms; apathy and disinhibition are common in tauopathies, and rapid-eye-movement sleep behavioral disorder occurs almost exclusively in synucleinopathies. Neuropsychiatric symptoms and syndromes are increasingly integrated into research diagnostic criteria for neurodegenerative disorders; they require clinician skills for recognition; their biology is better understood as their relationships to cognitive, motor, and autonomic symptoms of neurodegenerative disorders are studied.


CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model.
Chronic stress in the endoplasmic reticulum (ER) underlies many degenerative and metabolic diseases involving apoptosis of vital cells. A well-established example is autosomal dominant retinitis pigmentosa (ADRP), an age-related retinal degenerative disease caused by mutant rhodopsins. Similar mutant alleles of Drosophila Rhodopsin-1 also impose stress on the ER and cause age-related retinal degeneration in that organism. Well-characterized signalling responses to ER stress, referred to as the unfolded protein response (UPR), induce various ER quality control genes that can suppress such retinal degeneration. However, how cells activate cell death programs after chronic ER stress remains poorly understood. Here, we report the identification of a signalling pathway mediated by cdk5 and mekk1 required for ER-stress-induced apoptosis. Inactivation of these genes specifically suppressed apoptosis, without affecting other protective branches of the UPR. CDK5 phosphorylates MEKK1, and together, they activate the JNK pathway for apoptosis. Moreover, disruption of this pathway can delay the course of age-related retinal degeneration in a Drosophila model of ADRP. These findings establish a previously unrecognized branch of ER-stress response signalling involved in degenerative diseases.


[Cellular immunity: in vitro leukocyte migration inhibition does not correlate with the tuberculin skin test].
The leukocyte migration inhibition test (LMIT) is said to be an in-vitro correlate of cell mediated immunity in vivo. The authors' series of experiments, however, in which they compared skin tests and LMIT (taking the same tuberculin for both tests), showed wed no correlation between the two tests. The discrepancy between these results and those of other authors may be due to the fact that the authors worked under sterile conditions. It is known that contamination even by minute amounts of endotoxin may alter the results of in-vitro tests of cell mediated immunity. The authors therefore question the value of the LMIT as an in-vitro counterpart of the skin test.


Prostaglandin release mediates drug-induced stimulation of sodium transport in frog skin: the effects of quinacrine.
Quinacrine markedly increased the release of prostaglandin E2 (PGE2) into the basolateral solution of the bullfrog skin from a control value of 32.7 +/- 21.7 pg per 20 min period to a stimulated value of 8593.1 +/- 4112.3 pg per 20 min period. Quinacrine increased the amiloride-sensitive short circuit current from 20.7 +/- 2.1 microA cm-2 to 45.4 +/- 6.5 microA cm-2. The stimulatory effects of quinacrine on both short circuit current and prostaglandin release were blocked in skins pretreated with indomethacin (10(-6) M). Quinacrine did not block either the stimulation of the short circuit current or the increase in PGE2 release caused by the calcium ionophore, ionomycin. These results suggest: (a) the release of PGE2 and the stimulation of the short circuit current caused by quinacrine are linked since blocking PGE2 release inhibits the stimulation of the short circuit current; (b) given the complexity of its actions, quinacrine is a poor tool to examine whether the effects of a given agent are mediated through the activation of endogenous phospholipases. In addition our results taken together with other findings in the literature suggest that there is a diverse group of compounds that stimulate transepithelial sodium transport by releasing PGE2.


Appropriateness of the Direct Oral Anticoagulants Dosing in the Middle East Gulf Region.
Direct oral anticoagulants (DOACs) have proven efficacy to prevent cardioembolic strokes. Data are scarce about the appropriateness of DOAC dosing in the Middle East. We investigated the prevalence of inappropriate DOAC dosing in the region. A cross-sectional study was conducted at our hospital between April 2015 and February 2019 of patients receiving 1 of the 3 available DOACs. Patients with incomplete data sets, those prescribed DOACs for indications other than atrial fibrillation, on DOACs for <30 days, and dialysis patients were excluded. A total of 608 met the inclusion criteria. The mean age was 65.2 ± 13.9 years, and most were men (58.6%). The mean CHA2DS2-VASc score was 3.8 ± 2.0. There were 346 (56.9%) on apixaban, 123 (20.2%) on dabigatran, and 139 (22.9%) on rivaroxaban. The logistic regression model showed that for the 3 agents together, age, eGFR, major bleeding history, and history of prior stroke were significantly associated with the decision to inappropriately underdose (P < 0.05). Fifteen patients had an ischemic stroke after apixaban initiation (5 underdosed and 3 overdosed). Among patients with at least one follow-up encounter, major bleeding occurred in 13 patients (11.7%) with inappropriate dosing compared with 29 patients (6.0%) with appropriate dosing (P = 0.04). Ischemic stroke occurred in 11 patients (9.9%) with inappropriate dosing compared with 15 patients (3.1%) with appropriate dosing (P < 0.01). We concluded that inappropriate DOAC underdosing is common in our region, particularly with apixaban and rivaroxaban. It is associated with increased risk of stroke and bleeding. More education targeting prescribers is needed to encourage adherence to standard dosing criteria.


