Activation of α7 nicotinic acetylcholine receptor alleviates Aβ1-42-induced neurotoxicity via downregulation of p38 and JNK MAPK signaling pathways.
Amyloid β peptide 1-42 (Aβ1-42) could induce cognitive deficits through oxidative stress, inflammation, and neuron death in Alzheimer's disease (AD). MAPK pathways have been thought to mediate Aβ1-42-induced neuroinflammation responses, neuron death and cognitive decline in AD. The α7 nicotinic acetylcholine receptor (α7nAChR) exerts a neuroprotective effect. However, whether α7nAChR alleviates Aβ1-42-induced neurotoxicity through MAPKs (p38, ERK, JNK) in vivo remains unclear. In our study, memory was assessed in C57BL/6 mice using a Y-maze test. Cell death was assessed by Nissl and Hoechst staining and Bax, Bcl-2, Caspase 3, and Cytochrome C levels using Western blotting. Oxidative stress was assayed by superoxide dismutase (SOD), catalase (CAT), and malondialdehyde (MDA) levels. Inflammation was examined with GFAP and Iba1 using immunohistochemistry. The Aβ degrading enzymes insulin degrading enzyme (IDE) and neprilysin (NEP) were tested using Western blotting. We found that activating α7nAChR or inhibiting p38 or JNK pathway alleviated Aβ1-42-induced cognitive deficits and neuron loss and death by reducing oxidative stress. In addition, activating α7nAChR or inhibiting p38 or JNK pathway also reduced inflammation, which was observed as reduced GFAP and Iba1 levels with different effects on Aβ degrading enzymes. Finally, we found that the activation of α7nAChR led to the downregulation of pp38 and pJNK levels. Conversely, the inhibition of p38 or JNK resulted in the upregulation of α7nAChR levels in the hippocampus and cortex. Our data indicate that the activation of α7nAChR alleviates Aβ1-42-induced neurotoxicity, and this protective effect might act through the downregulation of p38 and JNK MAPKs.


Production of patulin by Micromycetes.
In the context of the screening for antifungal and antibacterial molecules among the Micromycetes, we investigated the ability of 850 strains grown in liquid medium to produce patulin. The compound was produced by 58 fungi, most of which had not been mentioned in the literature, especially Mucorales and Fungi Imperfecti. Biological tests showed that dermatophytes are the most sensitive to this molecule. It also appears that the origin of the producing strains influences their toxin producing activity.


Choice of birth place among antenatal clinic attendees in rural mission hospitals in Ebonyi State, South-East Nigeria.
Low utilization of health facilities for delivery by pregnant women poses a public health challenge in Nigeria. To determine the factors that influence the choice of birth place among antenatal clinic attendees. This was a cross-sectional study of the eligible antenatal clinic attendees recruited at Mater Misericordiae Hospital, Afikpo and Saint Vincent Hospital, Ndubia in Ebonyi State from February 1, 2016 to June 30, 2016. Analysis was done using EPI Info 7.21 software (CDC Atlanta Georgia). A total of 397(99.3%) completely filled questionnaires were collated and analysed. Approximately 71% of the health facilities closest to the respondents had maternity services. It took at least 1 hour for 80.9% of the respondents to access health facilities with maternity services. Most (60.2%) of the respondents had at least one antenatal clinic attendance and majority of them did so at public hospitals. Approximately 43.8% of the respondents were delivered by the skilled birth attendants. The respondents' age and the couple's educational level, history of antenatal clinic attendance, distance of the health facility and availability of transport fare had a significant effect on delivery by skilled birth attendants. The common determinants of birth place were nearness of the health facilities, familiarity of healthcare providers, improved services, sudden labour onset and cost. Also 61.7% of the respondents chose to deliver in public health facilities due to favourable reasons but this could be hampered by the rudeness of some healthcare providers at such facilities. A significant proportion of private health facilities had unskilled manpower and shortage of drugs. A greater proportion of women will prefer to deliver in health facilities. However there are barriers to utilization of these facilities hence the need to address such barriers.


Chondrocytes harvested from osteochondritis dissecans cartilage are able to undergo limited in vitro chondrogenesis despite having perturbations of cell phenotype in vivo.
Our objective was to characterize the variation in gene expression for key genes associated with chondrogenic phenotype of osteochondrosis (OC)-affected and normal chondrocytes, and to identify whether OC chondrocytes can redifferentiate and regain a phenotype similar to normal chondrocytes if appropriate chondrogenic signals are given. Equine articular cartilage removed at surgery to treat clinically significant OC lesions was collected (n = 10), and the gene expression evaluated and compared to aged-matched normal samples (n = 10). Cartilage was harvested from normal (n = 4) and OC (n = 3) joints from horses at necropsy. Chondrogenic pellet cultures were established following monolayer proliferation. After 14 days in culture, the pellets were assessed by histochemical and pellet weight analysis, assay of glycosaminoglycan (GAG) content, and gene expression. Chondrocytes from OC cartilage expressed significantly more Coll-I, -II, -III, and -X than chondrocytes from normal cartilage (all p < 0.0001). Furthermore, OC chondrocytes expressed significantly more MMP-13, ADAMTS-4 (both p < 0.0001), and TIMP-1 (p < 0.001) and significantly less TIMP-2 and TIMP-3. Pellets created from OC chondrocytes contained significantly less GAG (p = 0.0069) and expressed significantly less Sox9 and significantly more superficial zone protein (SZP) (p = 0.0105) than pellets created from normal cartilage. The results suggest that chondrocytes from OC cartilage at the time of surgical treatment have perturbations in phenotype compared to cells from normal cartilage. Despite these differences, following monolayer expansion and pellet culture under chondrogenic conditions, chondrocytes derived from OC cartilage retain some ability to undergo chondrogenic differentiation and synthesize an appropriate cartilage-like matrix. However, this chondrogenic differentiation potential is inferior to that seen in aged-matched normal chondrocytes.


Nomilin targets the Keap1-Nrf2 signalling and ameliorates the development of osteoarthritis.
Osteoarthritis (OA) is a long-term and inflammatory disorder featured by cartilage erosion. Here, we describe nomilin (NOM), a triterpenoid with inflammation modulatory properties in variety of disorders. In this study, we demonstrated the latent mechanism of NOM in alleviating the progress of OA both in vitro and in vivo studies. The results showed that NOM pre-treatment suppressed the IL-1β-induced over-regulation of pro-inflammation factors, such as NO, IL-6, PGE2 , iNOS, TNF-α and COX-2. Moreover, NOM also down-regulates the degradation of ECM induced by IL-1β. Mechanistically, the NOM suppressed NF-κB signalling via disassociation of Keap1-Nrf2 in chondrocytes. Furthermore, NOM delays the disease progression in the mouse OA model. To sum up, this research indicated NOM possessed a new potential therapeutic option in osteoarthritis.


Adjuvant PEFG (cisplatin, epirubicin, 5-fluorouracil, gemcitabine) or gemcitabine followed by chemoradiation in pancreatic cancer: a randomized phase II trial.
Information from randomized trials on the role of combination chemotherapy in the adjuvant treatment of pancreatic adenocarcinoma is limited. This randomized phase II trial aimed to identify the most promising regimen warranting phase III evaluation. Therapy-naive patients, age 18-75 years, Karnofsky Performance Status (KPS)>60, gross total resection of stage IB-III pancreatic adenocarcinoma, stratified for center and surgical margins, were randomly assigned to receive either gemcitabine 1 g/m2 weekly on days 1, 8, and 15 (arm A) or the PEFG regimen (cisplatin and epirubicin 40 mg/m2, day 1; gemcitabine 600 mg/m2, days 1, 8; 5-fluorouracil 200 mg/m2 daily, days 1-28) (arm B). Chemotherapy was administered every 4 weeks for 3 months and followed by irradiation concurrent to continuous infusion of 5-fluorouracil 250 mg/m2 daily. Primary endpoint was the probability of being disease-free at 1 year from surgery. Assuming P0=35% and P1=55%, α=.05 and β=.10, the study was to enroll 51 patients per arm. A total of 102 patients were randomized; 100 were eligible (arm A: 51; arm B: 49). Baseline characteristic (A/B) were: Median age was 61/60 years; 75% had KPS>80 75/76%; 36% grade 3 tumor 29/43%, 79% stage IIB/III 75/84%, 31% R1 resection 35/29%. Survival figures (A/B) were: Median disease-free survival was 11.7 and 15.2 months; 1-year disease-free survival 49.0% (95% confidence interval [95% CI] 35-63%) and 69.4% (95% CI 56-83%); median survival 24.8 and 28.9 months. Combination chemotherapy produced more hematological toxicity without relevant differences in nonhematological toxicities. The 4-drug regimen deserves further assessment in resectable pancreatic cancer.


MALDI-TOF MS database expansion for identification of Bacillus and related genera isolated from a pharmaceutical facility.
Bacillus and related genera are among the main bacterial groups isolated from pharmaceutical production areas. The identification of Bacillus species and related genera by classical methods is particularly difficult, due to similarities between closely related species. The Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) is one of the most promising techniques for chemotaxonomic characterization of microorganisms, being an alternative to genotypic methods. This study aimed to identify Bacillus strains and related genera isolated from immunobiological production areas by phylogenetic analysis of housekeeping genes and expand the database associated with MALDI-TOF MS to improve their identification. In a previous study, 97 aerobic endospore-forming bacteria isolated from a pharmaceutical facility were analyzed by MALDI-TOF MS and 16S rRNA gene full-length sequencing. All strains were identified as Bacillus and related genera by the latest methodology. Among the 97 strains, 22 were unidentified and 2 strains were misidentified by MALDI-TOF MS. In the present study, these 24 strains were subjected to 16S rRNA gene phylogenetic analysis. Strains not identified at species level by this methodology were submitted to rpoB gene phylogenetic analysis. After identifying the strains, 19 of the 24 strains were incubated for 24, 48, and 72 h on Tryptic Soy Agar and Sheep Blood Agar and subjected to analysis by MALDI-TOF MS. A SuperSpectrum for each strain was created and entered into the equipment database. Finally, the 24 strains were again submitted to proteomic analysis by MALDI-TOF MS, and, at this time, all were correctly identified. The genotypic identification of in-house isolated strains and the introduction of these spectra in MALDI-TOF MS, in order to obtain a customized database, proved to be an extremely effective tool in the identification of Bacillus and related genera from pharmaceutical industry origin.


