Special issue: redox active natural products and their interaction with cellular signalling pathways.
During the last decade, research into natural products has experienced a certain renaissance. The urgent need for more and more effective antibiotics in medicine, the demand for ecologically friendly plant protectants in agriculture, "natural" cosmetics and the issue of a sustainable and healthy nutrition in an ageing society have fuelled research into Nature's treasure chest of "green gold". Here, redox active secondary metabolites from plants, fungi, bacteria and other (micro-)organisms often have been at the forefront of the most interesting developments. These agents provide powerful means to interfere with many, probably most cellular signaling pathways in humans, animals and lower organisms, and therefore can be used to protect, i.e., in form of antioxidants, and to frighten off or even kill, i.e., in form of repellants, antibiotics, fungicides and selective, often catalytic "sensor/effector" anticancer agents. Interestingly, whilst natural product research dates back many decades, in some cases even centuries, and compounds such as allicin and various flavonoids have been investigated thoroughly in the past, it has only recently become possible to investigate their precise interactions and mode(s) of action inside living cells. Here, fluorescent staining and labelling on the one side, and appropriate detection, either qualitatively under the microscope or quantitatively in flow cytometers and plate readers, on the other, enable researchers to obtain the various pieces of information necessary to construct a fairly complete puzzle of how such compounds act and interact in living cells. Complemented by the more traditional activity assays and Western Blots, and increasingly joined by techniques such as proteomics, chemogenetic screening and mRNA profiling, these cell based bioanalytical techniques form a powerful platform for "intracellular diagnostics". In the case of redox active compounds, especially of Reactive Sulfur Species (RSS), such techniques have recently unraveled concepts such as the "cellular thiolstat", yet considerably more research is required in order to gain a full understanding of why and how such compounds act-often selectively-in different organisms.


Transamidation of aromatic amines with formamides using cyclic dihydrogen tetrametaphosphate.
Amide fragments are found to be one of the key constituents in a wide range of natural products and pharmacologically active compounds. Herein, we report a simple and efficient procedure for transamidation with a cyclic dihydrogen tetrametaphosphate. The protocol is simple, does not require any additives, and encompasses a broad substrate scope. To comprehend the mechanism of the present methodology, detailed spectroscopic and kinetic studies were undertaken.


Cholera toxin ADP-ribosylates the islet-activating protein substrate in adipocyte membranes and alters its function.
In adipocyte membranes, cholera toxin may ADP-ribosylate the islet-activating protein (IAP) substrate, under certain conditions. Covalent modification is maximal in the absence of a guanosine triphosphate; in the presence of 5'-guanylylimidodiphosphate, incorporation of [32P]ADP-ribose is markedly reduced. ADP-ribosylation by cholera toxin has similar functional consequences as does IAP-mediated modification, i.e. the biphasic response of isoproterenol-stimulated adenylate cyclase to GTP and the inhibition by N6-phenylisopropyladenosine is abolished, and only the stimulatory phase remains. In contrast, membranes treated with cholera toxin in the presence of GTP display both the stimulatory and inhibitory responses to GTP. The binding of the adenosine analog [3H]N6-phenylisopropyladenosine is increased in the presence of GTP. Treatment of the membranes with IAP, but not with cholera toxin in the absence of GTP, reverses this GTP effect on [3H]N6-phenylisopropyladenosine binding. However, [3H]N6-phenylisopropyladenosine binding is still sensitive to GTP in membranes treated with cholera toxin in the presence of GTP. In adipocyte and cerebral cortical membranes, the IAP substrate appears as a 39,000/41,000-Da doublet which does not appear to reflect protease activity. On two-dimensional polyacrylamide gels, these two proteins migrate with approximate pI values 6.0 and 5.6, respectively. Although both behave similarly under all conditions explored in this study, it is unknown whether both, or only one, are involved in inhibition of adenylate cyclase activity. These results extend the already striking homology between the adenylate cyclase complex and the visual system. Ni, as well as transducin, may be ADP-ribosylated by cholera toxin and by IAP, and, in all cases, there are functional consequences.


Theoretical error in radionuclide ejection fraction study due to photon attenuation.
The ejection fractions measured with the radionuclide method are usually lower than those measured with the X-ray contrast method in our hospitals. One of the reasons for this may be that the photon attenuation by the cardiac blood pool and soft tissue is greater for the larger end-diastolic ventricle than that for the end-systolic ventricle. Mathematically, the error due to photon attenuation in radionuclide ejection fraction study is calculated to be about 5 percentage points. Clinically, if 5 percentage points are added to the ejection fractions measured by the radionuclide method, the results would correlate better with the studies by the X-ray contrast method. The correction factors for photon attenuation may also be applied in calculation of the residual urinary bladder volume.


trans fatty acids. 5. Fatty acid composition of lipids of the brain and other organs in suckling piglets.
The effects of dietary trans fatty acids on the fatty acid composition of the brain in comparison with other organs were studied in 3-wk-old suckling piglets. In Experiment (Expt.) 1 the piglets were delivered from sows fed partially hydrogenated fish oil (PHFO) (28% trans), partially hydrogenated soybean oil (PHSBO) (36% trans) or lard (0% trans). In Expt. 2 the piglets were delivered from sows fed PHFO, hydrogenated fish oil (HFO) (19% trans) or coconut fat (CF) (0% trans) with two levels of dietary linoleic acid (1 and 2.7%) according to factorial design. In both experiments the mother's milk was the piglets' only food. The level of incorporation of trans fatty acids in the organs was dependent on the levels in the diets and independent of fat source (i.e., PHSBO, PHFO or HFO). Incorporation of trans fatty acids into brain PE (phosphatidylethanolamine) was non-detectable in Expt. 1. In Expt. 2, small amounts (less than 0.5%) of 18:1 trans isomers were found in the brain, the level being slightly more on the lower level of dietary linoleic acid compared to the higher. In the other organs the percentage of 18:1 trans increased in the following order: heart PE, liver mitochondria PE, plasma lipids and subcutaneous adipose tissue. Small amounts of 20:1 trans were found in adipose tissue and plasma lipids. Other very long-chain fatty acids from PHFO or HFO (i.e., 20:1 cis and 22:1 cis + trans) were found in all organ lipids except for brain PE. Dietary trans fatty acids increased the percentage of 22:5n-6 in brain PE.(ABSTRACT TRUNCATED AT 250 WORDS)


The Real-Life Efficacy of Fixed-Dose Hypomethylating Agents in Older Patients With Acute Myeloid Leukemia: A 10-Year Experience.
Hypomethylating agent (HMA) is one of recommended treatment for elderly patients with acute myeloid leukemia (AML); however, their high cost precludes their general use, especially in developing countries. Therefore, the fixed-dose HMAs approach was adopted to reduce the expenses. This study focuses on the clinical outcome of various treatment protocols, including intensive chemotherapy, fixed-dose HMAs, and palliative treatment in Thai elderly patients with AML. Fixed-dose HMAs include 5-azacitidine given at 100 mg per day for seven days and decitabine given at 30 mg per day for 5 days. We conducted a 10-year cohort study focused on elderly AML patients aged over 60 years. The exclusion criteria were acute promyelocytic leukemia. A total of 243 AML patients were enrolled. Comparing 3 groups of treatment regimens (intensive chemotherapy, fixed-dose HMAs, and palliative treatment), the proportions of patients in each category accounted for 23.5%, 21.4%, and 55.1%, respectively. The median overall survival (OS) in each therapeutic option was 7.7, 11, and 2.5 months, respectively. From multivariate analysis, palliative treatment was significantly inferior OS comparing to the fixed-dose HMAs and intensive treatment (hazard ratio [HR]: 0.42; 95% CI, 0.29-0.60; P value <.001 and HR: 0.41; 95% CI, 0.28-0.61; P value <.001, respectively). Nevertheless, the OS outcome in patients with fixed-dose HMAs was comparable to those who received intensive treatment. Our study demonstrates that the fixed-dose regimen of HMAs is the reasonable treatment for these patients, and this approach is not inferior to intensive therapy. Thai Clinical Trials Registry identifier: TCTR20210514007.