Extracellular Membrane Vesicles from Lactobacilli Dampen IFN-γ Responses in a Monocyte-Dependent Manner.
Secreted factors derived from Lactobacillus are able to dampen pro-inflammatory cytokine responses. Still, the nature of these components and the underlying mechanisms remain elusive. Here, we aimed to identify the components and the mechanism involved in the Lactobacillus-mediated modulation of immune cell activation. PBMC were stimulated in the presence of the cell free supernatants (CFS) of cultured Lactobacillus rhamnosus GG and Lactobacillus reuteri DSM 17938, followed by evaluation of cytokine responses. We show that lactobacilli-CFS effectively dampen induced IFN-γ and IL-17A responses from T- and NK cells in a monocyte dependent manner by a soluble factor. A proteomic array analysis highlighted Lactobacillus-induced IL-1 receptor antagonist (ra) as a potential candidate responsible for the IFN-γ dampening activity. Indeed, addition of recombinant IL-1ra to stimulated PBMC resulted in reduced IFN-γ production. Further characterization of the lactobacilli-CFS revealed the presence of extracellular membrane vesicles with a similar immune regulatory activity to that observed with the lactobacilli-CFS. In conclusion, we have shown that lactobacilli produce extracellular MVs, which are able to dampen pro-inflammatory cytokine responses in a monocyte-dependent manner.


Enantioselective Synthesis of Silicon-Stereogenic Monohydrosilanes by Rhodium-Catalyzed Intramolecular Hydrosilylation.
Enantiopure monohydrosilanes are versatile chiral reagents for alcohol resolution and mechanistic investigation. Herein, we have demonstrated the asymmetric synthesis of monohydrosilanes via an intramolecular hydrosilylation strategy. This protocol is suitable for the synthesis of five- and six-membered cyclic monohydrosilanes, including a class of chiral oxasilacycles, with excellent diastereo-, regio-, and enantioselectivities. Notably, the catalyst loading could be reduced to 0.1 mol % which makes this one of the most efficient methods to access chiral monohydrosilanes. Mechanistic studies and DFT calculations indicate this Rh-catalyzed intramolecular asymmetric hydrosilylation reaction might proceed via a Chalk-Harrod mechanism, and the enantio-determining step was predicted to be oxidative addition of Si-H bond.


Ecthyma Gangrenosum Secondary to Pseudomonal Sepsis Complicated by Acute Respiratory Distress Syndrome Following Craniotomy for Resection of a Metastasis.
Ecthyma gangrenosum is a rare physical exam finding pathognomonic for severe bacteremia and typically associated with pseudomonal sepsis. The characteristic skin lesions appear as ring-shaped hemorrhagic pustules that evolve into necrotic ulcers. In the present case, a 62-year-old woman with a pulmonary adenocarcinoma treated with surgical resection and adjuvant chemotherapy developed three symptomatic brain masses. The lesions were presumed metastatic and initially treated with stereotactic radiosurgery; however, follow-up imaging identified treatment failure of a cerebellar lesion, and the patient was subsequently taken to surgery on an elective basis for suboccipital craniotomy and tumor resection. Although her initial postoperative course was unremarkable, on postoperative day two, she experienced a rapidly progressive neurologic and hemodynamic decline. During this period, numerous ring-shaped, necrotic cutaneous lesions rapidly appeared, consistent with ecthyma gangrenosum. In spite of multi-modality critical care treatment and resuscitation, including milrinone, multiple vasopressors, anti-pseudomonal antibiotics, and prone positioning, the patient progressed to cardiorespiratory failure and died.