Combination of platelet-rich plasma and platelet gel in treatment of resistance androgenic alopecia: A case series study.
Androgenic alopecia is a common genetic disorder that characterized by progressive hair follicles and hair atrophy. Despite all available therapeutic techniques, there is low patient satisfaction rate. It seems finding new treatment options for androgenic alopecia is necessary. In the past decade, platelet-rich plasma (PRP), an autologous collection of concentrated platelets with hemostatic and tissue repairing effects, has received developing attention for androgenetic alopecia treatment as a valuable therapeutic technique. In this study, 8 patients suffering from resistance androgenic alopecia were enrolled. The PRP and platelet gel were prepared, and a total volume of 10 cc of the combination of PRP and platelet gel were injected in the scalp androgen-related areas using 23-gauge syringe. The treatment was performed one month and 3 months after first injection (three times). The hair pull test was done before treatment. The outcome was evaluated 3, 6, and 9 months after treatment by hair pull test, dermoscopy, photography, and patient's satisfaction. A significant reduction in hair loss was observed before and after treatment. Hair count (density) increased from average number of 72 (hair/cm2 ) to 210 hair/cm2 ). Also, the hair diameter was significantly increased before and after treatment for all patients (p < 0.05). After the treatment, the pull test was significantly decreased in 8 patients (p < 0.05). This study supports the combination therapy of PRP and platelet gel for resistance androgenic alopecia treatment. This technique is an uncomplicated, feasible, and cost-effective treatment option for resistance androgenic alopecia, with high patient satisfaction.


Valorization of millet agro-residues for bioenergy production through pyrolysis: Recent inroads, technological bottlenecks, possible remedies, and future directions.
Millets are receiving increasing attention, lately, in view of their preeminent agronomic traits, nutritional significance, and renewed emphasis on highlighting their health benefits through national and international programs. As a consequence, a variety of millets are being cultivated in different parts of the world resulting in significant amount of millet agro-residues. Present study comprehends critical analysis of reported investigations on pyrolysis of different millet agro-residues encompassing (i) physico-chemical characterization (ii) kinetics and thermodynamic parameters (iii) reactors employed and (iv) relationship between the reaction conditions and characteristics of millets-derived biochar and its prospective applications. Based on the analysis of reported investigations, specific research gaps have been figured out. Finally, future directions for leveraging the energy potential of millet agro-residues are also discussed. The analysis elucidated is expected to be useful for the researchers for making further inroads pertaining to sustainable utilization of millet agro-residues in tandem with other commonly employed agro-residues.


A new class of pyrazolopyridine nucleus with fluorescent properties, obtained through either a radical or a Pd arylation pathway from N-azinylpyridinium N-aminides.
The synthesis of dipyridopyrazole and pyridopyrazolopyrazine derivatives--both of which incorporate a 3-aryl moiety--can be achieved in moderate yields by intramolecular radical arylation of pyridinium N-aminides using tris(trimethylsilyl)silane and azobisisobutyronitrile. Improved results were obtained on using Pd direct arylation in conjunction with microwave irradiation. A preliminary study into the fluorescent properties of the target compounds is also reported.


Pathophysiological basis of drug-induced dyskinesias in Parkinson's disease.
Drug-induced dyskinesias (DID) represent a troublesome, dose-limiting, and common complication of long-term pharmacotherapy in Parkinson's disease (PD) patients. The pathophysiological basis and clinical nature of DID is of major interest for clinicians and neuroscientists. In this review article, we evaluate the theories of pathophysiology and molecular basis of DID, validity of various animal models used in DID related research, and electrophysiological characteristics of various basal ganglia nuclei during DID. We also discuss the relevance of various treatment strategies to the pathophysiological mechanisms.


Assessment of Commonly Measured Wastewater Parameters to Estimate Sewershed Populations for Use in Wastewater-Based Epidemiology: Insights into Population Dynamics in New York City during the COVID-19 Pandemic.
Understanding per capita rates of disease incidence or prevalence from wastewater surveillance data requires an estimate of the population contributing to wastewater samples, given that populations in large urban areas are dynamic, especially if major events, such as the onset of the COVID-19 pandemic, cause large population shifts. To assess whether commonly measured wastewater parameters can be used to estimate sewershed populations, we used wastewater data collected from New York City's (NYC) 14 wastewater treatment facilities to evaluate the relationship between influent loads of four wastewater parameters-ammonia, total Kjeldahl nitrogen, total suspended solids, and five-day carbonaceous biochemical oxygen demand-and census-based population estimates of the corresponding sewersheds during 2019, when populations were assumed to be relatively stable. Ammonia mass load had the most consistent relationship with sewershed population, regardless of wet weather contributions to NYC's predominantly combined sewer system. Changes in ammonia loads due to COVID-19 restrictions enacted in March 2020 generally reflected population shifts in sewersheds serving areas of Manhattan and Brooklyn, for which previous studies report decreased commuter mobility and residential populations. Our findings highlight the utility of ammonia mass load in influent wastewater as a population indicator to normalize wastewater-based epidemiology data and track sewershed population dynamics.


Single-shot, low-dose intratympanic gentamicin in Ménière disease: role of vestibular-evoked myogenic potentials and caloric test in the prediction of outcome.
The aim of this study was to assess the efficacy and safety of single and low-dose intratympanic gentamicin therapy in patients with Ménière disease and who were monitored both with caloric tests and vestibular-evoked myogenic potentials (VEMPs) to see if VEMPs have an additional role in predicting the efficacy of the drug. This is a prospective cohort study. Tertiary referral center is the study setting. Twenty-five intractable Ménière disease patients were included as the study group. Low-dose (16 mg/mL), single-shot intratympanic gentamicin was applied. VEMP and caloric test were applied 2 weeks after the application. Safety and efficacy of protocol were evaluated at the sixth month postoperatively with tonal audiogram and visual analog scale, respectively. Mean average pure-tone hearing threshold at 0.5, 1, 2, 4, and 8 kHz was 49.6 and 51.0 dB before and after the application, respectively (P > .05). Mean pretreatment and posttreatment visual analog scale scores of patients were 17.6 mm (10-30 mm) and 74.6 mm (41-100 mm), respectively (P < .01). Posttreatment VEMPs were absent in 17, deteriorated in 2, and not changed in 6 patients. VEMP was a significant predictor of posttreatment visual analog scale score, whereas caloric test was not (P < .01). Low-dose, single-shot intratympanic gentamicin treatment proved to be effective and safe among intractable Ménière patients. VEMPs obtained at posttreatment second week were significant predictors of patients posttreatment sixth-month dizziness status and vertigo control.


More than a hundred thousand respondents within 48 h: How the power of social media helped to understand pregnancy loss in Poland - A retrospective population-based cohort study.
Miscarriage is defined as the loss of pregnancy before 20-24 weeks of gestation, and it is the most common complication of early pregnancy. The aim of the study was to determine the prevalence and risk factors of spontaneous abortion in the population of Polish females to provide a reference for clinical work. A cross-sectional self-administered on-line survey was distributed between 4th and 5th of October 2019 in the social media across Poland. A total of 100,026 recipients responded to the questionnaire and 93,636 valid respondents were included in the analyses. Among respondents who had ever been pregnant, 31.2% reported at least one spontaneous abortion. The prevalence of miscarriage varied based on age, parity, place of residence and the education level. The first symptom of miscarriage was a vaginal bleeding (56.2%) and abdominal cramps (25.8%), while 43% of respondents had no symptoms and found out during doctor's visit. No medical assistance was required after complete spontaneous abortion in 39.2% of cases. Miscarriage is a common complication of pregnancy, but it is not yet fully understood. The goal of future medicine is to minimize the medicalization of spontaneous abortion and excessive medical intervention by raising awareness about natural miscarriage route.


Body segment inertial parameter estimation for the general population of older adults.
The practical determination of accurate body segment inertial parameters for the general older adult population remains a problem, especially in estimating these parameters for women and accounting for variations in body type. A method is presented for determining the mass and center of mass location of the body segments of individuals within the general population of older adults. Effects of sex and body type on older adult mass distribution are accounted for using 32 easily obtainable body measurements. The method is based on existing results from different data sources and employs a combination of validated estimation approaches, including: body mass and segment length proportions, linear and nonlinear regression equations, and a mathematical model of the trunk. The method was applied to a validation sample of healthy, community-dwelling older adults (29 men, 50 women). Predicted body mass was 96.7+/-4.8% and 95.7+/-3.7% of measured body mass in the men and women, respectively. The estimates of body segment mass and trunk center of mass location for the sample population approximate those reported in the literature, supporting the validity of the described method. By producing practical, subject-specific estimates of body segment inertial parameters, the method should allow more accurate biomechanical analyses of the older adult population.


A scoping review on psychosocial consequences of pandemics on parents and children: Planning for today and the future.
The COVID-19 worldwide pandemic has forced individuals into an unnatural way of life. Families with children experience unique stressors, such as school closures, disrupted childcare arrangements, requirement of parents to uptake additional responsibilities such as homeschooling, possible financial strain, and lack of breathing space between family members. The adjustments required of parents and children during a pandemic presumably impacts the psychosocial wellbeing of parents and children in different ways. To better under the psychosocial consequences of pandemics on parents, children, and youth, this scoping review used Arksey and O'Malley (2005) five-stage framework to examine the existing research literature on Severe Acute Respiratory Syndrome (SARS), Influenza Type A virus (H1N1), and COVID-19 to answer the following two research questions: (1) What are the psychosocial consequences of pandemics on parents of children and youth? (2) What are the psychosocial consequences of pandemics on children and youth? With the application of inclusion criteria, 29 articles were selected for analysis. Four major themes, including sub-themes emerged: 1) Each family members' emotions influence one another; 2) Parents experience greater levels of psychosocial problems than adults without children; 3) During a pandemic, parents require informal (social) and formal (specialized professional) support and; 4) Psychosocial consequences of pandemics on children/youth are understudied, indicating the need for more research on children/youth under the age of 20 years. Clinical prevention and intervention suggestions to support the psychosocial wellbeing of parents, children and youth during a pandemic are discussed.