Optical and chemical characteristics of the atmospheric aerosol in four towns in southern Poland.
The absorption coefficient a(p) [m(-1)] as well as the mass absorption coefficient sigma(p) [m(2)/g] has been estimated for PM10 and PM2.5 in four towns located in southern Poland, based on the assumption that the reflectance of aerosol-laden filters is a good proxy for the absorptivity of aerosols. The optical properties of the airborne particles were also compared with their surface composition obtained by photoelectron spectroscopy (XPS). It was found that coarse particles, which constituted 20-30% of PM10, exhibited insignificant contribution to the absorption. The most absorptive aerosols were found in the towns located in Upper Silesia, a highly industrialized area. This reflects both the relative content of carbon in PM2.5 and the mass concentration of the fine mode. It was found that oxides and sulfates play an important role in promoting the reflectance of light from aerosols in the winter. These results support the suggestion that the revision of existing air quality standards for particulate pollution is needed.


Sibling Bullying, School Bullying, and Children's Subjective Well-Being Before and During the COVID-19 Pandemic in Indonesia.
The aims of this study are threefold. The first aim is to examine the prevalence of sibling and school bullying before and during the COVID-19 pandemic in Indonesia. The second aim is to investigate the subjective well-being (SWB) of children who were bullied or never bullied before and during COVID-19. The third aim is to investigate factors associated with sibling and school bullying before and during the COVID-19 pandemic. This study uses two separate cross-sectional datasets from the Children's Worlds survey in Indonesia. Data in Study 1 were collected in October 2017 (N = 12,794; 48.2% boys; 51.8% girls, mean age = 10.56), while data in Study 2 were collected from July to September 2021 (N = 2,222; 46.1% boys; 53.9% girls; mean age = 10.77). Five items were used to measure sibling and school bullying. The five-item version of the Children's Worlds Subjective Well-Being Scale (CW-SWBS5) was used as the SWB indicator. Three groups of independent variables (family, friends and school climate) were analysed using linear regression to investigate the contribution of each variable to sibling and school bullying. Results show that the prevalence of sibling bullying during the COVID-19 pandemic is higher than before the pandemic, while the frequency of school bullying incidents during COVID-19 is lower than before COVID-19. SWB scores of children during COVID-19 are lower than SWB scores of children before the COVID-19 pandemic, both for bullied or never-bullied children. The fact that children report that parents listen to them and take what they say into account is positively associated with a lower frequency of being bullied at home before and during COVID-19 and being bullied at school only during the pandemic. Although samples are not strictly comparable, the SWB indicators used in both studies showed sensitivity to the changes in children's lives in previous studies. Therefore, the SWB indicators are supposed to be sensitive to changes associated with children's new everyday life COVID-19 has implied.


Inhibition of citric acid- and capsaicin-induced cough by novel TRPV-1 antagonist, V112220, in guinea-pig.
Cough reflex can be induced by the pepper extract capsaicin and by low pH in guinea-pig airways. Transient receptor potential vanniloid-1 (TPRV-1) is expressed in the sensory and afferent nerve fibres in airways. We hypothesized that a novel pyridazinylpiperazine analog TPRV-1 inhibitor can effectively reduce cough reflex stimulated by citric acid and capsaicin. Guinea pigs were injected with specific TPRV-1 inhibitor, V112220, a pyridazinylpiperazine analog of N-(4-tertiarybutylphenyl)-4-(3-chloropyridin-2-yl) tetrahydropyrazine-1(2H)-carbox-amide (BCTC) (3 mg/kg) intra-peritoneally. One hour before cough response assessment. Coughs were recorded using a recorder system that identified cough sound and accompanying expiratory flows, distinct from sneezes. Guinea-pigs exposed to citric acid (0.4 M) and to capsaicin (10-4M) aerosols, in succession separately by 2 hours. V112220 significantly inhibited the number of coughs induced by citric acid (73 +/- 11%, p < 0.01) and capsaicin (70 +/- 9.4%, p < 0.05) compared to vehicle control. A novel pyridazinylpiperazine analog TPRV-1 inhibitor can inhibit the cough reflex, induced by both low pH and capsaicin, suggesting that it could be clinically beneficial in treatment of cough.


circ_0086296 induced atherosclerotic lesions via the IFIT1/STAT1 feedback loop by sponging miR-576-3p.
Extensive inflammation of endothelial cells (ECs) facilitates atherosclerotic lesion formation. Circular RNA (circRNA) participates in atherosclerosis (AS)-related inflammation responses; however, whether and how circ_0086296 regulates atherosclerotic inflammation and lesions have not been investigated. Microarray analysis, quantitative real-time polymerase chain reaction, and fluorescence in situ hybridization assay were performed to detect the expression and location of hsa_circ_0086296 in human carotid artery plaques, aorta of atherosclerotic mice, and human umbilical vein endothelial cells (HUVECs). Sanger sequencing was used to verify the loop structure of circ_0086296. The relationship among circ_0086296, miR-576-3p, IFIT1, STAT1, and EIF4A3 was validated using bioinformatics, luciferase assay, RNA pull-down assay, and RNA immunoprecipitation. The atherosclerosis mouse model was used to evaluate the function of circ_0086296 in vivo. circ_0086296 expression was significantly upregulated in human carotid artery plaques, oxidized low-density lipoprotein (ox-LDL)-treated HUVECs, and the aorta of atherosclerotic mice. Functional analysis indicated that circ_0086296 promotes ECs injury in vitro and atherosclerosis progression in vivo. The mechanism analysis indicated that circ_0086296 sponged miR-576-3p to promote IFIT1-STAT1 expression. Moreover, STAT1 upregulated circ_0086296 expression, forming the circ_0086296/miR-576-3p/IFIT1/STAT1 feedback loop. Notably, inhibition of the circ_0086296/miR-576-3p/IFIT1 axis could block atherosclerotic lesion formation both in vivo and in vitro. Finally, circ_0086296 was overexpressed in exosomes of patients with atherosclerosis and exosomes of ox-LDL-treated ECs. Therefore, the circ_0086296/miR-576-3p/IFIT1/STAT1 feedback loop participates in atherosclerosis progression and contributes to the high circ_0086296 expression observed in the exosomes of serum of patients with atherosclerosis. This study sought to provide a deep understanding of the mechanisms underlying the aberrant EC phenotype in AS.


Aerodynamic assessment of the Henley-Cohn tracheoesophageal prosthesis.
In vitro airway resistance measurements were performed for eight Henley-Cohn voice prostheses. The results of these measures demonstrated that the Henley-Cohn device offers substantially less resistance to the flow of air than either the Blom-Singer or Panje devices. The lower overall resistance of the Henley-Cohn device was shown to be due to both its larger inner cross sectional area and to an improved valve tip design. The lower airway resistance of the Henley-Cohn prosthesis should theoretically result in more "efficient" production of esophageal voice than would be the case when using the Blom-Singer or Panje devices. However, the results of this investigation also point to the need for the development of methods which will enable investigators to evaluate the in vivo performance of tracheoesophageal prostheses.