Mapping the intracellular metabolome of yeast biocapsules - Spherical structures of yeast attached to fungal pellets.
Co-culture conditions are beneficial for study due to the advances which arise from symbiotic interactions and which cannot be replicated under pure culture conditions. Here, the focus is on the connection between two fungi - a yeast, Saccharomyces cerevisiae, and a filamentous fungus, Penicillium chrysogenum - in a yeast immobilization system termed' yeast biocapsules', where the yeast and filamentous fungus are strongly attached to one another, forming spherical structures. This co-culture condition hinders filamentous fungal biomass growth, while immobilization of yeast cells continues to increase. The effect of the co-culture condition on endometabolites or intracellular metabolites were tracked during the beginning and end of the yeast biocapsule formation period, and metabolites analyzed by Gas Chromatography-Mass Spectrometry Detector (GC-MSD). Distinct metabolite profiles were found between single culture conditions, involving each organism separately, and with the co-culture condition, where there were differences in 54 endometabolites. Specifically, co-culture condition compounds such as fructose, glycolic acid and glyceric acid were present in higher concentrations at the end of biocapsule formation. These results shed light on the mechanisms and biochemical impact of the interaction between the yeast and filamentous fungus and serve as a basis to apply and further develop yeast biocapsules as a new biotechnological tool with benefits for industry.


Synergistic effect of cyclosporin A and verapamil in overcoming vincristine resistance of multidrug-resistant cultured human leukemia cells.
Reversal of vincristine (VCR) resistance by cyclosporin A (CyA) or the combination of CyA and verapamil (VER) was investigated by using four P-glycoprotein (P-gp)-associated human multidrug-resistant (MDR) cell lines (K562/ADM, KYO-1, HEL and CMK). Drug sensitivity was expressed as 50% inhibitory concentration (IC50). The degree of reversal of resistance was expressed as x-fold decrease by dividing the IC50 value without modifier(s) by that with modifier(s). CyA overcame P-gp-associated MDR significantly in all four MDR cell lines. Reversal of VCR resistance by CyA appeared to be dose-dependent. In the case of low-grade MDR cell lines (KYO-1, HEL and CMK), CyA at the low concentration of 0.5 microgram/ml was still effective. The degree of reversal of VCR resistance in this condition was greater (6.3- to 16-fold decrease) in the low-grade MDR cell lines than in a high-grade MDR cell line (K562/ADM) (2.9-fold decrease). At a high concentration (5 micrograms/ml) of CyA, however, it was greater (240-fold decrease) in the high-grade MDR cell lines than in the low-grade MDR cell line (20- to 100-fold decrease). This indicates that concentration of CyA required for overcoming drug resistance in MDR cells was dependent on the degree of drug resistance. CyA overcame VCR resistance more efficiently than VER. The combination of CyA and VER enhanced reversal of VCR resistance in a supra-additive or at least an additive manner and overcame VCR resistance at low concentrations of both modifiers that are clinically achievable with safety.


Engineered Exosomes as a Photosensitizer Delivery Platform for Cancer Photodynamic Therapy.
Photodynamic therapy (PDT), a non-/minimally invasive cancer treatment method, has the advantages of low side effects, high selectivity, and low drug resistance. It is currently a popular cancer treatment method. However, given the shortcomings of photosensitizers such as poor photostability, poor water solubility, and short half-life in vivo when used alone, the development of photosensitizer nano-delivery platforms has always been a research hotspot to overcome these shortcomings. In the human body, various types of cells generally release bilayer extracellular vesicles known as exosomes. Compared with traditional materials, exosomes are currently an ideal drug delivery platform due to their homology, low immunogenicity, easy modification, high biocompatibility, and natural carrying capacity. Therefore, in this concept, we focus on the research status and prospects of engineered exosome-based photosensitizer nano-delivery platforms in cancer PDT.


Isolation of axial conformers of chloro- and bromocyclohexane in a pure state as inclusion complexes with 9,9'-bianthryl, and the discovery of a novel 1,3 diaxial Cl...H weak interaction.
The axial conformers of chloro- and bromocyclohexane were isolated in a pure state as inclusion complexes with 9,9'-bianthryl, and a 1,3 diaxial Cl...H weak interaction was discovered by X-ray analysis of the axial conformer of chlorocyclohexane.