Accurate virus identification with interpretable Raman signatures by machine learning.
Rapid identification of newly emerging or circulating viruses is an important first step toward managing the public health response to potential outbreaks. A portable virus capture device, coupled with label-free Raman spectroscopy, holds the promise of fast detection by rapidly obtaining the Raman signature of a virus followed by a machine learning (ML) approach applied to recognize the virus based on its Raman spectrum, which is used as a fingerprint. We present such an ML approach for analyzing Raman spectra of human and avian viruses. A convolutional neural network (CNN) classifier specifically designed for spectral data achieves very high accuracy for a variety of virus type or subtype identification tasks. In particular, it achieves 99% accuracy for classifying influenza virus type A versus type B, 96% accuracy for classifying four subtypes of influenza A, 95% accuracy for differentiating enveloped and nonenveloped viruses, and 99% accuracy for differentiating avian coronavirus (infectious bronchitis virus [IBV]) from other avian viruses. Furthermore, interpretation of neural net responses in the trained CNN model using a full-gradient algorithm highlights Raman spectral ranges that are most important to virus identification. By correlating ML-selected salient Raman ranges with the signature ranges of known biomolecules and chemical functional groups—for example, amide, amino acid, and carboxylic acid—we verify that our ML model effectively recognizes the Raman signatures of proteins, lipids, and other vital functional groups present in different viruses and uses a weighted combination of these signatures to identify viruses.


Exercise and sodium butyrate transform a subthreshold learning event into long-term memory via a brain-derived neurotrophic factor-dependent mechanism.
We demonstrate that exercise enables hippocampal-dependent learning in conditions that are normally subthreshold for encoding and memory formation, and depends on hippocampal induction of brain-derived neurotrophic factor (BDNF) as a key mechanism. Using a weak training paradigm in an object location memory (OLM) task, we show that sedentary mice are unable to discriminate 24 h later between familiar and novel object locations. In contrast, 3 weeks of prior voluntary exercise enables strong discrimination in the spatial memory task. Cognitive benefits of exercise match those attained with post-training sodium butyrate (NaB), a histone deacetylase (HDAC) inhibitor previously shown to enable subthreshold learning. We demonstrate that the enabling effects of exercise and NaB on subthreshold OLM learning are dependent on hippocampal BDNF upregulation, and are blocked by hippocampal infusion of BDNF short-interfering RNA. Exercise and NaB increased bdnf transcripts I and IV, and the increases were associated with BDNF promoter acetylation on H4K8 but not H4K12. These data provide support for the concept that exercise engages epigenetic control mechanisms and serves as a natural stimulus that operates in part like NaB and potentially other HDAC inhibitors, placing the brain into a state of readiness for plasticity.


NIR-II Responsive Upconversion Nanoprobe with Simultaneously Enhanced Single-Band Red Luminescence and Phase/Size Control for Bioimaging and Photodynamic Therapy.
Lanthanide based upconversion (UC) nanoprobes have emerged as promising agents for biological applications. Extending the excitation light to the second near-infrared (NIR-II), instead of the traditional 980/808 nm light, and realizing NIR-II responsive single-band red UC emission is highly demanded for bioimaging application, which has not yet been explored. Here, a new type of NIR-II (1532 nm) light responsive UC nanoparticles (UCNPs) with enhanced single-band red UC emission and controllable phase and size is designed by introducing Er3+ as sensitizer and utilizing Mn2+ as energy manipulator. Through tuning the content of Mn2+ in NaLnF4 :Er/Mn, the crystal phase, size, and emitting color are readily controlled, and the red-to-green (R/G) ratio is significantly increased from ≈20 to ≈300, leading to NIR-II responsive single band red emission via efficient energy transfer between Er3+ and Mn2+ . In addition, the single band red emitting intensity can be further improved by coating shell to avoid the surface quenching effect. More importantly, NIR-II light activated red UC bioimaging and photodynamic therapy through loading photosensitizer of zinc phthalocyanine are successfully achieved for the first time. These findings provide a new strategy of designing NIR-II light responsive single-band red emissive UCNPs for biomedical applications.


Chronic exposure by ingestion of environmentally relevant doses of (226)Ra leads to transient growth perturbations in fathead minnow (Pimephales promelas, Rafinesque, 1820).
To assess the impact of environmentally relevant levels of ingested (226)Ra on a common freshwater fish species. Fathead minnow (Pimephales promelas, Rafinesque) were obtained at the first feeding stage and established on a commercial fish food diet containing (226)Ra in the activity range 10 mBq/g(-1), -10,000 mBq/g(-1). They remained on this diet for 24 months and were sampled invasively at 1,6,18 and 24 months to assess growth, biochemical indices and accumulated dose and non-invasively also at 12 and 15 months to assess growth. Fish fed 10 and 100 mBq/g(-1) diet showed a small transitory deregulation of growth at 6 and 12 months. Fish fed higher activities showed less significant or insignificant effects. There was a trend at 18 months which was stronger at 24 months for the population distribution to change in all of the (226)Ra fed groups so that smaller fish were smaller and bigger fish were bigger than the controls. There were also significant differences in the ratios of protein:DNA at 24 months which were seen as a trend but were not significant at earlier time points. Fish fed a radium diet for 2 years show a small and transitory growth dysregulation at 6 and 12 months. The effects predominate at the lower activities suggesting hormetic or homeostatic adjustments. There was no effect on growth of exposure to the high activities (226)Ra. This suggests that radium does not have a serious impact on the ecology of the system and the level of radium that would be transferred to humans is very low. The results may be important in the assessment of long-term environmental impacts of (226)Ra exposure.


Guanine nucleotide-binding protein regulation of microsomal phospholipase D activity of canine cerebral cortex.
The hydrolytic activity of microsomal phospholipase D from canine cerebral cortex was measured by a radiochemical assay using 1,2-dipalmitoyl-sn-glycerol-3-phosphoryl[3H]choline and 1-palmitoyl-2-[9,10(n)-3H]palmitoyl-sn-glycerol-3-phosphorylcholine as the exogenous substrates. Of several detergents tested, Triton X-100 was found to be the most effective in allowing expression of phospholipase D hydrolytic activity. The microsomal phospholipase D does not require any metal ion for its hydrolytic activity. Calcium and magnesium were slightly inhibitory between concentrations of 1 and 4 mM, but zinc was greatly inhibitory, causing a loss of greater than 90% activity at the 4 mM concentration. Non-hydrolyzable guanine nucleotide analogues such as guanosine 5'-(3-O-thio)triphosphate and guanyl-5'-yl-(beta, gamma-methylene)diphosphonate but not guanosine 5'-(2-thio)diphosphate were able persistently to stimulate phospholipase D hydrolytic activity at micromolar concentrations. Guanosine 5'-(2-thio)diphosphate was capable of partially blocking guanosine 5'-(3-O-thio)triphosphate stimulation of phospholipase D. Aluminum fluoride was able to cause a two- to threefold increase in hydrolytic activity of the phospholipase D. Cholera toxin had a stimulatory effect on the hydrolytic activity of phospholipase D, whereas islet-activating protein pertussis toxin had no effect. These results indicate that regulation of microsomal phosphatidylcholine phospholipase D activity by the guanine nucleotide-binding protein(s) in canine cerebral cortex may play an important role in signal transduction processes as well as in brain choline metabolism.


18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study.
To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.


Low postnatal care rates in two rural counties in Anhui Province, China: perceptions of key stakeholders.
to explore the perceptions of stakeholders on postnatal care and to describe the rate of postnatal home visits in two rural counties in Anhui Province, China. this was a mixed methods study which uses mainly qualitative methods including focus group discussions, in- depth interviews and key informant interviews. A household survey of postpartum women was used to calculate the rates of postnatal home visits. two rural counties in Anhui Province, China. qualitative study participants: officials responsible for maternal health care at county level, health providers at township and village level and maternal health-care users. Household survey participants: 2326 women who gave birth in the two counties from January 2005 to December 2006. the survey of postpartum women revealed that only 4.2% and 4.5% of women received one or more postnatal visits at home in County A and County B. Qualitative interviews revealed a range of perceived reasons for this low rate of provision and utilisation of postnatal care, including: inadequate funding for maternal health care; limited human resources; lack of transport in township hospitals; and limited value placed on postnatal care by women and providers. In addition, where services were provided, a number of factors were likely to restrict health providers from delivering high-quality postnatal health service, such as: weak skills and knowledge of staff; inadequate in-service training; lack of equipment in township hospitals; and poor supervision and monitoring. the rate of postnatal visits was extremely low in two counties in rural China. Understaffing and inadequate funding are the main factors that affect provision of postnatal health care. more emphasis should be attached to political support and funding for postnatal care. Research into feasible ways to provide quality postnatal care needs to be conducted.


Association between anion gap and all-cause mortality of critically ill surgical patients: a retrospective cohort study.
There are few widely accepted and operationally feasible models for predicting the mortality risk of patients in surgical intensive care unit (SICU). Although serum anion gap (AG) is known to be correlated with severe metabolic acidosis, no investigations have been reported about the association between AG level and the outcome during hospitalization in SICU. This study aimed to explore the predictive power of AG for 90-day all-cause mortality in SICU. Data of the eligible patients in SICU from 2008 to 2019 was obtained from the Medical Information Mart for Intensive Care IV version 2.0 (MIMIC-IV v2.0) database. Baseline clinical data of the selected patients was compared in different groups stratified by the outcome during their admission via univariate analysis. Restricted cubic spline (RCS) was drawn to confirm the relationship of AG and the short-term mortality. Kaplan-Meier survival curve was plotted in different AG level groups. Univariate and multivariate Cox analyses were performed, and Cox proportional-hazards models were built to investigate an independent role of AG to predict 90-day all-cause mortality risk in SICU. Receiver operating characteristics (ROC) curves analysis was performed to evaluate the predictive value of AG on the 90-day prognosis of patients. A total of 6,395 patients were enrolled in this study and the 90-day all-cause mortality rate was 18.17%. Univariate analysis showed that elevated serum AG was associated with higher mortality (P < 0.001). RCS analysis indicated a positively linear relationship between serum AG and the risk of 90-day all-cause mortality in SICU (χ2 = 4.730, P = 0.193). Kaplan-Meier survival analysis demonstrated that low-AG group (with a cutoff value of 14.10 mmol/L) had a significantly higher cumulative survival rate than the counterpart of high-AG group (χ2 = 96.370, P < 0.001). Cox proportional-hazards models were constructed and confirmed the independent predictive role of AG in 90-day all-cause mortality risk in SICU after adjusting for 23 confounding factors gradually (HR 1.423, 1.246-1.625, P < 0.001). In the further subgroup analyses, a significant interaction was confirmed between AG and sepsis as well as surgery on the risk for the 90-day mortality. The ROC curve showed that the optimal cut-off value of AG for predicting 90-day mortality was 14.89 with sensitivity of 60.7% and specificity of 54.8%. The area under curve (AUC) was 0.602. When combined with SOFA score, the AUC of AG for predicting 90-day prognosis was 0.710, with a sensitivity and specificity of 70% and 62.5% respectively. Elevated AG (≥ 14.10 mmol/L) is an independent risk factor for predicting severe conditions and poor prognosis of critical ill surgical patients.