Megakaryoblastic leukemia: a study on novel role of clinically significant long non-coding RNA signatures in megakaryocyte development during treatment with phorbol ester.
Acute megakaryocytic leukemia (AMKL) is one of the rarest sub-types of acute myeloid leukemia (AML). AMKL is characterized by high proliferation of megakaryoblasts and myelofibrosis of bone marrow, this disease is also associated with poor prognosis. Previous analyses have reported that the human megakaryoblastic cells can be differentiated into cells with megakaryocyte (MK)-like characteristics by phorbol 12-myristate 13-acetate (PMA). However, little is known about the mechanism responsible for regulating this differentiation process. We performed long non-coding RNA (lncRNA) profiling to investigate the differently expressed lncRNAs in megakaryocyte blast cells treated with and without PMA and examined those that may be responsible for the PMA-induced differentiation of megakaryoblasts into MKs. We found 30 out of 90 lncRNA signatures to be differentially expressed after PMA treatment of megakaryoblast cells, including the highly expressed JPX lncRNA. Further, in silico lncRNA-miRNA and miRNA-mRNA interaction analysis revealed that the JPX is likely involved in unblocking the expression of TGF-β receptor (TGF-βR) by sponging oncogenic miRNAs (miR-9-5p, miR-17-5p, and miR-106-5p) during MK differentiation. Further, we report the activation of TGF-βR-induced non-canonical ERK1/2 and PI3K/AKT pathways during PMA-induced MK differentiation and ploidy development. The present study demonstrates that TGF-βR-induced non-canonical ERK1/2 and PI3K/AKT pathways are associated with PMA-induced MK differentiation and ploidy development; in this molecular mechanism, JPX lncRNA could act as a decoy for miR-9-5p, miR-17-5p, and miR-106-5p, titrating them away from TGF-βR mRNAs. Importantly, this study reveals the activation of ERK1/2 and PI3K/AKT pathway in PMA-induced Dami cell differentiation into MK. The identified differentially expressed lncRNA signatures may facilitate further study of the detailed molecular mechanisms associated with MK development. Thus, our data provide numerous targets with therapeutic potential for the modulation of the differentiation of megakaryoblastic cells in AMKL.


Fatal perinatal nephropathy with onset in intrauterine life.
A girl, born at 29 weeks' gestation, died of renal failure aged 16 days. Postmortem histology showed diffuse mesangial sclerosis with failure of development of the cortex. This is an unusual cause of neonatal renal failure, and it demonstrates the effect of disease arising in utero and influencing the development of the kidney.


A phylogenetic framework for the kingdom Fungi based on 18S rRNA gene sequences.
The usage of molecular phylogenetic approaches is critical to advance the understanding of systematics and community processes in the kingdom Fungi. Among the possible phylogenetic markers (or combinations of them), the 18S rRNA gene appears currently as the most prominent candidate due to its large availability in public databases and informative content. The purpose of this work was the creation of a reference phylogenetic framework that can serve as ready-to-use package for its application on fungal classification and community analysis. The current database contains 9329 representative 18S rRNA gene sequences covering the whole fungal kingdom, a manually curated alignment, an annotated and revised phylogenetic tree with all the sequence entries, updated information on current taxonomy, and recommendations of use. Out of 201 total fungal taxa with more than two sequences in the dataset, 179 were monophyletic. From another perspective, 66% of the entries had a tree-derived classification identical to that obtained from the NCBI taxonomy, whereas 34% differed in one or the other rank. Most of the differences were associated to missing taxonomic assignments in NCBI taxonomy, or the unexpected position of sequences that positioned out of their theoretically corresponding clades. The strong correlation observed with current fungal taxonomy evidences that 18S rRNA gene sequence-based phylogenies are adequate to reflect genealogy of Fungi at the levels of order and above, and justify their further usage and exploration.


The bright side of personality.
The article addresses the question, which personality dimensions mostly contribute to the positive human functioning, especially to wellbeing and prosocial values. As we predicted, the three dimensions from the Big Five factors are mostly opposed to the negative personality characteristics known as Dark Triad (narcissism, Machiavellianism and psychopathy), namely emotional stability (low neuroticism), agreeableness and conscientiousness. The results demonstrated negative relationship between these personality dimensions (labeled Bright Triad) and Dark Triad. Both Dark and Bright Triad dimensions are substantially loaded with one single bipolar latent dimension, the Dark versus Bright Personality. The results also confirmed the substantial connections of the Bright Triad dimensions to the wellbeing and the values. The Bright Triad dimensions are positively associated with general life satisfaction and traditional, social, cognitive and democratic values and tend to be negatively associated with status or power values. On the other side, Dark Triad dimensions are positively related to the status values and tend to be negatively related to the prosocial values.


Electrospun reduced graphene oxide/TiO2/poly(acrylonitrile-co-maleic acid) composite nanofibers for efficient adsorption and photocatalytic removal of malachite green and leucomalachite green.
Electrospun reduced graphene oxide/TiO2/poly(acrylonitrile-co-maleic acid) composite nanofibers (E-spun RGO/TiO2/PANCMA NFs) were fabricated using electrospinning of the dispersive solution of PANCMA, GO and TiO2 followed by post-chemical reduction. The obtained composite nanofibers were compressed in a dialyzer and then used to absorb and degrade malachite green (MG) and leucomalachite green (LMG) from aqueous solution. Compared to the E-spun TiO2/PANCMA and GO/TiO2/PANCMA NFs, the E-spun RGO/TiO2/PANCMA NFs exhibited higher adsorption capacity and photocatalytic degradation ability. Under optimized conditions, 90.6% of MG and 93.7% of LMG from 50 mL aqueous sample solution were adsorbed on the RGO/TiO2/PANMA NFs (3.0 mg fibers) in 2.0 min, and subsequent the 91.4% and 95.2% of MG and LMG adsorbed on the NFs were degradated in 60 min under UV irradiation, respectively. In addition, the E-spun RGO/TiO2/PANMA NFs exhibited good reusability and could be reused in multiple cycles of operations for adsorption and photocatalytic degradation of MG and LMG. This work demonstrated that the electrospun composite nanofibers are promising materials for removal of pollutants from environmental water samples.


PIM2 Promotes the Development of Ovarian Endometriosis by Enhancing Glycolysis and Fibrosis.
Endometriosis is a common gynecological disorder characterized by the presence of the endometrial glands and the stroma outside the uterine cavity. The disease affects reproductive function and quality of life in women of reproductive age. Endometriosis is similar to tumors in some characteristics, such as glycolysis. PIM2 can promote the development of tumors, but the mechanism of PIM2 in endometriosis is still unclear. Therefore, our goal is to study the mechanism of PIM2 in endometriosis. Through immunohistochemistry, we found PIM2, HK2, PKM2, SMH (smooth muscle myosin heavy chain), Desmin, and α-SMA (α-smooth muscle actin) were strongly expressed in the ovarian endometriosis. In endometriotic cells, PIM2 enhanced glycolysis and fibrosis via upregulating the expression of PKM2. Moreover, the PIM2 inhibitor SMI-4a inhibited the development of endometriosis. And we established a PIM2 knockout mouse model of endometriosis to demonstrate the role of PIM2 in vivo. In summary, our study indicates that PIM2 promotes the development of endometriosis. PIM2 may serve as a promising therapeutic target for endometriosis.


The influence of social media on recruitment to surgical trials.
Social media has changed the way surgeons communicate worldwide, particularly in dissemination of trial results. However, it is unclear if social media could be used in recruitment to surgical trials. This study aimed to investigate the influence of Twitter in promoting surgical recruitment in The Emergency Laparotomy and Frailty (ELF) Study. The ELF Study was a UK-based, prospective, observational cohort that aimed to assess the influence of frailty on 90-day mortality in older adults undergoing emergency surgery. A power calculation required 500 patients to be recruited to detect a 10% change in mortality associated with frailty. A 12-week recruitment period was selected, calculated from information submitted by participating hospitals and the numbers of emergency surgeries performed in adults aged > 65 years. A Twitter handle was designed (@ELFStudy) with eye-catching logos to encourage enrolment and inform the public and clinicians involved in the study. Twitter Analytics and Twitonomy (Digonomy Pty Ltd) were used to analyse user engagement in relation to patient recruitment. After 90 days of data collection, 49 sites from Scotland, England and Wales recruited 952 consecutive patients undergoing emergency laparotomy, with data logged into a database created on REDCap. Target recruitment (n = 500) was achieved by week 11. A total of 591 tweets were published by @ELFStudy since its conception, making 218,136 impressions at time of writing. The number of impressions (number of times users see a particular tweet) prior to March 20th 2017 (study commencement date) was 23,335 (343.2 per tweet), compared to the recruitment period with 114,314 impressions (256.3 per tweet), ending June 20th 2017. Each additional tweet was associated with an increase in recruitment of 1.66 (95%CI 1.36 to 1.97; p < 0.001). The ELF Study over-recruited by nearly 100%, reaching over 200,000 people across the U.K. Branding enhanced tweet aesthetics and helped increase tweet engagement to stimulate discussion and healthy competition amongst clinicians to aid trial recruitment. Other studies may draw from the social media experiences of the ELF Study to optimise collaboration amongst researchers. This study is registered online at www.clinicaltrials.gov (registration number NCT02952430 ) and has been approved by the National Health Service Research Ethics Committee.