Anti-hepatoma activity of resveratrol in vitro.
To study the anti-tumor effect of resveratrol alone and the synergistic effects of resveratrol with 5-FU on the growth of H22 cells line in vitro. The number of cells was measured by MTT method the morphological changes of H22 cells were investigated under microscopy and electron microscopy examination. Resveratrol inhibited the growth of hepatoma cells line H22 in a dose- and time-dependent manner, IC50 of the resveratrol on H22 cells was 6.57mg x L(-1),The synergistic anti-tumor effects of resveratrol with 5-FU increased to a greater extent than for H22 cells treated with 5-FU alone (70.2% vs 28.4%) P<0.05 .Under microscope and electron microscope, characteristics of apoptosis such as typical apoptotic bodies were commonly found in tumor cells in the drug-treated groups. Resveratrol can suppresses the growth of H22 cells in vitro,its anti-tumor activity may occur through the induction of apoptosis.


Occult pulmonary artery associated with failure to thrive and recurrent pneumonia--a case report.
Occult pulmonary artery is an uncommon cardiovascular defect. Associated symptoms include recurrent pulmonary infections and congestive heart failure. The authors describe a one-year-old boy initially diagnosed as having broncho-pulmonary dysplasia who developed severe failure to thrive, recurrent pneumonias, and pulmonary hypertension. The presence of an occult right pulmonary artery was suspected by lung perfusion scan and diagnosed by cardiac catheterization and angiography. After surgical repair, his clinical course improved and his growth and development were normal. This case demonstrates the importance of including occult pulmonary artery in the differential diagnosis of infants with failure to thrive associated with recurrent pulmonary infection.


Cellular angiofibroma of the vulva: a poorly known entity, a case report and literature review.
Cellular angiofibroma represents a newly described, site specific tumor. Histologically, CAF is a benign mesenchymal neoplasm characterized by two principal components: bland spindle cells and prominent small to medium-sized vessels with mural hyalinization. The indolent nature of the lesion is underscored by the uniformity of its constituent stromal cells, and their lack of nuclear atypia. Characterization by immunohistochemistry is helpful distinguishing Cellular angiofibroma from other mesenchymal lesions. We report the case of a 37-year-old woman, presenting with a painless nodule involving the vulva. This lesion had gradually increased in size; a simple excision was performed, and follow up was unremarkable. Gross examination showed a well circumscribed, firm tumor measuring 3× 3 × 2,5 cm. Histologically, the tumor was composed of uniform, short spindle-shaped cells, proliferating in an edematous to fibrous stroma and numerous small to medium-sized thick-walled vessels. A panel of immunohistochemical stains was performed, and confirmed the diagnosis of Cellular angiofibroma. In this report we aim to describe the clinical, pathological and immunohistochemical features of this rare entity through a literature review, and to discuss other vulvar mesenchymal lesions.


Rotavirus - Global research density equalizing mapping and gender analysis.
Rotaviruses are the leading reason for dehydration and severe diarrheal disease and in infants and young children worldwide. An increasing number of related publications cause a crucial challenge to determine the relevant scientific output. Therefore, scientometric analyses are helpful to evaluate quantity as well as quality of the worldwide research activities on Rotavirus. Up to now, no in-depth global scientometric analysis relating to Rotavirus publications has been carried out. This study used scientometric tools and the method of density equalizing mapping to visualize the differences of the worldwide research effort referring to Rotavirus. The aim of the study was to compare scientific output geographically and over time by using an in-depth data analysis and New quality and quantity indices in science (NewQIS) tools. Furthermore, a gender analysis was part of the data interpretation. We retrieved all Rotavirus-related articles, which were published on "Rotavirus" during the time period from 1900 to 2013, from the Web of Science by a defined search term. These items were analyzed regarding quantitative and qualitative aspects, and visualized with the help of bibliometric methods and the technique of density equalizing mapping to show the differences of the worldwide research efforts. This work aimed to extend the current NewQIS platform. The 5906 Rotavirus associated articles were published in 138 countries from 1900 to 2013. The USA authored 2037 articles that equaled 34.5% of all published items followed by Japan with 576 articles and the United Kingdom - as the most productive representative of the European countries - with 495 articles. Furthermore, the USA established the most cooperations with other countries and was found to be in the center of an international collaborative network. We performed a gender analysis of authors per country (threshold was set at a publishing output of more than 100 articles by more than 50 authors whose names could be identified in more than 50% of cases) showed a domination of female scientists in Brazil, while in all other countries, male scientists predominate. Relating the number of publications to the population of a country (Q1) and compared to the GPD (Q2), we found that European and African countries as well as Australia and New Zealand - not the USA - were among the top ranked nations. Regarding rotavirus-related scientific output, the USA was the overall leading nation when qualitative and qualitative aspects were taken into account. In contrast to these classical scientometric variables, indices such as Q1 and Q2 enable comparability between countries with unequal conditions and scientific infrastructures helping to differentiate publishing quality and quantity in a more relevant way. Also, it was deduced that counties with a high rotavirus-associated child mortality, like the Democratic Republic of Congo, should be integrated into the collaborative efforts more intensively.