Automatic classification and segmentation of single-molecule fluorescence time traces with deep learning.
Traces from single-molecule fluorescence microscopy (SMFM) experiments exhibit photophysical artifacts that typically necessitate human expert screening, which is time-consuming and introduces potential for user-dependent expectation bias. Here, we use deep learning to develop a rapid, automatic SMFM trace selector, termed AutoSiM, that improves the sensitivity and specificity of an assay for a DNA point mutation based on single-molecule recognition through equilibrium Poisson sampling (SiMREPS). The improved performance of AutoSiM is based on accepting both more true positives and fewer false positives than the conventional approach of hidden Markov modeling (HMM) followed by hard thresholding. As a second application, the selector is used for automated screening of single-molecule Förster resonance energy transfer (smFRET) data to identify high-quality traces for further analysis, and achieves ~90% concordance with manual selection while requiring less processing time. Finally, we show that AutoSiM can be adapted readily to novel datasets, requiring only modest Transfer Learning.


Association of congenital microtia with environmental risk factors in South Korea.
Though there are reports regarding congenital microtia in various populations, few studies have focused on patients in South Korea. The objectives of the present study were to investigate the characteristics of microtia in South Korea and demonstrate the contribution of environmental risk factors to the occurrence of microtia. We performed a retrospective chart review of congenital microtia patients who presented to our institution between January 2002 and December 2010. A case-control study was performed in 169 microtia patients and 128 controls to investigate the impact of environmental and prenatal factors on the development of congenital microtia. The data were gathered by personal interviews and detailed questionnaires filled out by the patients' parents. A total of 374 microtia patients were included in the present study. Most cases were sporadic, and most were male. Unilateral microtia was more common, especially on the right side, while bilateral microtia occurred in only 25 patients. Two hundred forty-three patients had isolated microtia with no other congenital anomalies. In subgroups divided by type, lobule-type microtia was more common than concha-type microtia, and patients with anotia were the least common. Risk factors analyzed using multivariate regression models between groups, resident area during pregnancy, threatened abortion history, rubella vaccination, medication history during the first trimester, and alcohol consumption during the first trimester had significant impacts on the development of isolated microtia. The characteristics of congenital microtia in South Korea are similar to those in other populations, including the predominance of sporadic occurrence, male gender, lobule type, and isolated microtia. Several environmental risk factors can have significant impacts on the development of microtia.


Single Layer Bismuth Iodide: Computational Exploration of Structural, Electrical, Mechanical and Optical Properties.
Layered graphitic materials exhibit new intriguing electronic structure and the search for new types of two-dimensional (2D) monolayer is of importance for the fabrication of next generation miniature electronic and optoelectronic devices. By means of density functional theory (DFT) computations, we investigated in detail the structural, electronic, mechanical and optical properties of the single-layer bismuth iodide (BiI3) nanosheet. Monolayer BiI3 is dynamically stable as confirmed by the computed phonon spectrum. The cleavage energy (Ecl) and interlayer coupling strength of bulk BiI3 are comparable to the experimental values of graphite, which indicates that the exfoliation of BiI3 is highly feasible. The obtained stress-strain curve shows that the BiI3 nanosheet is a brittle material with a breaking strain of 13%. The BiI3 monolayer has an indirect band gap of 1.57 eV with spin orbit coupling (SOC), indicating its potential application for solar cells. Furthermore, the band gap of BiI3 monolayer can be modulated by biaxial strain. Most interestingly, interfacing electrically active graphene with monolayer BiI3 nanosheet leads to enhanced light absorption compared to that in pure monolayer BiI3 nanosheet, highlighting its great potential applications in photonics and photovoltaic solar cells.


Effect of ATP level and its metabolic turnover in liver on the proteosynthesis postmortem.
The level of ATP in liver tissue kept at 37 degrees C decreases rapidly. Its concentration decreases to 20% of the original one 2 hr postmortem and disappears completely in the following 2 hr. The decrease of ATP concentration is independent of both the degree of mechanical disintegration of the tissue (mash, homogenate) and of the presence of inhibitors of ATP biosynthesis (2,4-dinitrophenol, monoiodoacetate). The application of precursors of ATP biosynthesis, labeled with suitable radionuclides (32Pi and [14C]ADP), makes it possible to prove that ATP is formed in the absence of inhibitors. Increased biosynthesis of ATP simultaneously enables an increase in metabolic turnover. Higher consumption of ATP, under conditions of its higher biosynthesis, is the reason for the identical decrease of ATP concentration in liver postmortem, independently of the intensity of its biosynthesis. The gradual fall of ATP level postmortem causes a corresponding decrease of proteosynthesis. At that moment when ATP disappears, proteosynthesis is stopped as well. However, the synthesis of proteins can continue even in this period if exogenous source of energy (ATP) is added.


Potential role of gabapentin and extended-release gabapentin in the management of menopausal hot flashes.
About 80% of postmenopausal women experience vasomotor symptoms, such as hot flashes and night sweats - symptoms that are associated with sleep disruption and can lead to fatigue and mood changes. Moreover, hot flashes can be embarrassing for women, causing difficulties at work and in their social lives. Many therapies have been advocated for relief of vasomotor symptoms, but only hormone therapy has been US Food and Drug Administration approved. However, after the Women's Health Initiative Study suggested that there was a correlation between hormone therapy and increased risk for breast cancer and cardiovascular events, many women stopped taking hormone therapy, and many do not want to initiate it. Hormone therapy is also contraindicated in certain women, such as those with a history of hormone-stimulated cancer like breast and uterine cancer. Gabapentin (Neurontin) has shown efficacy in relieving vasomotor symptoms and is used as off-label for this indication. A new extended-release formulation of gabapentin has also shown efficacy in treating hot flashes and improving sleep quality with possibly fewer side effects than regular gabapentin.


Anticancer potential of alkaloids: a key emphasis to colchicine, vinblastine, vincristine, vindesine, vinorelbine and vincamine.
Cancer, one of the leading illnesses, accounts for about 10 million deaths worldwide. The treatment of cancer includes surgery, chemotherapy, radiation therapy, and drug therapy, along with others, which not only put a tremendous economic effect on patients but also develop drug resistance in patients with time. A significant number of cancer cases can be prevented/treated by implementing evidence-based preventive strategies. Plant-based drugs have evolved as promising preventive chemo options both in developing and developed nations. The secondary plant metabolites such as alkaloids have proven efficacy and acceptability for cancer treatment. Apropos, this review deals with a spectrum of promising alkaloids such as colchicine, vinblastine, vincristine, vindesine, vinorelbine, and vincamine within different domains of comprehensive information on these molecules such as their medical applications (contemporary/traditional), mechanism of antitumor action, and potential scale-up biotechnological studies on an in-vitro scale. The comprehensive information provided in the review will be a valuable resource to develop an effective, affordable, and cost effective cancer management program using these alkaloids.


Intensive intervention for maltreated infants and toddlers in foster care.
We have described a program that integrates clinical approaches of infant mental health to infants and toddlers in foster care. The juxtaposition of a mental health program in a forensic setting creates a number of special features that we have highlighted. Unique from the clinical perspective, the team is explicitly relationship-focused, attempting to understand all of the young child's caregiving relationships as they affect development. We strive to enhance the quality of all of relationships in which infants participate, fostering healthy attachments and development. Also unique is the emphasis on system liaison, and making programmatic efforts to affect various systems involved in making custody determinations about infants and toddlers. Unique from the forensic perspective, we offer multidisciplinary expertise about an especially high-risk population, a comprehensive service delivery system in which we provide or coordinate and monitor all intervention efforts for a given family, a prevention orientation, and clinical follow-up with infants for as long as they are in care. The goals of the program include expediting permanency planning decisions, increasing continuity in high-quality foster care placements, increasing court satisfaction with mental health consultation, decreasing the number of court-ordered evaluations for adjudicated families, and increasing CPS satisfaction with available treatment and continuity of care. We believe that this approach integrates delivery of services to the youngest and most vulnerable victims of maltreatment and expedites permanency planning.


A possible explanation of mechanisms inducing inhibition of vascularization of tumours by antifibrinolytic drugs--the influence of migratory behaviour of endothelial cells.
The observation that administration of antifibrinolytic drugs results in tumour growth stasis, having possibly its origin in reduced vascularization of the tumour, led us to investigate the migratory behaviour of bovine endothelial cells under in vitro conditions in the presence of drugs known to influence the activity of fibrinolytic enzymes. The Boyden-technique and microcinematography were used for this analysis. It could be shown that aprotinin, an inhibitor of serine proteinases and para-methylaminobenzoic acid, a specific inhibitor of plasminogen activation and plasmin action greatly reduced the migratory rate of the cells. Streptokinase, a plasminogen activator, stimulated the cell migration in optimal concentrations. The authors hypothesize that tumour vascularization is initiated by immigration of endothelial cells into the tumour by fibrinolytic action following a fibrin gradient induced by the tumour themselves. Fibrinolytic inhibitors suppress this process.