Assisting clients experiencing family violence: Clinician and client survey responses in a child and family health service.
To determine the baseline levels of training, knowledge and confidence working in the area of family violence in staff at a public child and maternal health service in Melbourne, Australia, as well as perceived staff barriers to working effectively in this area. This study also aimed to explore the client perception of existing screening practices. Family violence is a global concern with pregnancy and the postnatal period times of particularly high risk. Child and maternal health services are well placed to screen for violence, yet clinician and client perceptions of screening remain poorly characterised. Thirty-five staff and 15 mothers participated in this cross-sectional, mixed-method study, via an online survey. Strengthening the Reporting of Observational studies in Epidemiology (STROBE) cross-sectional guidelines were used. The majority of staff screened clients for family violence, at least some of the time, with over 50% often or always screening. However, only half of staff respondents indicated that they believed they knew how to screen appropriately. Screening occurred most often over the phone or at the first service visit. The most commonly reported barriers to screening were suspected perpetrators being present during consultations and language barriers. Most clients reported being screened for physical violence and safety in the home with few being asking about financial and sexual abuse, or psychological violence and coercive control. Clients who disclosed violence reported being well supported. While some baseline staff knowledge and skills have been identified, further support for clinicians is needed to ensure best practice and improve services and outcomes, particularly in regard to screening for different types of violence across the spectrum. This study helps to inform clinical screening practices in maternal health services through an exploration of facilitators and barriers in the screening process.


Periprosthetic femoral fractures following total hip and total knee arthroplasty.
Total joint arthroplasties are increasing worldwide in both frequency and prevalence. When successful, they offer great improvements in quality of life. However, fractures around implants are often difficult to manage and require prolonged inpatient stays in tertiary hospitals. Management may differ between surgeons, but most patients will be managed surgically if mobility or joint stability is threatened. Those affected are often at higher risk from surgery, are frailer and at higher risk of mortality and a lifelong reduction in mobility. The incidence of these fractures is increasing, and patients should appreciate the risk and implications of this recognised complication of joint arthroplasty.


Laser treatment of infantile hemangioma.
Infantile hemangiomas (IH) are common benign tumors of infancy. Most IH either involute spontaneously or respond to treatment with systemic Beta- blockers, but unfortunately not in all cases. In poor responses or in cases of contra indications for pharmacological treatment, laser treatment poses a very good solution. As a search strategy and study selection we searched the MEDLINE database via PubMed starting 1982 to June 2022 using a key terms related to interventions for IH (e.g., infantile hemangioma, laser, Beta blockers). In this article, we reviewed the published data regarding the use of energy-based devices in treatment of children with IH, and noted our experience over the course of treating dozens of cases over the years. There are many laser systems used for the treatment of hemangioma and vascular tumors. These laser systems are of different wavelengths and penetration depths, however, they operate by similar mechanisms and in some cases two or more lasers can be applied during the course of treating these lesions.


Development of a rapid RP-HPLC method for the determination of clonazepam in human plasma.
A rapid and sensitive high-performance liquid chromatography method with UV detection was developed for the determination of clonazepam in human plasma using 3-methylclonazepam, as internal standard. A one-step extraction of both compounds was performed with a mixture of hexane/ethyl acetate (90:10, v/v). The HPLC analysis was carried out on a Nova Pak((R)) C(18) reversed-phase column with a mobile phase of acetonitrile-0.01 M sodium acetate adjusted to pH 7 with dilute acetic acid (40:60, v/v). A linear response was observed over the concentration range 5-100 ng/mL. Intra- and inter-day assay precision and accuracy fulfilled the international requirements. The lower limit of quantification was 5 ng/mL without interference of endogenous components. For analytical purpose, the stability of clonazepam in bidistilled water and plasma has been studied. A rapid degradation was noticed when clonazepam was stored in bidistilled water at the daylight following a first-order kinetic rate with a 87 min half life whereas no significant degradation was observed in plasma. This method was applied to measure plasma concentrations of clonazepam either in patients receiving therapeutic doses or in poisoning cases.


Angiotensin receptors in vascular tissue.
The biologic effect of angiotensin II is triggered by its interaction with components of target organs, which specifically recognize the hormone. These receptors have been studied with the use of radioactive angiotensin and, as for other peptidic hormones, have been localized in the plasma membrane of target cells. Such angiotensin receptors have been characterized in three target organs: vascular tissue, uterus and adrenal cortex. The binding characteristics differ in contractile tissue and in adrenal glands, the N and C terminal ends of angiotensin being involved in the former, whereas the N terminus does not appear to have the same importance in the latter. Numerous factors, including ionic composition, seem to be able to modify angiotensin-receptor interaction in vascular smooth muscle. However, the molecular mechanisms responsible for angiotensin binding and for the transmission of the signal determined by receptor-angiotensin interaction are not yet understood. As observed with other peptidic hormones, the number of angiotensin receptors seems to be susceptible to variation under certain conditions. In uterine smooth muscle, it was shown that the number of receptors increased after nephrectomy, a phenomenon which was prevented by the prolonged infusion of angiotensin. The significance of such a variation remains unknown, but it may be partially responsible for the inverse relationship that exists between the endogenous angiotensin level and the pressor effect of exogenous angiotensin. In the near future, investigation of the angiotensin-receptor mechanism will probably answer whether the variation in angiotensin receptors is similar in all target tissues and whether an angiotensin-receptor mechanism is involved in the pathogenesis of certain varieties of hypertension. In addition, a precise understanding of the angiotensin-receptor interaction with help the development of new angiotensin antagonists.


Hepatic Dysfunction in a Child Post Bone Marrow Transplantation.
A 10-year-old female child, a known case of Beta-Thalassemia major with superimposed chronic Hepatitis C Viral (HCV) infection, underwent bone marrow transplantation and presented, 7 months later, with worsening hepatic functions and skin rash. Considering the wide variety of possible etiologies, she was evaluated and later confirmed as a case of hepatic dysfunction secondary to HCV related hepatic injury with concomitant chronic graft versus host disease (dermatological involvement only).


Scarface, a secreted serine protease-like protein, regulates polarized localization of laminin A at the basement membrane of the Drosophila embryo.
Cell-matrix interactions brought about by the activity of integrins and laminins maintain the polarized architecture of epithelia and mediate morphogenetic interactions between apposing tissues. Although the polarized localization of laminins at the basement membrane is a crucial step in these processes, little is known about how this polarized distribution is achieved. Here, in Drosophila, we analyse the role of the secreted serine protease-like protein Scarface in germ-band retraction and dorsal closure-morphogenetic processes that rely on the activity of integrins and laminins. We present evidence that scarface is regulated by c-Jun amino-terminal kinase and that scarface mutant embryos show defects in these morphogenetic processes. Anomalous accumulation of laminin A on the apical surface of epithelial cells was observed in these embryos before a loss of epithelial polarity was induced. We propose that Scarface has a key role in regulating the polarized localization of laminin A in this developmental context.