Retention of chylomicron remnants by arterial tissue; importance of an efficient clearance mechanism from plasma.
Atherosclerosis is thought to begin with the trapping of cholesterol rich lipoproteins within the intima of arterial vessels. Thereafter a complex inflammatory cascade involving recruitment and transformation of leukocytes, accumulation of sterols in macrophages and cellular proliferation, can lead to a progressive occlusion in blood flow, or an unstable arterial lesion prone to prothrombotic events. Primary intervention strategies aimed at reducing atherogenesis are designed to achieve reductions in sterol rich lipoproteins, primarily low density lipoproteins, given the hypothesis that decreased exposure will attenuate the rate of arterial cholesterol accumulation. Epidemiological evidence has clearly identified a positive relationship between poor dietary (fat) habits and the onset and progression of atherosclerosis. However lipoproteins which mediate the transport of dietary lipid, that is chylomicrons, are not normally considered to be directly involved in atherogenesis, because of their larger size and inability to efficiently penetrate arterial tissue. In contrast, this article reviews recent evidence which suggests that once chylomicrons are hydrolysed to their remnant form, the triglyceride depleted chylomicron remnants penetrate arterial tissue and moreover, become preferentially trapped within the subendothelial space as concentrated focii. Ongoing studies demonstrate that significant chylomicron remnant accumulation can occur in a number of primary and secondary lipid disorders and in normolipidemic subjects with coronary artery disease. Chylomicron remnant dyslipidemia in conditions prone to premature atherosclerosis is consistent with the putative atherogenicity of these particles and can be explained by increased arterial exposure to cholesterol rich chylomicron remnants.


Role of admission cardiotocography in predicting the obstetric outcome in term antenatal women: A prospective observational study.
Admission cardiotocography (CTG) used for fetal heart rate monitoring is an easy, cost-effective, non-invasive screening method for fetal well-being. To evaluate the role of admission CTG in predicting fetal hypoxia in term antenatal women during labour ward admission and to correlate the results with perinatal and maternal outcomes. The present prospective observational study was conducted in the Obstetrics and Gynecology Department of the rural tertiary centre in Northern India over one year on 100 term antenatal women admitted to the labour ward in the first stage of labour. Participants were subjected to admission CTG for 20 minutes, and the pattern of fetal heart rate (reactive, suspicious, ominous) was recorded. Perinatal and maternal outcomes were assessed based on the fetal heart rate pattern on the admission CTG. Of 100 term antenatal women, 51 were low-risk and 49 were high-risk cases. In the low-risk group, 92.16% had reactive traces, 3.92% suspicious and 3.92% ominous traces on admission CTG, whereas, in the high-risk group, 40.81% had reactive, 32.65% suspicious and 26.54% ominous tracing (p < 0.0001). The most common mode of delivery in both groups with ominous tracing was cesarean section (p = 0.0001). Abnormal CTG was significantly associated with adverse perinatal outcomes including poor one-minute Apgar scores (p < 0.05), need for resuscitation and NICU admission (p < 0.05). The specificity and negative predictive value of admission CTG in low- and high-risk groups were 97.9% and 93.6%, and 85.0% and 85.0%, respectively. Admission CTG is an effective, inexpensive, non-invasive technique to detect fetal hypoxia in low-and high-risk pregnancies in developing countries with an increased workload.


Corrigendum: The epidemiological trend of monkeypox and monkeypox-varicella zoster viruses co-infection in North-Eastern Nigeria.
[This corrects the article DOI: 10.3389/fpubh.2022.1066589.].


Activation of the iNOS gene promoter by Brn-3 POU family transcription factors is dependent upon the octamer motif in the promoter.
The promoter of the gene encoding the inducible nitric oxide synthase (iNOS) contains an octamer motif which is of importance for its activation by specific stimuli. We show that in contrast to the promoter of the neuronal nitric oxide synthase gene (nNOS) which is strongly activated by the Oct-2 octamer-binding POU family transcription factor, the iNOS gene is only weakly activated by Oct-2 via its octamer motif. Unlike the nNOS promoter, however, the iNOS promoter is strongly activated by the POU family transcription factors Brn-3a and Brn-3b. This activation is dependent upon the octamer motif in the iNOS promoter and requires the activation domain located within the POU domain of Brn-3a or Brn-3b but not the N-terminal activation domain of Brn-3a. Thus different but related POU proteins play important roles in the regulation of the genes encoding different forms of nitric oxide synthase.