Effect of removing outliers on statistical inference: implications to interpretation of experimental data in medical research.
Data editing with elimination of "outliers" is commonly performed in the biomedical sciences. The effects of this type of data editing could influence study results, and with the vast and expanding amount of research in medicine, these effects would be magnified. We first performed an anonymous survey of medical school faculty at institutions across the United States and found that indeed some form of outlier exclusion was performed by a large percentage of the respondents to the survey. We next performed Monte Carlo simulations of excluding high and low values from samplings from the same normal distribution. We found that removal of one pair of "outliers", specifically removal of the high and low values of the two samplings, respectively, had measurable effects on the type I error as the sample size was increased into the thousands. We developed an adjustment to the t score that accounts for the anticipated alteration of the type I error (tadj=tobs-2(log(n)^0.5/n^0.5)), and propose that this be used when outliers are eliminated prior to parametric analysis. Data editing with elimination of outliers that includes removal of high and low values from two samples, respectively, can have significant effects on the occurrence of type 1 error. This type of data editing could have profound effects in high volume research fields, particularly in medicine, and we recommend an adjustment to the t score be used to reduce the potential for error.


Parietal and medial temporal lobe interactions in working memory goal-directed behavior.
Working memory is essential for the organization of goal-directed behavior, which involves multiple brain networks. The frontoparietal network has been proposed as a central node for the maintenance and manipulation of information. However, the exact contribution of the frontal and parietal lobes is still unclear as is that of the medial temporal lobe (MTL). Here, we investigated how the frontoparietal network and the MTL coordinate cognitive functions to control working memory in 12 participants, including five men, with medically intractable epilepsy. Participants performed a modified Sternberg working memory task during intracranial electroencephalography recording. The present working memory task was designed to test the different neural states of working memory subprocesses during memory maintenance and operation. First, we observed increased and sustained low-frequency (2-7 Hz) power in the frontal lobe and MTL, relative to baseline activity during the entire working memory task. Parietal alpha (8-13 Hz) power exhibited peak activity during memory operation. Finally, we found a positive correlation in the alpha band between the MTL and the parietal lobe during memory operation. These results indicate that as task demands become specific and goal-directed, the correlation between the MTL and the parietal lobe increases. This finding provides novel insight into the contribution of the MTL-parietal lobe network to voluntary control of working memory.


Physicians' beliefs and behaviour during a randomized controlled trial of episiotomy: consequences for women in their care.
To evaluate whether physicians' beliefs concerning episiotomy are related to their use of procedures and to differential outcomes in childbirth. Post-hoc cohort analysis of physicians and patients involved in a randomized controlled trial of episiotomy. Two tertiary care hospitals and one community hospital in Montreal. Of the 703 women at low risk of medical or obstetric problems enrolled in the trial we studied 447 women (226 primiparous and 221 multiparous) attended by 43 physicians. Subjects attended by residents or nurses were excluded. intact perineum v. perineal trauma, length of labour, procedures used (instrumental delivery, oxytocin augmentation of labour, cesarean section and episiotomy), position for birth, rate of and reasons for not assigning women to a study arm, postpartum perineal pain and satisfaction with the birth experience, physicians: beliefs concerning episiotomy. Women attended by physicians who viewed episiotomy very unfavorably were more likely than women attended by the other physicians to have an intact perineum (23% v. 11% to 13%, p < 0.05) and to experience less perineal trauma. The first stage of labour was 2.3 to 3.5 hours shorter for women attended by physicians who viewed episiotomy favourably than for women attended by physicians who viewed episiotomy very unfavorably (p < 0.05 to < 0.01), and the former physicians were more likely to use oxytocin augmentation of labour. Physicians who viewed episiotomy more favourably failed more often than those who viewed the procedure very unfavourably to assign patients to a study arm late in labour (odds ratio [OR] 1.88, p < 0.05), both overall and because they felt that "fetal distress" or cesarean section necessitated exclusion of the subject. They used the lithotomy position for birth more often (OR 3.94 to 4.55, p < 0.001), had difficulty limiting episiotomy in the restricted-use arm of the trial and diagnosed fetal distress and perineal inadequacy more often than the comparison groups. The patients of physicians who viewed episiotomy very favourably experienced more perineal pain (p < 0.01), and of those who viewed episiotomy favourably and very favourably experienced less satisfaction with the birth experience (p < 0.01) than the patients of physicians who viewed the procedure very unfavourably. Physicians with favourably views of episiotomy were more likely to use techniques to expedite labour, and their patients were more likely to have perineal trauma and to be less satisfied with the birth experience. This evidence that physician beliefs can influence patient outcomes has both clinical and research implications.


Histamine release by phosphatidic acid from isolated mast cells of two types of genetically different rats.
Phosphatidic acid produced a similar dose-dependent release of histamine from isolated peritoneal mast cells of two types of rat, one of which did not release histamine when dextran was present in the incubation mixture. This release induced by phosphatidic acid resembled that evoked by a basic secretagogue like compound 48/80, being independent of exogenous calcium and unaffected by either phosphatidyl serine or its lyso derivative. The non-cytotoxic release of histamine induced by phosphatidic acid is therefore distinct from that by dextran and does not involve dextran receptors residing on the plasma membrane of mast cells of rats which show the dextran anaphylactoid reaction.


Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism.
Patients with adrenal incidentalomas (AIs) and subclinical hypercortisolism (SH) have increased risk of fracture independent of bone mineral density (BMD) and possibly due to reduced bone quality. The trabecular bone score (TBS) has been proposed as a index of bone microarchitecture. The aim of the study was to investigate TBS in AI. In 102 AI patients, SH was diagnosed in the presence of at least two of the following: (1) urinary free cortisol >70 µg/24 h (193.1 nmol/L); (2) cortisol after 1-mg dexamethasone suppression test (1-mg DST) >3.0 µg/dL (82.8 nmol/L); or (3) adrenocorticotropic hormone (ACTH) <10 pg/mL (<2.2 pmol/L). In patients and in 70 matched controls, BMD was measured at lumbar spine (LS) and femur (neck [FN] and total [FT]) by dual X-ray absorptiometry and TBS was assessed in the region of LS-BMD; BMD and TBS data were reported as Z-scores. In patients, vertebral deformities were assessed by radiograph. Patients with SH (n = 34) had lower LS-BMD (-0.31 ± 1.17), FT-BMD (-0.29 ± 0.91), and TBS (-3.18 ± 1.21) than patients without SH (n = 68, 0.31 ± 1.42, p = 0.03; 0.19 ± 0.97, p = 0.01; -1.70 ± 1.54, p < 0.0001, respectively) and controls (0.42 ± 1.52, p = 0.02; 0.14 ± 0.76, p = 0.02; -1.19 ± 0.99, p < 0.0001, respectively). TBS was inversely correlated with 1-mg DST (β = -0.26, t = -2.79, p = 0.006) regardless of age, LS-BMD, body mass index (BMI), and gender. The presence of fracture was associated with low TBS alone (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.85-12.42, p = 0.001) and with the cluster low TBS plus low LS-BMD (OR, 4.37; 95% CI, 1.71-11.4, p = 0.002), after adjustment for age, BMI, and gender. Low TBS plus low LS-BMD showed a good specificity (79%) for predicting fractures, whereas normal TBS (ie, > -1.5) plus normal LS-BMD high specificity (88.1%) for excluding fractures. Finally, TBS predicted the occurrence of a new fracture in 40 patients followed for 24 months (OR, 11.2; 95%CI, 1.71-71.41, p = 0.012) regardless of LS-BMD, BMI, and age. In SH, bone quality, as measured by TBS, is altered. TBS is useful in detecting AI patients at risk of fractures.


Isolation of Histoplasma capsulatum from tissues of bats captured in the Aguas Buenas Caves, Aguas Buenos, Puerto Rico.
Of 30 bats belonging to four species, only one species, Brachyplylla cavernarum, yielded positive for Histoplasma capsulatum. Bats were collected at the Aguas Buenas Caves in Puerto Rico. The other species are: Artibeus jamaicensis, Monophyllus redmani portoricensis, and Erophylla bibombifrons; these resulted negative for the fungus.


iGMDR: Integrated Pharmacogenetic Resource Guide to Cancer Therapy and Research.
Current pharmacogenetic studies have obtained many genetic models that can predict the therapeutic efficacy of anticancer drugs. Although some of these models are of crucial importance and have been used in clinical practice, these very valuable models have not been well adopted into cancer research to promote the development of cancer therapies due to the lack of integration and standards for the existing data of the pharmacogenetic studies. For this purpose, we built a resource investigating genetic model of drug response (iGMDR), which integrates the models from in vitro and in vivo pharmacogenetic studies with different omics data from a variety of technical systems. In this study, we introduced a standardized process for all integrations, and described how users can utilize these models to gain insights into cancer. iGMDR is freely accessible at https://igmdr.modellab.cn.


Gender differences in incidence and determinants of disability in activities of daily living among elderly individuals: SABE study.
Determining the groups that are most susceptible to developing disability is essential to establishing effective prevention and rehabilitation strategies. The aim of the present study was to determine gender differences in the incidence of disability regarding activities of daily living (ADL) and determinants among elderly residents of Sao Paulo, Brazil. In 2000, 1634 elderly with no difficulties regarding ADL (modified Katz Index) were selected. These activities were reassessed in 2006 and disability was the outcome for the analysis of determinants. The following characteristics were analyzed at baseline: socio-demographic, behavioral, health status, medications, falls, hospitalizations, depressive symptoms, cognition, handgrip, mobility and balance. The incidence density was 42.4/1000 women/year and 17.5/1000 men/year. After adjusting for socioeconomic status and health conditions, women with chronic diseases and social vulnerability continued to have a greater incidence of disability. The following were determinants of the incidence of disability: age and depressive symptoms in both genders; stroke and slowness on the sit-and-stand test among men; and osteoarthritis and sedentary lifestyle among women. Better cognitive performance and handgrip strength were protective factors among men and women, respectively. Adverse clinical and social conditions determine differences between genders regarding the incidence of disability. Decreased mobility and balance and health conditions that affect the central nervous system or lead to impaired cognition disable men more, whereas a sedentary lifestyle, reduction in muscle strength and conditions that affect the osteoarticular system disable women more.