Androgen replacement therapy for cancer-related symptoms in male: result of prospective randomized trial (ARTFORM study).
Hypogonadism associated with cancer is reported to cause cachexia and a variety of physical and psychological symptoms. This study aims to evaluate whether androgen replacement therapy can improve cancer-related symptoms in male advanced cancer patients. An investigator-initiated, prospective, and randomized controlled study was conducted. Patients with low serum testosterone levels (total or free testosterone levels were <2.31 ng/mL or <11.8 pg/mL, respectively) were randomly assigned to the control or testosterone enanthate administration (testosterone group) groups. Testosterone enanthate was injected into the muscle tissue at a dose of 250 mg every 4 weeks (baseline, week 4, and week 8). Differences in quality of life questionnaires and cachexia-related serum protein levels between groups were assessed. This study enrolled and randomized 106 and 81 patients, respectively. Moreover, 41 and 40 patients were in the control and testosterone groups, respectively. Although no significant differences in the change of subscales and total scores in Functional Assessment of Anorexia/Cachexia Treatment were noted from the baseline between the two groups, the testosterone group showed a significantly better change in the 'unhappiness' item of the Edmonton Symptom Assessment System at week 12 compared with baseline versus the control group (-1.4 and 0.0 points, respectively; mean, P = 0.007). No significant differences exist in the change of serum interleukin-6 and insulin-like growth factor-1 levels at week 12 from the baseline between the control and testosterone groups. Consequently, the testosterone group significantly inhibited the change in serum tumour necrotic factor-α level at week 12 from the baseline compared with the control group (+0.4 and +0.1 pg/mL, respectively; mean, P = 0.005). Although testosterone enanthate did not improve most of the items in health-related quality of life questionnaires, testosterone enanthate induced a significantly better change in the 'unhappiness' item at week 12 compared with the control. Testosterone enanthate may be a potential treatment option for male advanced cancer patients.


Long-term safety and outcomes in hereditary tyrosinaemia type 1 with nitisinone treatment: a 15-year non-interventional, multicentre study.
Since the EU approval of nitisinone in 2005, prognosis for patients with hereditary tyrosinaemia type 1 has changed dramatically, with patients living with the disease now reaching adulthood for the first time in history. This study aimed to assess the long-term safety and outcomes of nitisinone treatment in patients with hereditary tyrosinaemia type 1. We did a non-interventional, non-comparative, multicentre study in 77 sites across 17 countries in Europe and collected retrospective and prospective longitudinal data in patients with hereditary tyrosinaemia type 1 who were treated with oral nitisinone during the study period (Feb 21, 2005, to Sept 30, 2019). There were no specific exclusion criteria. Patients were followed-up with an investigator at least annually for as long as they were treated, or until the end of the study. The primary endpoints, occurrence of adverse events related to hepatic, renal, ophthalmic, haematological, or cognitive or developmental function, were assessed in the complete set (all patients already receiving treatment at the index date [Feb 21, 2005] or starting treatment thereafter) and the index set (the subset of patients who had their first dose on the index date or later only). 315 patients were enrolled during the study period (complete set). Additionally, data from 24 patients who had liver transplantation or died during the post-marketing surveillance programme were retrieved (extended analysis set; 339 patients). Median treatment duration was 11·2 years (range 0·7-28·4); cumulative nitisinone exposure was 3172·7 patient-years. Patients who were diagnosed by neonatal screening started nitisinone treatment at median age 0·8 months versus 8·5 months in those who presented clinically. Incidences of hepatic, renal, ophthalmic, haematological, or cognitive or developmental adverse events were low. Occurrence of liver transplantation or death was more frequent the later that treatment was initiated (none of 70 patients who started treatment at age <28 days vs 35 [13%] of 268 patients who started treatment at age ≥28 days). 279 (89%) of 315 patients were assessed as having either very good or good nitisinone treatment compliance. Treatment and diet compliance declined as patients aged. Suboptimal plasma phenylalanine and tyrosine levels were observed. The majority of patients were reported to have good overall clinical condition throughout treatment; 176 (87%) of 203 during the entire study, 98% following 1 year of treatment. Long-term nitisinone treatment was well tolerated and no new safety signals were revealed. Life-limiting hepatic disease appears to have been prevented by early treatment start. Neonatal screening was the most effective way of ensuring early treatment. Standardised monitoring of blood tyrosine, phenylalanine, and nitisinone levels has potential to guide individualised therapy. Swedish Orphan Biovitrum (Sobi).


Association between empathy and clinical symptoms in chronic schizophrenia: A large sample study based on Chinese Han population.
In patients with schizophrenia, clinical symptoms and cognitive impairment are its core features, both of which have a significant impact on the prognosis and functional outcome. Empathy, as an important social cognition, has been found to be associated with the clinical symptoms in schizophrenia, but the conclusions on this issue are inconsistent. Therefore, this study will continue to explore it through a large sample of inpatients with chronic schizophrenia in the Chinese Han population. We obtained the sociodemographic characteristics of 987 inpatients, measured their clinical symptoms using the Positive and Negative Syndrome Scale (PANSS), and assessed their self-reported empathy using the Interpersonal Reactivity Index (IRI). The factor score for negative symptoms (FSNS) of PANSS was additionally calculated. Correlation and linear regression analysis showed that patients' PANSS scores were widely correlated with their IRI scores. In particular, the negative symptoms of patients were significantly correlated to IRI total score (r = -0.131, p < .001) and subscales such as Perspective Taking (PT) (r = -0.233, p < .001). FSNS had close relationships with empathy as well. There are also many significant associations between other dimensions, such as general psychopathology and Perspective Taking (PT) or Fantasy (FS) (all p < .05). Our results indicated that clinical symptoms, especially negative symptoms, were closely related to their current empathy in patients with schizophrenia, suggesting that the severity of clinical symptoms may be a powerful factor in predicting social cognition such as empathy of schizophrenia.


A perceptual analysis of stiffness.
The perception of stiffness was studied in ten human subject using two servo-controlled electromagnetic linear motors with computer-controlled stiffness, one motor coupled to each wrist of the subject. Using the contralateral limb-matching procedure in which subjects adjusted the stiffness of the motor connected to one (matching) arm until it was perceived to be the same as that connected to the other (reference) arm, a psychophysical function for stiffness was calculated. Eight different stiffness intensities were matched by subjects with five repetitions at each stimulus amplitude. The relation between the stiffness of the reference and matching motors was linear, and the accuracy with which subjects could match stiffness paralleled that reported previously for force and displacement. The Weber fraction for stiffness was 0.23 which is three times that reported for elbow flexion forces and forearm displacement. These findings were interpreted as indicating that subjects can perceive changes in the stiffness of mechanical devices used to effect action in the environment and that these perceptions are based on sensory signals conveying force and movement information.


Using prosody to infer discourse prominence in cochlear-implant users and normal-hearing listeners.
Cochlear implants (CIs) provide speech perception to adults with severe-to-profound hearing loss, but the acoustic signal remains severely degraded. Limited access to pitch cues is thought to decrease sensitivity to prosody in CI users, but co-occurring changes in intensity and duration may provide redundant cues. The current study investigates how listeners use these cues to infer discourse prominence. CI users and normal-hearing (NH) listeners were presented with sentences varying in prosody (accented vs. unaccented words) while their eye-movements were measured to referents varying in discourse status (given vs. new categories). In Experiment 1, all listeners inferred prominence when prosody on nouns distinguished categories ("SANDWICH"→not sandals). In Experiment 2, CI users and NH listeners presented with natural speech inferred prominence when prosody on adjectives implied contrast across both categories and properties ("PINK horse"→not the orange horse). In contrast, NH listeners presented with simulated CI (vocoded) speech were sensitive to acoustic differences in prosody, but did not use these cues to infer discourse status. Together, this suggests that exploiting redundant cues for comprehension varies with the demands of language processing and prior experience with the degraded signal.