Impact of perforation size and predictive factors for successful pediatric gelfoam myringoplasty.
Rates of success with pediatric myringoplasty range from 35 to 95%. The objective of this study is to evaluate the impact of perforation size on successful closure of the tympanic membrane (TM) after gelfoam myringoplasty. We also aim to identify variables that affect perforation closure rates and define predictive factors for successful TM closure. A retrospective chart review of all patients that underwent gelfoam myringoplasty by a single surgeon from August 2008 through January 2015 was performed. One hundred fifty-nine patients met inclusion criteria and underwent a total of 219 procedures. Overall, gelfoam myringoplasty had an 83.1% rate of successful closure. Average perforation size was 15.31%. Classification tree analysis separated our cohort into three groups based on perforation size: Group 1 (<16.25%) had a 91% closure rate, group 2 (16.25% to <31.25%) had a 66.0% closure rate and group 3 (≥31.25%) had a 30.0% closure rate. Smaller perforations (P ≤0.001) were associated with increased success rates. Other factors associated with successful closure of the TM included younger age at the time of myringoplasty (P ≤0.001), fewer number of prior tympanostomy tubes (P = 0.016), and lesser duration of tube retention (P = 0.003). Gelfoam myringoplasty provides good overall TM closure rates and may be considered as a potential first-line option for repair of perforations, including those involving up to 40% of the TM. Younger patients with smaller perforations, fewer sets of tubes, shorter length of tube retention are more likely to have successful closure of the tympanic membrane.


Atomic-level analysis of membrane-protein structure.
Membrane proteins are substantially more challenging than natively soluble proteins as subjects for structural analysis. Thus, membrane proteins are greatly underrepresented in structural databases. Recently, focused consortium efforts and advances in methodology for protein production, crystallographic analysis and cryo-EM analysis have accelerated the pace of atomic-level structure determination of membrane proteins.


Spouse similarity for IQ and personality and convergence.
A similar pattern of spousal association for IQ scores and personality traits was found in two British samples from Oxford and Cambridge. There was no indirect evidence from either sample to suggest that convergence occurred during marriage. All observed assortative mating might well be due to initial assortment.


Contractile recovery of heart muscle after hypothermic hypoxia is improved by nicorandil via mitochondrial K(ATP) channels.
The ATP-sensitive potassium channel (K(ATP)) opener nicorandil used instead of potassium in hypothermic cardioplegia significantly improves preservation of cardiac function and energetics in the in situ heart preparation. The present study, therefore, examines the effect of nicorandil at different temperatures and the role of sarcolemmal and mitochondrial K(ATP) channels under ex vivo conditions using contractile force (CF) and action potential duration (APD) as end points. Guinea-pig papillary muscles at 37, 27, or 22 degrees C (1Hz) were exposed to nicorandil 0.2-1.1 mM. The contributions of K(ATP) channel subtypes in cardioprotection were examined using mitochondrial (mito) (0.1 mM) or non-selective (1.0 mM) concentrations of nicorandil, mito K(ATP) blocker 5-hydroxyl decanoate (5HD, 300 microM) or sarcolemmal (sarc) K(ATP) blocker HMR1098 (30 microM) before and during 140 min of hypothermic (22 degrees C) glucose-free hypoxia. Nicorandil >0.5 mM shortened the APD, and this was abolished by hypothermia and HMR1098 but not by 5HD. Nicorandil in both tested concentrations preserved contractile force after hypoxia-reoxygenation significantly better than control (73.7+/-4.4% and 75.8+/-3.9% vs 40.6+/-2.6%, n=6 in each group). Protection was blocked by 5HD but not by HMR1098. 5HD and HMR1098 alone did not change recovery of contractile force compared to control. Shortening of APD and activation of sarc K(ATP) by nicorandil were not related to myocardial protection. Thus, the mito K(ATP) seems to play a significant role in cardioprotection compared to the sarc K(ATP) also when substrate depletion and hypoxia are combined with hypothermia.