Establishment of an optimised protocol for a Golgi-electron microscopy method based on a Golgi-Cox staining procedure with a commercial kit.
The introduction of the FD Rapid GolgiStain Kit has enabled many researchers to easily examine the morphology of neurons. Owing to an improved Golgi-Cox impregnation method, both stable and highly sensitive stained images of neurons can be acquired using this kit. To analyse microstructures such as dendritic spines and growth cones at detail, we attempted to create a useful method combining Golgi-Cox staining and electron microscopy (Golgi-EM method) so that the prepared Kit-stained samples would be appropriate for use in electron microscopy (EM) studies. Results from the present study suggest the importance of the glutaraldehyde fixation step in the Golgi-EM method. Here, we introduce the recommended protocol for the Golgi-EM method, which is available for ultrahigh-voltage electron microscopy and transmission electron microscopy. We are confident that our Golgi-EM method may become a reliable and important method that can contribute to new discoveries in neuronal morphology.


Aortic Dissection.
Acute aortic dissection is a highly morbid condition with high mortality that requires emergent surgical evaluation and repair. The intraoperative management of acute aortic dissection requires the anesthesiologist to do far more than administer anesthesia and begins before the patient arrives at the operative theater. High-fidelity communication with the surgeon, knowledge of the surgical plan, knowledge of the anatomy of the dissection, and a nuanced understanding of aortic dissection pathophysiology are all critical aspects of anesthetic management.


High-throughput single-EV liquid biopsy: Rapid, simultaneous, and multiplexed detection of nucleic acids, proteins, and their combinations.
MicroRNAs (miRNAs), mRNA, and proteins in/on extracellular vesicles (EVs) represent potential cancer biomarkers. Concurrent detection of multiple biomarkers at a single-EV level would greatly improve prognosis and/or diagnosis and understanding of EV phenotypes, biogenesis, and functions. Here, we introduced a High-throughput Nano-bio Chip Integrated System for Liquid Biopsy (HNCIB) system for simultaneous detection of proteins and mRNA/miRNA in a single EV. Validated through systematic control experiments, HNCIB showed high reliability, sensitivity, and specificity. In a panel of 34 patients with lung adenocarcinoma (LUAD) and 35 healthy donors, HNCIB detected an up-regulated expression of programmed death-ligand 1 mRNA and protein and miR-21 in EVs derived from patients with LUAD compared to those from healthy donors. HNCIB has low sample requirement (~90 μl), fast assay time (~6 hours), and high throughput (up to 384 samples per assay) and would have great potential in the study of EVs and their clinical applications.


Combination drug therapy for chronic pain: a call for more clinical studies.
Chronic pain is a debilitating clinical condition associated with a variety of disease entities including diabetic neuropathy, postherpetic neuralgia, low back pathology, fibromyalgia, and neurological disorders. For many general practitioners and specialists, managing chronic pain has become a daunting challenge. As a modality of multidisciplinary chronic pain management, medications are often prescribed in combinations, an approach referred to as combination drug therapy (CDT). However, many medications for pain therapy, including antidepressants and opioid analgesics, have significant side effects that can compound when used in combination and impact the effectiveness of CDT. To date, clinical practice of CDT for chronic pain has been based largely on clinical experiences. In this article, we will focus on (1) the scientific basis and rationales for CDT, (2) current clinical data on CDT, and (3) the need for more clinical studies to establish a framework for the use of CDT. More preclinical, clinical, and translational studies are needed to improve the efficacy of combination drug therapy that is an integral part of a comprehensive approach to the management of chronic pain.


Development of a vitrification method for preserving human myoblast cell sheets for myocardial regeneration therapy.
Tissue-engineered cardiac constructs have potential in the functional recovery of heart failure; however, the preservation of these constructs is crucial for the development and widespread application of this treatment. We hypothesized that tissue-engineered skeletal myoblast (SMB) constructs may be preserved by vitrification to conserve biological function and structure. Scaffold-free cardiac cell-sheet constructs were prepared from SMBs and immersed in a vitrification solution containing ethylene glycol, sucrose, and carboxyl poly-L-lysine. The cell sheet was wrapped in a thin film and frozen rapidly above liquid nitrogen to achieve vitrification (vitrification group, n = 8); fresh, untreated SMB sheets (fresh group, n = 8) were used as the control. The cryopreserved SMB sheets were thawed at 2 days, 1 week, 1 month, and 3 months after cryopreservation for assessment. Thawed, cryopreserved SMB sheets were transplanted into rat hearts in a myocardial infarction nude rat model, and their effects on cardiac function were evaluated. Cell viability in the cardiac constructs of the vitrification group was comparable to that of the fresh group, independent of the period of cryopreservation (p > 0.05). The structures of the cell-sheet constructs, including cell-cell junctions such as desmosomes, extracellular matrix, and cell membranes, were maintained in the vitrification group for 3 months. The expression of cytokine genes and extracellular matrix proteins (fibronectin, collagen I, N-cadherin, and integrin α5) showed similar levels in the vitrification and fresh groups. Moreover, in an in vivo experiment, the ejection fraction was significantly improved in animals treated with the fresh or cryopreserved constructs as compared to that in the sham-treated group (p < 0.05). Overall, these results show that the vitrification method proposed here preserves the functionality and structure of scaffold-free cardiac cell-sheet constructs using human SMBs after thawing, suggesting the potential clinical application of this method in cell-sheet therapy.


Changes in serum levels of IGF-1 and in growth following adenotonsillectomy in children.
Adenotonsillar hypertrophy can cause upper airway obstruction and may be associated with growth delay in children. The objective of this study was to evaluate the long-term effects of adenotonsillectomy on height, weight, and body mass index (BMI) in children with sleep-disordered breathing (SDB). Fifty-two children (mean age 6.2+/-2.3 years) clinically diagnosed with SDB were enrolled. Children were diagnosed and scheduled for adenotonsillectomy (T&A) based on their responses to the validated, 22-item Sleep Related Breathing Disorder (SRDB) scale and a physical examination that showed adenotonsillar hypertrophy. Weight, height, and BMI were evaluated before and 5 years after T&A. Serum levels of insulin-like growth factor-1 (IGF-1) were measured before and 1 month after T&A. Serum levels of IGF-1 were significantly higher at 1 month after T&A compared to before T&A (p<0.001). Thirty children (58%) returned for follow-up testing 5 years later. Their Z scores (standard deviation scores) for weight, height, and BMI of 30 children were significantly higher 5 years after T&A compared to before T&A (p<0.01). Children with SDB who undergo adenotonsillectomy show significant, long-term increases in weight, height and BMI, as well as a significant increase in serum levels of IGF-1.


Towards integration of 64Cu-DOTA-trastuzumab PET-CT and MRI with mathematical modeling to predict response to neoadjuvant therapy in HER2 + breast cancer.
While targeted therapies exist for human epidermal growth factor receptor 2 positive (HER2 +) breast cancer, HER2 + patients do not always respond to therapy. We present the results of utilizing a biophysical mathematical model to predict tumor response for two HER2 + breast cancer patients treated with the same therapeutic regimen but who achieved different treatment outcomes. Quantitative data from magnetic resonance imaging (MRI) and 64Cu-DOTA-trastuzumab positron emission tomography (PET) are used to estimate tumor density, perfusion, and distribution of HER2-targeted antibodies for each individual patient. MRI and PET data are collected prior to therapy, and follow-up MRI scans are acquired at a midpoint in therapy. Given these data types, we align the data sets to a common image space to enable model calibration. Once the model is parameterized with these data, we forecast treatment response with and without HER2-targeted therapy. By incorporating targeted therapy into the model, the resulting predictions are able to distinguish between the two different patient responses, increasing the difference in tumor volume change between the two patients by > 40%. This work provides a proof-of-concept strategy for processing and integrating PET and MRI modalities into a predictive, clinical-mathematical framework to provide patient-specific predictions of HER2 + treatment response.


Site-Specific Fluorescent Labeling, Single-Step Immunocytochemistry, and Delivery of Nanobodies into Living Cells.
The smallest natural antibody fragments currently available are single-domain antibodies obtained from camelid species and sharks (variable new antigen receptors). These molecules consist of a single amino acid chain of ~120 amino acids that adopts a typical immunoglobulin fold. Single-domain antibodies (nanobodies) are monovalent and can be isolated from immunized animals, from naïve libraries, or from synthetic libraries. Importantly, their complete DNA sequences are readily obtained by default, which greatly facilitates their rapid manipulation for various applications. Here, a PCR-based protocol for inserting a sortase A recognition sequence at the carboxy-terminus of a nanobody is described. Subsequently, a sortase A-catalyzed biochemical reaction results in tagging of the nanobody with a short carboxy-terminal amino acid sequence that carries a non-canonical residue (propargyl glycine). This allows click chemistry to be performed with an azido-derivatized fluorophore, with the ensuing fluorescent nanobody being covalently and site-specifically labeled. The labeled nanobody can be used directly for immunocytochemistry, omitting the classical secondary antibody step. Also described are methods for delivery of fluorescent nanobodies into the cytoplasm of mammalian cells by photoporation, a very low-toxicity approach involving laser light and graphene quantum dots. The combined protocol embodies a novel route for studying protein function in living cells at high resolution.


The role of different glutamate receptors in the mediation of glutamate-evoked excitation of red nucleus neurons after simulated microgravity in rat.
The present study investigates changes in red nucleus (RN) neuronal activity and the role of glutamate receptors (GluRs) after simulated microgravity (tail-suspension) in the rat using single-unit recording and microinjection. The results showed that tail-suspension for 3, 7, and 14 days could induce a significant decrease in spontaneous firing rate of RN neurons in a time-dependent manner. Unilateral microinjection of glutamate into the RN significantly increased the firing rate of RN neurons, but the increased firing rate was significantly reduced following tail-suspension time. Microinjection of the NMDA receptor antagonist MK-801 or the non-NMDA receptor antagonist DNQX into the RN blocked this excitatory effect induced by glutamate. However, microinjection of the metabotropic glutamate receptor (mGluR) antagonist (+/-)-MCPG into the RN had no effect. These results suggest that simulated microgravity can reduce excitability of RN neurons following a functional impairment of glutamate receptors. NMDA and non-NMDA receptors, but not mGluRs, are involved in the mediation of glutamate-evoked excitation of RN neurons. The decrease in excitability of RN neurons may be involved in simulated microgravity-induced muscle atrophy.