[Educational perspectives in emergency paramedicine : Interdisciplinary discourse on education, professional practice, and challenges in the field of emergency medical services].
Societal developments that result in an increase in geriatric, psychosocial, and subacute (i.e. not time-critical) emergencies are changing the demands on emergency care and posing challenges to the system of emergency care and emergency medical services (EMS). The training of emergency paramedics (NotSan) lays the foundation for finding a qualified systemic response to evolving patient needs and requirements. By extending and strengthening their competencies, NotSan are to be understood as basic emergency care providers. Their training should therefore be further developed in terms of evidence-based and patient-centered care in order to increase their competency to act and to achieve demand-oriented holistic (outpatient) care. New EMS resources such as community paramedics (GNFS) and telemedical support systems offer opportunities to strengthen competencies in patient care. The guiding principles of care should be patient safety and patient centeredness. In addition to increasing the basic competencies and equipment of existing EMS resources as well as continuous training opportunities, innovative cross-sectoral and cross-professional care concepts are necessary and must be supported.


Assessment of radiolucent lines in patients with lateral unicompartmental knee arthroplasty and the relationship between these lines and the outcome.
To assess the radiolucent lines (RLLs) around both tibial and femoral components in patients following lateral unicompartmental knee arthroplasty (UKA). We performed a retrospective review of the records of a consecutive series of patients who had undergone lateral UKA. The RLLs were assessed with standard anteroposterior and lateral radiographs post-operatively. The patient-reported outcome measures included the Hospital for Special Surgery (HSS) score and Oxford knee score (OKS). The femoral component position (FCP) and femoral-tibial angle (FTA) were also recorded. A total of 198 UKAs that had appropriate radiographs and outcome scores were reviewed with a median follow-up of 33 (range, 12-71) months. The results suggested that 69 cases (34.8%) had RLLs on the standard radiographs. The incidence rates of femoral and tibial physiological RLLs were 11.6% (23/198) and 26% (52/198), respectively, of which 3% (6/198) concerned both components. All RLLs were considered "physiologic lines" that developed within one year after surgery. There were no significant differences among the types of RLLs in any of the outcome measures. No differences in FCP (P = .359) or FTA (P = .111) at the last follow-up were seen. It was found that one-third of UKAs had RLLs on radiographs following lateral UKA. All RLLs developed within one year after surgery. As a clinical consequence, the development of RLLs does not affect the short-term outcomes after lateral UKA.


3D laser surface scanning and geometric morphometric analysis of craniofacial shape as an index of cerebro-craniofacial morphogenesis: initial application to sexual dimorphism.
Over early fetal life, when disturbances in schizophrenia have been posited and craniofacial dysmorphogenesis reported, cerebral morphogenesis proceeds in embryological intimacy with craniofacial morphogenesis. Digitization technologies now allow 3D recording of craniofacial surface landmarks and modeling of craniofacial shape differences using geometric morphometrics. Using normal sexual dimorphism as an exemplar, facial surfaces of 131 Medical School employees [82 females, 49 males] were recorded in 3D using a portable, hand-held laser scanner; 3D coordinate data were then analyzed using geometric morphometrics. Males and females differed markedly on an omnibus test of craniofacial shape. Logistic regression analysis of 16 principal components of shape variability, explaining 84.9% of the overall sample variance, generated 8 principal components as significant and independent discriminators. On visualization, the female face is wider and flatter; the eyes are more lateral, anterior and are further apart, and nasal bridge is posterior; the nose is smaller; the lips are fuller and the chin more forward. These findings are complementary to sexual dimorphism in cerebral structures. This technique reliably discriminates geometric features of craniofacial morphology that are associated with aspects of cerebral morphology, and may inform on putative neurodevelopmental disorders characterised by dysmorphogenesis.


Urokinase therapy for a catheter-related right atrial thrombus and pulmonary embolism in a 2-month-old infant.
Thrombolytic therapy seems to be effective in clearing catheter-related thrombi, allowing subsequent reuse of the Broviac catheter. We have confirmed the previously theoretical risk that thrombolytic therapy in such cases may create pulmonary emboli, but such therapy (in our very limited experience) dissolves the clot extremely quickly. This latter observation may mean that thrombolytic therapy is particularly useful for pulmonary emboli in infants and young children.


Interaction between nesiritide and a heparin-coated pulmonary artery line during an infusion for decompensated heart failure.
Because it is known that intravenous nesiritide is not compatible with unfractionated heparin, we sought to determine the effect that heparin coating on a pulmonary artery catheter may have on the efficacy of a nesiritide infusion. The efficacy of a nesiritide infusion given through a heparin-coated pulmonary artery line was compared with that of a nesiritide infusion administered in the same patient through a heparin-free peripheral line. The rate of infusion was titrated to maintain consistent hemodynamic parameters. When nesiritide was administered through a heparin-coated line, the infusion rate escalated from 0.01 microg/kg/minute to 0.07 microg/kg/minute. After the route of administration was switched to a heparin-free line, the same hemodynamic parameters were maintained. The heparin-free line made it possible to reduce the infusion rate by 57.1% over the next 24 hours to 0.03 microg/kg/minute. The interaction of nesiritide with heparin-coated pulmonary artery lines has the potential to be clinically significant. Clinicians should be educated about this potential interaction. Nesiritide should be infused only through heparin-free lines.


A new class of high affinity thyromimetics containing a phenyl-naphthylene core.
High affinity thyromimetics containing a novel phenyl-naphthylene core are reported. The functionalized core is readily accessible via a Suzuki coupling protocol. Examples of this new class of TR ligands have sub-nanomolar binding affinities for the TRbeta receptor and low to modest selectivity for TRbeta. They also exhibit an SAR that diverges from other thyromimetics that are based on the diaryl ether core found in 3,5,3'-triiodothyronine.


Does the method of primary treatment affect the pattern of first recurrence in high-grade serous ovarian cancer?
To determine if the primary treatment approach (primary debulking surgery (PDS) versus neoadjuvant chemotherapy and interval debulking surgery (NACT-IDS)) influences the pattern of first recurrence in patients with completely cytoreduced advanced high-grade serous ovarian carcinoma (HGSOC). This retrospective study included 178 patients with newly diagnosed stage IIIC-IV HGSOC, complete gross resection during PDS (n = 124) or IDS (n = 54) from January 2008-March 2013, and baseline and first recurrence contrast-enhanced computed tomography scans. Clinical characteristics and number of disease sites at baseline were analyzed for associations with time to recurrence. In 135 patients who experienced recurrence, the overlap in disease locations between baseline and recurrence and the number of new disease locations at recurrence were analyzed according to the primary treatment approach. At univariate and multivariate analyses, NACT-IDS was associated with more overlapping locations between baseline and first recurrence (p ≤ 0.003) and fewer recurrences in new anatomic locations (p ≤ 0.043) compared with PDS. The same results were found in a subgroup that received intra-peritoneal adjuvant chemotherapy after either treatment approach. At univariate analysis, patient age, primary treatment approach, adjuvant chemotherapy route, and number of disease locations at baseline were associated with time to recurrence (p ≤ 0.009). At multivariate analysis, older patient age, NACT-IDS, and greater disease locations at baseline remained significant (p ≤ 0.018). The distribution of disease at the time of first recurrence varied with the choice of primary treatment. Compared to patients treated with PDS, patients who underwent NACT-IDS experienced recurrence more often in the same locations as the original disease.