Malnutrition is associated with postoperative complications in elderly patients undergoing total hip arthroplasty.
Malnutrition in elderly patients with hip fracture has been described as a factor associated with poor outcomes. This evidence for elderly patients undergoing elective total hip arthroplasty (THA) for osteoarthritis is not well-established. We retrospectively studied a cohort of patients with an age ≥65 years admitted to the hospital for THA between January 2018 and December 2020. Demographic characteristics were collected. Albumin and total lymphocyte count were included in the pre-operative analysis and 24h postoperatively. Nutritional screening was carried out 24h postoperatively. GLIM criteria were applied for the diagnosis of malnutrition. 25 patients out of the total cohort of 65 (38.4%) were malnourished. Five out of six patients (83.3%) with postoperative complications presented malnutrition compared with 20 of 59 patients (33.8%) without postoperative complications (P=0.028). Mean length of stay (LOS) was 3.49±0.88 days. Five out of six (83.3%) patients with postoperative complications presented LOS >3 days compared with one out of six patients (16.6%) with LOS ≤3 days (P=0.009). 26 patients (40%) were referred to a community health centre, no differences in diagnosis of malnutrition were detected compared with patients who were discharged home. Patients with a diagnosis of malnutrition were significantly older, had a lower body mass index (BMI), a lower preoperative and postoperative albumin and worse anthropometric parameters. Malnutrition is associated with postoperative complications and longer LOS in elderly patients with elective THA. Risk factors for malnutrition are older age and low BMI.


D-dimer levels over time after anticoagulation and the association with recurrent venous thromboembolism.
D-dimer measured shortly after discontinuation of anticoagulation by an immunoturbidimetric assay predicts the risk of recurrent venous thromboembolism (VTE). We assessed the performance of this assay over time and its association with recurrent VTE. We followed 556 patients with a first VTE for a median of 9.6 years. The study end point was recurrent VTE. D-dimer was measured 3 weeks, and 3, 9, and 15 months after discontinuation of anticoagulation in plasma using an immunoturbidimetric assay (INNOVANCE D-Dimer). To estimate the effect of longitudinal D-dimer on the recurrence risk, we used a dynamic prediction Cox model with landmark times (3 weeks, and 3, 9, 15 months) as a stratification factor. 135 patients had recurrent VTE. D-dimer levels varied between patients but without a consistent pattern. Levels increased slightly over time [0.7% increase (95% CI: 0.5-0.9; p < 0.001)/month]. D-dimer levels were positively correlated with body mass index (BMI) [2% (95% CI: 1.1-2.9; p < 0.001) increase/1 unit BMI increase], and were 14.8% (95% CI: 5.1-25.3; p = 0.002) higher in women than in men. The recurrence risk with doubling D-dimer levels was higher after 3 weeks, 3, 9 and 15 months [hazard ratios 1.4 (1.06-1.84), 1.37 (1.06-1.77), 1.31 (1.04-1.65) and 1.26 (1.01-1.57), respectively]. In patients with a first VTE, immunoturbidimetric D-dimer levels are associated with the risk of recurrence at multiple times points from 3 weeks up to 15 months after discontinuation of oral anticoagulation.


Experimental short-term fetal bladder outflow obstruction: I. Morphology and cell biology associated with urinary flow impairment.
In fetal sheep, combined urethral and urachal obstruction initiated at 75 days' gestation and maintained for 30 days led to dysmorphic bladders, similar to those found in humans with prune belly syndrome, and uniformly disrupted kidney development. We aimed to create a less severe model of fetal bladder outlet obstruction, more closely resembling infants with posterior urethral valves, and additionally to further our understanding on the role of the urachus. We hypothesized that milder morphological renal tract changes would occur after shorter term experimental obstruction. Male fetal lambs were assigned to urachal and urethral ligation, urachal ligation only or sham operations. Analyses were performed after 9 days. Concurrent urachal and urethral obstruction resulted in increased bladder weight, and protein and DNA content. Detrusor smooth muscle was well maintained, as assessed by light and electron microscopy, although urothelia showed basal apoptosis. Bladder obstruction led to hydronephrosis but failed to produce significant perturbations in urine osmolality. The nephrogenic cortex was either well preserved or was replaced by glomerular cysts; the latter group tended to have heavier bladders. Urachal obstruction alone produced similar changes suggesting that the male sheep fetal urethra is a high-resistance conduit in mid-gestation. Concurrent urachal and urethral obstruction, or urachal obstruction alone, initiated in mid-gestation and maintained for 9 days leads to bladder overgrowth but preserved renal tubular function. In future, it will be interesting to determine whether bladder decompression around this stage leads to reversal of bladder overgrowth and/or ameliorates severe renal tract damage described after longer term fetal bladder outflow obstruction.