Chest compression release velocity: Association with survival and favorable neurologic outcome after out-of-hospital cardiac arrest.
We evaluated the association between chest compression release velocity (CCRV) and outcomes after out-of-hospital cardiac arrest (OHCA). CPR quality was measured using a defibrillator with accelerometer-based technology (E Series, ZOLL Medical) during OHCA resuscitations by 2 EMS agencies in Arizona between 10/2008 and 06/2013. All non-EMS-witnessed adult (≥ 18 years) arrests of presumed cardiac etiology were included. The association between mean CCRV (assessed as an appropriate measure of central tendency) and both survival to hospital discharge and neurologic outcome (Cerebral Performance Category score = 1 or 2) was analyzed using multivariable logistic regression to control for known and potential confounders and multiple imputation to account for missing data. 981 OHCAs (median age 68 years, 65% male, 11% survival to discharge) were analyzed with 232 (24%) missing CPR quality data. All-rhythms survival varied significantly with CCRV [fast (≥ 400 mm/s) = 18/79 (23%); moderate (300-399.9 mm/s) = 50/416 (12%); slow (<300 mm/s) 17/255 (7%); p < 0.001], as did favorable neurologic outcome [fast = 14/79 (18%); moderate = 43/415 (10%); slow = 11/255 (4%); p < 0.001]. Fast CCRV was associated with increased survival compared to slow [adjusted odds ratio (aOR) 4.17 (95% CI: 1.61, 10.82) and moderate CCRV [aOR 3.08 (1.39, 6.83)]. Fast CCRV was also associated with improved favorable neurologic outcome compared to slow [4.51 (1.57, 12.98)]. There was a 5.2% increase in the adjusted odds of survival for each 10mm/s increase in CCRV [aOR 1.052 (1.001, 1.105)]. CCRV was independently associated with improved survival and favorable neurologic outcome at hospital discharge after adult OHCA.


Probing DNA sequences by anthraquinone-modified DNA that is immobilized on gold surface.
2'-Anthraquinone-modified oligonucleotide (AQ-ODN) possessing disulfide terminus has been immobilized on the gold electrode surface. The AQ-ODN-modified electrode showed faster electron transferability in double-stranded form than that in single-stranded form.


Self-assembly of a metal-ion-bound monolayer of trigonal connectors on mercury: an electrochemical Langmuir trough.
The adsorption of the trigonal connector, 1,3,5-tris[10-(3-ethylthiopropyl)dimethylsilyl-1,10-dicarba-closo-decaboran-1-yl]benzene (1), from acetonitrile/0.1 M LiClO(4) on the surface of mercury at potentials ranging from +0.3 to -1.4 V (vs. aqueous Ag/AgCl/1 M LiCl) was examined by voltammetry, Langmuir isotherms at controlled potentials, and impedance measurements. No adsorption is observed at potentials more negative than approximately -0.85 V. Physisorption is seen between approximately -0.85 and 0 V. At positive potentials, adsorbate-assisted anodic dissolution of mercury occurs and an organized surface layer is formed. Although the mercury cations are reduced at -0.10 V, the surface layer remains metastable to potentials as negative as -0.85 V. Its surface areas per molecule and per redox center are compatible with a regular structure with the connectors 1 woven into a hexagonal network by RR'S-->Hg(2)(2+)<--SRR' or RR'S-->Hg(2+)<--SRR' bridges. The structure is simulated closely by geometry optimization in the semiempirical AM1 approximation.


Combination of alpha-fetoprotein and neutrophil-to-lymphocyte ratio to predict treatment response and survival outcomes of patients with unresectable hepatocellular carcinoma treated with immune checkpoint inhibitors.
Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of hepatocellular carcinoma (HCC). However, long-term survival outcomes and treatment response of HCC patients undergoing immunotherapy is unpredictable. The study aimed to evaluate the role of alpha-fetoprotein (AFP) combined with neutrophil-to-lymphocyte ratio (NLR) to predict the prognosis and treatment response of HCC patients receiving ICIs. Patients with unresectable HCC who received ICI treatment were included. The HCC immunotherapy score was developed from a retrospective cohort at the Eastern Hepatobiliary Surgery Hospital to form the training cohort. The clinical variables independently associated with overall survival (OS) were identified using univariate and multivariate Cox regression analysis. Based on multivariate analysis of OS, a predictive score based on AFP and NLR was constructed, and patients were stratified into three risk groups according to this score. The clinical utility of this score to predict progression-free survival (PFS) and differentiate objective response rate (ORR) and disease control rate (DCR) was also performed. This score was validated in an independent external validation cohort at the First Affiliated Hospital of Wenzhou Medical University. Baseline AFP ≤ 400 ng/ml (hazard ratio [HR] 0.48; 95% CI, 0.24-0.97; P = 0.039) and NLR ≤ 2.77 (HR 0.11; 95% CI, 0.03-0.37; P<0.001) were found to be independent risk factors of OS. The two labolatory values were used to develop the score to predict survival outcomes and treatment response in HCC patients receiving immunotherapy, which assigned 1 point for AFP > 400 ng/ml and 3 points for NLR > 2.77. Patients with 0 point were classified as the low-risk group. Patients with 1-3 points were categorized as the intermediate-risk group. Patients with 4 points were classified as the high-risk group. In the training cohort, the median OS of the low-risk group was not reached. The median OS of the intermediate-risk group and high-risk group were 29.0 (95% CI 20.8-37.3) months and 16.0 (95% CI 10.8-21.2) months, respectively (P < 0.001). The median PFS of the low-risk group was not reached. The median PFS of the intermediate-risk group and high-risk group were 14.6 (95% CI 11.3-17.8) months and 7.6 (95% CI 3.6-11.7) months, respectively (P < 0.001). The ORR and DCR were highest in the low-risk group, followed by the intermediate-risk group and the high-risk group (P < 0.001, P = 0.007, respectively). This score also had good predictive power using the validation cohort. The HCC immunotherapy score based on AFP and NLR can predict survival outcomes and treatment response in patients receiving ICI treatments, suggesting that this score could serve as a useful tool for identification of HCC patients likely to benefit from immunotherapy.


Class key feature extraction and fusion for 2D medical image segmentation.
The size variation, complex semantic environment and high similarity in medical images often prevent deep learning models from achieving good performance. To overcome these problems and improve the model segmentation performance and generalizability. We propose the key class feature reconstruction module (KCRM), which ranks channel weights and selects key features (KFs) that contribute more to the segmentation results for each class. Meanwhile, KCRM reconstructs all local features to establish the dependence relationship from local features to KFs. In addition, we propose the spatial gating module (SGM), which employs KFs to generate two spatial maps to suppress irrelevant regions, strengthening the ability to locate semantic objects. Finally, we enable the model to adapt to size variations by diversifying the receptive field. We integrate these modules into class key feature extraction and fusion network (CKFFNet) and validate its performance on three public medical datasets: CHAOS, UW-Madison, and ISIC2017. The experimental results show that our method achieves better segmentation results and generalizability than those of mainstream methods. Through quantitative and qualitative research, the proposed module improves the segmentation results and enhances the model generalizability, making it suitable for application and expansion.


Wound management and nutrition for optimal wound healing.
The process of wound healing is complicated and requires optimization of wound bed conditions locally through wound management and systemically through proper nutritional care. Although there are a variety of local and systemic factors that can adversely influence healing, the wound environment can be treated through proper dressings to decrease necrotic debris, bacterial load, and foreign bodies. In addition, maintaining or improving patient nutritional status will help the body to supply the necessary building blocks and cellular response for healing to take place.


Epigenetic regulation of airway inflammation.
Diverse cellular functions including the regulation of inflammatory gene expression, DNA repair and cell proliferation are regulated by epigenetic changes. Transcriptional co-activators possess intrinsic histone acetyltransferase (HAT) activity, and histone acetylation plays a major role in inflammatory gene expression. Other marks such as histone methylation are also associated with gene induction and gene repression. Recent evidence implicates histone acetylation and methylation as being crucial for the development of tolerance in macrophages and CpG methylation for T regulatory cell development and function. The expression of the enzymes that lay down or remove these epigenetic marks have not been well studied in human airways disease, but reduced HDAC2 expression and activity is reported in lung macrophages, biopsies and blood cells from patients with COPD, severe asthma and smoking asthma. In vitro, inhibitors of histone deacetylases (HDAC) often lead to a further induction of inflammatory gene expression. This is not always the case, however, as HATs and HDACs also target non-histone proteins particularly transcription factors to alter their activity. Furthermore, trichostatin A, an HDAC inhibitor, can reduce inflammation in a murine model of allergic asthma. This effect of HDAC inhibitors may be due to their effects on cell death acting through acetylation of non-histone proteins. The role of epigenetic modifications in inflammatory gene expression and in the control of cell function in the airways is becoming clearer. Targeting specific enzymes involved in this process may lead to new therapeutic agents, in particular, in situations where current anti-inflammatory therapies are currently suboptimal.


Myocardial oxidative stress in patients with active infective endocarditis.
Infective endocarditis (IE) induces the rise of pro-inflammatory cytokines. Some of them can stimulate oxidants production in myocardium with subsequent peroxidative damage to various biomolecules. We compared indices of oxidative stress: H2O2, thiobarbituric acid-reactive substances (TBARs), thiols in myocardium specimens between patients with active IE and those with valvular heart disease (VHD) of rheumatic etiology who underwent surgical valve replacement. 17 left ventricle papillary muscle specimens and 28 specimens of auricle of the right heart were collected from 45IE patients, and 16 papillary muscle and 12 auricle specimens from 28 VHD patients, respectively. Patients groups had similar NYHA functional class and majority of echocardiographic indices of heart morphology. H2O2 and TBARs were determined fluorometrically in myocardium homogenates whereas thiols with photometric method. Between and within groups comparisons and mutual correlations between variables were analyzed. H2O2 generation from all myocardium specimens and auricles was 2.14- and 2.59- times higher (p<0.001) in IE patients than in VHD group. Auricles had the highest H2O2 levels within IE group. TBARs were 10-times higher (p<0.05) in IE when compared to VHD group in auricles and papillary muscles. Thiols did not differ between groups. H2O2 positively correlated with TBARs and negatively with thiols in all IE myocardium specimens (r=0.31 and r=-0.46, p<0.05) and auricles (r=0.58 and r=-0.67, p<0.05), respectively. No such associations were noted in VHD specimens. Active IE induces enhanced myocardial production of H2O2 and formation of TBARs which proves occurrence of oxidative stress in the heart.