Long-term safety and efficacy of deferasirox in young pediatric patients with transfusional hemosiderosis: Results from a 5-year observational study (ENTRUST).
Children with red blood cell disorders may receive regular transfusions from an early age and consequently accumulate iron. Adequate iron chelation therapy can prevent organ damage and delayed growth/development. Deferasirox is indicated for treatment of pediatric patients with chronic iron overload due to transfusional hemosiderosis; however, fewer than 10% of patients in the registration studies were aged 2 to less than 6 years. Deferasirox, a once-daily oral iron chelator, was evaluated in young pediatric patients with transfusional hemosiderosis during the observational 5-year ENTRUST study. Patients aged 2 to less than 6 years at enrollment received deferasirox according to local prescribing information, with the primary objective of evaluating safety, specifically renal and hepatic function. Serum ferritin was observed as a surrogate efficacy parameter. In total, 267 patients (mean age 3.2 years) predominantly with β-thalassemia (n = 176, 65.9%) were enrolled. Mean ± standard deviation deferasirox dose was 25.8 ± 6.5 mg/kg per day over a median of 59.9 months. A total of 145 patients (54.3%) completed 5 years' treatment. The proportion of patients with two or more consecutive postbaseline measurements (≥7 days apart) of serum creatinine higher than age-adjusted upper limit of normal (ULN) and alanine aminotransferase more than five times the ULN was 4.4% (95% confidence interval [CI]: 2.1-7.9) and 4.0% (95% CI: 1.8-7.4), respectively. Median serum ferritin decreased from 1,702 ng/ml at baseline to 1,127 ng/ml at 5 years. There were no new safety signals. Safety and efficacy of deferasirox in young pediatric patients in this long-term, observational study in everyday clinical practice were consistent with the known deferasirox profile.


Human follicular dendritic cells in vitro and follicular dendritic-cell-like cells.
Human follicular dendritic cell (FDC)-like cells (FLC) have been utilized for the in vitro analysis of germinal center reactions. However, there is no consensus whether FLC represent FDC in vitro. The purpose of the present study has therefore been to determine distinguishing features of FDC and FLC in vitro. The expression of CD40, CD54, CD49d, cytokine (gamma-IFN and IL-4)-dependent MHC-class II, and CD106 was observed to be specific for the determination of FDC in long-term culture. The cytokine-dependent emperipolesis of germinal center B cells was establised as another discriminating property for FDC in vitro. In 2 out of 72 long-term cultures of FDC, we encountered dividing cells among the non-dividing population of FDC. The dividing cells expressed accessory molecules similar to those of FDC but showed emperipolesis only for the initial few days of their growth. FDC did not enhance the CD40-dependent proliferation of germinal center B cells; in contrast, FLC augumented it. Both types of cells produced a significant amount of cytokine-dependent IL-6. Further studies are needed to determine whether FLC originate from FDC in vitro.


Increased plasma levels of palmitoleic acid may contribute to beneficial effects of Krill oil on glucose homeostasis in dietary obese mice.
Omega-3 polyunsatuarted fatty acids (PUFA) are associated with hypolipidemic and anti-inflammatory effects. However, omega-3 PUFA, usually administered as triacylglycerols or ethyl esters, could also compromise glucose metabolism, especially in obese type 2 diabetics. Phospholipids represent an alternative source of omega-3 PUFA, but their impact on glucose homeostasis is poorly explored. Male C57BL/6N mice were fed for 8 weeks a corn oil-based high-fat diet (cHF) alone or cHF-based diets containing eicosapentaenoic acid and docosahexaenoic acid (~3%; wt/wt), admixed either as a concentrate of re-esterified triacylglycerols (ω3TG) or Krill oil containing mainly phospholipids (ω3PL). Lean controls were fed a low-fat diet. Insulin sensitivity (hyperinsulinemic-euglycemic clamps), parameters of glucose homeostasis, adipose tissue function, and plasma levels of N-acylethanolamines, monoacylglycerols and fatty acids were determined. Feeding cHF induced obesity and worsened (~4.3-fold) insulin sensitivity as determined by clamp. Insulin sensitivity was almost preserved in ω3PL but not ω3TG mice. Compared with cHF mice, endogenous glucose production was reduced to 47%, whereas whole-body and muscle glycogen synthesis increased ~3-fold in ω3PL mice that showed improved adipose tissue function and elevated plasma adiponectin levels. Besides eicosapentaenoic and docosapentaenoic acids, principal component analysis of plasma fatty acids identified palmitoleic acid (C16:1n-7) as the most discriminating analyte whose levels were increased in ω3PL mice and correlated negatively with the degree of cHF-induced glucose intolerance. While palmitoleic acid from Krill oil may help improve glucose homeostasis, our findings provide a general rationale for using omega-3 PUFA-containing phospholipids as nutritional supplements with potent insulin-sensitizing effects.


Association of adverse childhood experiences (ACEs) and substance use disorders (SUDs) in a multi-site safety net healthcare setting.
Adverse childhood experiences (ACEs) and substance use disorders (SUDs) are highly prevalent public health challenges that have been shown to be strongly correlated. Although previous research has suggested a dose-response relationship between ACEs and SUDs, less is known about this phenomenon and the prevalence of ACEs in lower income, racially/ethnically diverse populations. This study sought to examine these relationships in a population treated at a multi-site safety net provider. The ACEs survey was delivered as a standard assessment to all behavioral health patients seen at a large Federally Qualified Health Center (FQHC) in Connecticut. 4378 patients completed the questionnaire. Both total score and individual ACE questions were correlated with diagnostic history, according to chi-square and multiple-group structural equation modeling tests. 84.8% of patients reported at least one ACE and 49.1% had an ACE score ≥ 4. Experiencing 1 or more ACEs predicted having any SUD, after controlling for race/ethnicity and gender. Parent substance use, physical abuse, and sexual abuse in particular were the strongest predictors of developing any SUD. Men and non-white individuals were more likely to develop an SUD with lower ACE scores than women and white individuals. While ACEs predict an increased likelihood of developing any SUD, the nature of this relationship differs by both gender and race/ethnicity. In this FQHC patient population there is no obvious dose-response relationship between ACEs and SUDs. Additional research is required to help understand why the relationship between ACEs and SUDs observed here differs from other populations.


Intravenous self-administration of phentermine in food-deprived rats: effects of abrupt refeeding and saline substitution.
The objectives in these experiments were to determine the effects on intravenous phentermine self-administration of abrupt refeeding and of saline substitution in food-deprived rats. In Experiment 1, 32 naive rats, reduced to 80% free-feeding weight (FFW), were assigned randomly to four equal-sized groups. Two groups self-administered phentermine, the other two saline over two consecutive six-day phases. In phase 1, all animals were maintained at 80% FFW, while in phase 2, one phentermine- and one saline-reinforced group was abruptly food satiated. Results showed that phentermine self-administration was suppressed. In Experiment 2, another 32 naive rats were assigned to four equal-sized groups and tested over two consecutive six-day phases. Two groups were FF, the other two were reduced to 80% FFW. In phase 1, a group of FF and 80% FFW animals self-administered phentermine, the other two saline, while in phase 2, treatments were reversed: previously phentermine-reinforced animals self-administered saline and vice versa. Findings showed that 80% FFW rats rapidly discriminate the introduction or removal of phentermine and alter responding accordingly, while FF animals respond at low rates throughout.


Complex I: inhibitors, inhibition and neurodegeneration.
Complex I is the first protein component of the mitochondrial respiratory chain and as such plays a crucial role in ATP production and mitochondrial function in general. Mitochondrial dysfunction has been identified in a number of neurodegenerative diseases. In some of these the mitochondrial abnormality is primary and in others secondary. Mitochondrial toxins are capable of producing relatively selective neuronal cell death and have been used to produce models of human neurodegenerative diseases e.g. 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine (MPTP) for Parkinson's disease, and 3-nitropropionic acid for Huntington's disease. Annonacin, an ingredient of local soursop, is a Complex I inhibitor and has been incriminated as the cause of a parkinsonian tauopathy disorder in Guadeloupe. A systematic analysis has identified several environmentally available potent lipophilic Complex I inhibitors that can induce neuronal cell death in striatal cultures and somatodendritic redistribution of tau protein. It is possible that these compounds may contribute to the pathogenesis of neurodegenerative disorders, although further work must be done to confirm their potential participation in pathogenesis.