Crossed immunoelectrophoresis of rat serum.
A crossed immunoelectrophoresis (X-IEP) reference profile of normal (Sprague-Dawley) rat serum antigens was developed. Twenty-three antigens were detected; 13 were identified. These included inter-alpha-trypsin inhibitor, alpha 1-antichymotrypsin, and fibronectin, which had not previously been identified in rat serum. Many of the antigens were similar electrophoretically to their analogs in human and mouse serum, but some were substantially different. Inter-alpha-trypsin inhibitor, fibronectin, and C3 globulin were more anodic, while transferrin was more cathodic. Rat haptoglobin's mobility was between those of human and mouse haptoglobins. As in the mouse, but more so, alpha-macroglobulin in the rat had alpha 1 mobility rather than alpha 2 seen for this protein in human serum. Only rat alpha 1-antichymotrypsin exhibited a double peak. There were variations in haptoglobin and alpha 1-lipoprotein mobilities among different strains of rat. This establishment of a standard X-IEP map of rat serum will simultaneously permit multiple quantitative and qualitative analyses of rat serum antigens for various experimental and clinical purposes.


Pharmacokinetics and Safety of Vedolizumab Following Administration of a Single Intravenous Dose in Healthy Chinese Subjects.
Vedolizumab is a humanized monoclonal antibody, indicated for the treatment of moderately to severely active ulcerative colitis (UC) or Crohn's disease (CD), that specifically binds to the α4β7 integrin. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of vedolizumab following a single intravenous (IV) infusion in healthy adult Chinese subjects. Sixteen participants received a single IV infusion of vedolizumab (300 mg). Blood samples were collected to measure vedolizumab serum concentrations. The safety of all subjects was monitored. The pharmacokinetic analysis showed that vedolizumab reached the maximum observed serum concentration (Cmax) at approximately 1.32 hours. The mean Cmax and area under the concentration-time curve from time 0 to time of the last quantifiable concentration (AUC0-t) and to infinity (AUC0-∞) were 137.25 µg/mL, 2360 days·µg/mL, and 2395 days·µg/mL, respectively. The elimination of vedolizumab was relatively slow, with a mean terminal disposition phase half-life elimination (t1/2) of 20.23 days. Six subjects were positive for anti-vedolizumab antibodies (AVAs) on day 106 and day 127. Finally, 4 out of 16 subjects (25.0%) had treatment-emergent adverse events (TEAEs), all of which were upper respiratory tract infections. Vedolizumab was well tolerated in healthy Chinese subjects when administered as a single-dose IV 300 mg infusion. In this study, the rate of AVA positivity was 37.5%, which occurred near the end of the study; no significant differences in pharmacokinetic profiles were observed between the AVA-positive and AVA-negative groups. http://www.chinadrugtrials.org.cn : CTR20171528.


Posterior mono-segmental fixation, combined with anterior debridement and strut graft, for treatment of the mono-segmental lumbar spine tuberculosis.
A retrospective study was conducted to determine the beneficial effect of posterior mono-segmental fixation, combined with anterior debridement and strut graft for the treatment of mono-segmental lumbar spine tuberculosis. From February 2002 to February 2008, a total of 34 cases with mono-segmental lumbar spine tuberculosis were treated by posterior mono-segmental fixation, combined with anterior debridement and strut graft. The degree of damage to the patients' vertebral bodies was 1/3-2/3 height. Antituberculous therapy was performed both before and after surgery. None of the patients suffered from spinal cord, nerve, great vessel or organ damage, with all patients passing through the peri-operative period successfully. Graft union was observed four to six months after surgery, with a mean of five months. In addition, no fracture or prolapsed internal fixation was found. The Cobb's angle prior to and after surgery, and at the final follow-up were 22.70 ± 9.8°, 4.5 ± 8.4° and 5.30 ± 7.10°, respectively, with a mean correction of 18.20 ± 5.8° after surgery; however, 1.70 ± 1.0° loss was observed at the final follow-up. Four cases with neurological lesions recovered to 'E' grade. At the final follow-up, all patients could live and work normally. The results demonstrated that for cases with 1/3-2/3 height of vertebral body damaged in mono-segmental lumbar spine tuberculosis, treatment with posterior mono-segmental fixation, combined with anterior debridement and strut graft, can cure foci, rebuild spinal stability, reduce fused segments, and retain maximal function of the motion units.