Single nucleotide polymorphisms in the mitochondrial control region are associated with metabolic phenotypes and oxidative stress.
To identify the mitochondrial DNA (mtDNA) single nucleotide polymorphisms (SNPs) in the control region and elucidate their role in metabolic phenotypes and oxidative stress. A total of 861 nondiabetic subjects were enrolled, including 250 impaired fasting glucose (IFG) and 370 obese subjects (body mass index [BMI]>25 kg/m(2)). Antioxidant status presented as total free thiol level was determined from serum samples. DNA was extracted from peripheral blood leucocytes, and the sequences were analyzed using the DNASTAR software. SNPs were identified by comparison with the Cambridge Reference Sequence. After adjusting odds ratios for age, sex, and BMI, the selected independently significant SNPs indicated 4 susceptible SNPs: SNP-16126C and SNP-16261T, which were related to abdominal obesity (P=0.009; 0.06); SNP-16390A, related to hypertension (HTN) (P=0.007); and SNP-16092C, related to decreased antioxidant capacity (P=0.015). In the obese subgroup, 3 susceptible SNPs included SNP-16189C and SNP-16260T, which showed significantly higher IFG prevalence (P=0.016 and 0.024, respectively), and SNP-16519C, which was significantly higher in the HTN group (P=0.036). As to protective SNPs, 5 protective SNPs were identified in all subjects but only one SNP-16093C is consistent in obese group, which showed a significantly lower prevalence in patients with abdominal obesity and was associated with a higher antioxidant status (P<0.001). SNPs in the mtDNA control region are associated with metabolic phenotypes and oxidative stress markers. Some SNPs are relating to the interaction between obesity and genetic factors. The beneficial effects of these protective SNPs were insignificant and some susceptible SNPs became dominant within the obese subgroup. Subjects harboring these SNPs should avoid excessive weight gain.


Bluegill virus is a ribovirus of positive-strand polarity.
RNA was extracted from purified Bluegill virus (BGV) and fractionated onto a poly (U)-Sepharose-4 B column. More than 70 per cent of this RNA became bound and could be subsequently eluted from the column. By polynucleotide phosphorylase digestion, the poly (A) sequences were located at the 3'-terminus of the RNA. This RNA and purified BGV RNA were infectious as shown by plaque assay titration of the virus produced. Furthermore, we were unable to detect RNA polymerase activity in preparations of BGV. These results indicate that the genome in the BGV particle is a positive-strand RNA.


Understanding neuroinflammation through central nervous system infections.
Neuroinflammation is now recognized to compound many central nervous system (CNS) pathologies, from stroke to dementia. As immune responses evolved to handle infections, studying CNS infections can offer unique insights into the CNS immune response and address questions such as: What defenses and strategies do CNS parenchymal cells deploy in response to a dangerous pathogen? How do CNS cells interact with each other and infiltrating immune cells to control microbes? What pathways are beneficial for the host or for the pathogen? Here, we review recent studies that use CNS-tropic infections in combination with cutting-edge techniques to delve into the complex relationships between microbes, immune cells, and cells of the CNS.


Assessment of Circadian-based Antioxidants Plus a Comprehensive Brightener in Skin of Color Patients With Hyperpigmentation.
Hyperpigmentation disorders disproportionately affect individuals with skin of color. There is an unmet need for safe and effective topical treatments for this population. The efficacy and tolerability of LYT2 in combination with LVS were assessed in skin of color patients with moderate to severe facial hyperpigmentation. A single-arm study was performed in Asian, Hispanic, or African American patients (Fitzpatrick phototypes III–VI). Subjects applied LYT2 and LVS daily, in addition to a basic skincare regimen, for 12 weeks. Overall hyperpigmentation, skin-tone evenness, and radiance were evaluated by the investigator, and subjects completed questionnaires regarding self-perceived efficacy. After 12 weeks, the combination of LYT2 and LVS produced a 23% improvement in overall hyperpigmentation, a 33% increase in skin-tone evenness, and a 51% increase in radiance compared to baseline. At the study conclusion, all patients noted at least a slight improvement in skin condition, and 70% reported good or excellent satisfaction. One subject (8%) experienced a treatment-related adverse event. The combination of LYT2 and LVS was well-tolerated and improved the appearance of hyperpigmentation and overall quality in skin of color. J Drugs Dermatol. 2022;21(4):376-380. doi:10.36849/JDD.6687.


[The condition of crowding and spacing. Measuring or estimation?].
Two methods for the assessment of the amount of crowding or spacing (measuring and assessment by eye) are compared. Both methods are well comparable and reproducible. Assessment by eye has the practical advantage that it takes considerable less time.


Effect of emotion regulation training in patients with panic disorder: Evidenced by heart rate variability measures.
We aimed to examine the effect of emotion regulation training in patients with panic disorder (PD) by measuring heart rate variability (HRV). Forty-eight patients with PD were randomly divided into emotion regulation group (n=25) and no-regulation group (n=23). Three five-minute ECG recordings were taken in the following states: 1) baseline, 2) while subjects viewed 15 aversive pictures (active stimulus), 3) resting state after aversive pictures (post-stimulus). The emotion regulation group briefly received acceptance technique training for five minutes before performing the experimental task. Spectral analysis measures included a high-frequency (HF; 0.15-0.4 HZ) component, a low-frequency (LF; 0.04-0.15Hz) component, and an LF/HF ratio. The mean change in LF/HF ratio from baseline to active stimulus was significantly lower in the emotion regulation group than in the no-regulation group (emotion regulation group, 0.13; no-regulation group, 2.31; t=-2.67; P<.05). This suggests that brief emotion acceptance training could decrease aversive stimulus-induced sympathetic hyperactivity in patients with PD.


Evaluation of the gut microbiota after metformin intervention in children with obesity: A metagenomic study of a randomized controlled trial.
Metformin, a first-line oral antidiabetic agent that has shown promising results in terms of treating childhood and adolescent obesity, might influence the composition of the gut microbiota. We aimed to evaluate whether the gut microbiota of non-diabetic children with obesity changes after a metformin intervention. The study was a multicenter and double-blind randomized controlled trial in 160 children with obesity. Children were randomly assigned to receive either metformin (1 g/day) or placebo for 6 months in combination with healthy lifestyle recommendations in both groups. Then, we conducted a metagenomic analysis in a subsample obtained from 33 children (15 metformin, 18 placebo). A linear mixed-effects model (LMM) was used to determine the abundance changes from baseline to six months according to treatment. To analyze the data by clusters, a principal component analysis was performed to understand whether lifestyle habits have a different influence on the microbiota depending on the treatment group. Actinobacteria abundance was higher after placebo treatment compared with metformin. However, the interaction time x treatment just showed a trend to be significant (4.6% to 8.1% after placebo vs. 3.8 % to 2.6 % after metformin treatment, p = 0.055). At genus level, only the abundance of Bacillus was significantly higher after the placebo intervention compared with metformin (2.5% to 5.7% after placebo vs. 1.5 % to 0.8 % after metformin treatment, p = 0.044). Furthermore, different ensembles formed by Firmicutes, Bacteroidetes, and Verrucomicrobia were found according to the interventions under a similar food consumption. Further studies with a large sample size controlled by lifestyle patterns are required in obese children and adolescents to clarify whether metformin might trigger gut microbiota alterations. Registered on the European Clinical Trials Database (EudraCT, ID: 2010-023061-21) on 14 November 2011.


Bright and ultrafast electron point source made of LaB6 nanotip.
The development of time-resolved transmission electron microscopy (TEM), ultrafast electron spectroscopy and pulsed X-ray sources relies on the realization of stable and high brightness sources of ultra-short electron bunches with a long service time. The flat photocathodes implanted in thermionic electron guns have been replaced by Schottky-type or cold-field emission sources driven by ultra-fast laser. Recently, lanthanum hexaboride (LaB6) nanoneedles have been reported to have high brightness and high emission stability when working in a continuous emission mode. Here, we prepare nano-field emitters from bulk LaB6 and we report on their use as ultra-fast electron sources. Using a high repetition rate laser in the infrared range, we present different field emission regimes as a function of the extraction voltage and laser intensity. The properties of the electron source (brightness, stability, energy spectrum and emission pattern) are determined for the different regimes. Our results show that LaB6 nanoneedles can be used as ultrafast and ultra-bright sources for time-resolved TEM, with better performances as compared to metallic ultra-fast field-emitters.


Effect of different frequencies of tensile strain on human dermal fibroblast proliferation and survival.
The aim of this study is to compare the effect of a high-frequency repetitive (HF) stretch or an intermittent (I) stretch on the cell proliferation and survival of human dermal fibroblasts and to determine the activation of any relevant signal pathways. Cultured human dermal fibroblasts were exposed to either HF or I stretch. Cell number was measured by counting, while DNA synthesis was assessed by 5-bromo-2'-deoxyuridine (BrdU) staining and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling staining. To investigate the potential mechanisms of repetitive strain on the proliferation and survival of fibroblasts, the activation of relevant transduction pathways, such as p38 mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK)1/2, AKT, and BAD, was assessed by Western blot. In addition, the effect of inhibition of these pathways on the fibroblast response was also studied. After either HF or I stretch for 7 days, fibroblast number was significantly decreased and there were less BrdU-positive cells. The numbers of apoptotic and/or necrotic fibroblasts were not affected. p38 MAPK and ERK1/2 were significantly activated after HF stretch, but AKT and BAD were significantly activated after I stretch. The inhibitors of p38 MAPK and MAPK/ERK kinase as well as dominant-negative AKT reduced cell number after both HF and I stretch but these pathways were not critical for the stretch-induced decrease in cell number.