Acoustic estimates of respiration in the pain cries of newborns.
The purpose of the present study was to examine the temporal features of pain-elicited crying demonstrated by healthy full term infants to estimate (1) the respiratory rate during cry and (2) the inspiratory and expiratory phase composition of the cry respiratory cycle. The pain-elicited cries of 12 newborn infants were recorded within the first 2 weeks following birth. A complete crying episode was analyzed for each infant and acoustically measured for the number and duration of inspiratory and expiratory cry components. These components were then used to estimate the respiratory rate of infant crying, as well as the inspiratory and expiratory phase composition of the cry respiratory cycles. Acoustic analysis revealed that the average rate of crying was 57 breaths min⁻¹ with the inspiratory phase contributing 27% to the overall respiratory cycle. However, considerable variability was found across infants with distinct patterns of respiration associated with high versus low respiratory rates. The respiratory patterns associated with pain cries is highly variable and may be associated with variations in stress-arousal, strength of emotional expression, and overall fitness. This study supports the notion that the respiratory activity surrounding newborn infant crying is unique to the type of cry sampled.


National Maintenance Cost for Precision Diagnostics Under the Verifying Accurate Leading-Edge In Vitro Clinical Test Development (VALID) Act of 2020.
The proposed legislation Verifying Accurate and Leading-edge In vitro clinical test Development (VALID) clarifies the US Food and Drug Administration's authority to regulate laboratory-developed tests. Many stakeholders have pointed out that the lack of direct US Food and Drug Administration oversight has led to erroneous results that have serious patient consequences-in particular for patients with cancer. Technology Certification is a key provision proposed in VALID to navigate the balance between safety, patient access, and innovation; however, the maintenance cost of the proposed framework after implementation is unclear. On the basis of 2019 retrospective data from a laboratory-developed test-based cancer diagnostics laboratory, we expressed laboratory complexity by the number and complexity of assays and in vitro diagnostic technologies. We estimated the national health care cost increase by modeling three stringencies of complying with the Act. We performed sensitivity analysis of our regulatory stringency model taking into account number of patients tested, materials, submission cost, and labor using extra cost per patient as the output. We estimate the national health care cost increase to range from $33M US dollars (USD) to $1,110M USD or $0.21 USD to $0.70 USD per employed person in the United States. Sensitivity analysis demonstrates that regulatory stringency is the primary driver of extra cost per patient. Cancer testing does not reflect all areas of in vitro diagnostics affected by VALID; nonetheless, concrete cost models are paramount in informing the ongoing legislative negotiations. Our findings show the critical importance of clarity in the legislative language to ensure balance between VALID's goals of assuring high-quality test performance and the burden to laboratories and overall health care cost.


Determining Top Fully Connected Layer's Hidden Neuron Count for Transfer Learning, Using Knowledge Distillation: a Case Study on Chest X-Ray Classification of Pneumonia and COVID-19.
Deep convolutional neural network (CNN)-assisted classification of images is one of the most discussed topics in recent years. Continuously innovation of neural network architectures is making it more correct and efficient every day. But training a neural network from scratch is very time-consuming and requires a lot of sophisticated computational equipment and power. So, using some pre-trained neural network as feature extractor for any image classification task or "transfer learning" is a very popular approach that saves time and computational power for practical use of CNNs. In this paper, an efficient way of building full model from any pre-trained model with high accuracy and low memory is proposed using knowledge distillation. Using the distilled knowledge of the last layer of pre-trained networks passes through fully connected layers with different hidden layers, followed by Softmax layer. The accuracies of student networks are mildly lesser than the whole models, but accuracy of student models clearly indicates the accuracy of the real network. In this way, the best number of hidden layers for dense layer for that pre-trained network with best accuracy and no-overfitting can be found with less time. Here, VGG16 and VGG19 (pre-trained upon "ImageNet" dataset) is tested upon chest X-rays (pneumonia and COVID-19). For finding the best total number of hidden layers, it saves nearly 44 min for VGG19 and 36 min and 37 s for VGG16 feature extractor.


Gold-binding peptide as a selective layer for electrochemical detection of SARS-CoV-2 antibodies.
Electrochemical immunosensors are excellent alternatives to prepare portable platforms used for rapid and inexpensive diagnostic of infectious diseases such as the recently emerged COVID-19. Incorporating synthetic peptides as selective recognition layers combined with nanomaterials such as gold nanoparticles (AuNPs) can significantly enhance the analytical performance of immunosensors. In the present study, an electrochemical immunosensor based on solid-binding peptide was built and evaluated towards SARS-CoV-2 Anti-S antibodies detection. The peptide used as recognition site has two important portions: one based on the viral receptor binding domain (RBD), capable of recognizing antibodies of the spike protein (Anti-S), and another suitable for interacting with gold nanoparticles. Gold-binding peptide (Pept/AuNP) dispersion was used directly to modify a screen-printed carbon electrode (SPE). The voltammetric behavior of the [Fe(CN)6]3-/4- probe after every construction and detection step was recorded using cyclic voltammetry by assessing the stability of the Pept/AuNP as a recognition layer onto the electrode surface. Differential pulse voltammetry was used as a detection technique, and a linear working range from 75 ng mL-1 to 15 μg mL-1 was established, with 1.059 μA dec-1 of sensitivity and R2 = 0.984. The response selectivity against SARS-CoV-2 Anti-S antibodies was investigated in presence of concomitant species. The immunosensor was used to detect SARS-CoV-2 Anti-spike protein (Anti-S) antibodies in human serum samples, successfully differentiating between negative and positive responses of samples at a 95% confidence level. Therefore, the gold-binding peptide is a promising tool to be applied as a selective layer for antibody detection.


Language and Geographic Representation of Neurosurgical Journals: A Meta-Science Study.
Medical journals have a role in promoting representation of neurosurgeons who speak primary languages other than English. We sought to characterize the language of publication and geographic origin of neurosurgical journals, delineate associations between impact factor (IF) and language and geographic variables, and describe steps to overcome language barriers to publishing. Web of Science, Scopus, and Ulrich's Serial Analysis system were searched for neurosurgery journals. The journals were screened for relevance. Language of publication, country and World Health Organization region, World Bank income status and gross domestic product, and citation metrics were extracted. Of 867 journals, 74 neurosurgical journals were included. Common publication languages were English (52, 70.3%), Mandarin (5, 6.8%), and Spanish (4, 5.4%). Countries of publication for the greatest number of journals were the United States (23, 31.1%), United Kingdom (8, 10.8%), and China (6, 8.1%). Most journals originated from the Americas region (29, 39.2%), the European region (28, 37.8%), and from high-income countries (n = 54, 73.0%). Median IF was 1.55 (interquartile range [IQR] 0.89-2.40). Journals written in English (1.77 [IQR 1.00-2.87], P = 0.032) and from high-income countries (1.81 [IQR 1.0-2.70], P = 0.046) had highest median IF. When excluding outliers, there was a small but positive correlation between per capita gross domestic product and IF (β = 0.021, P = 0.03, R2 = 0.097). Language concordance represents a substantial barrier to research equity in neurosurgery, limiting dissemination of ideas of merit that currently have inadequate outlets for readership. Initiatives aimed at increasing the accessibility of neurosurgical publishing to underrepresented authors are essential.


Plasma glucocorticoids differentially modulate phasic and tonic GABA inhibition during early postnatal development in rat spinal lamina II.
Nociceptive processing is tuned by GABAA receptor-mediated inhibition in the spinal cord dorsal horn that undergoes postnatal maturation in rodents. These GABAergic inhibitory postsynaptic currents (IPSCs) are modulated by 3α5α-reduced steroids during early postnatal development in spinal cord lamina II. Thus an enhanced phasic inhibition is present in neonates and decreases over time. GABA can also activate extrasynaptic receptors, giving rise to tonic inhibition. In this study, we characterized the contribution of plasma corticosterone (CORT) to postnatal maturation of spinal phasic and, for the first time, tonic GABAergic inhibitions. We used Fisher and Lewis rat strains displaying respectively high and low hypothalamic-pituitary-adrenal axis reactivity, compared to control Sprague-Dawley rats. Measured plasma CORT levels were significantly higher in Fisher rats, which also displayed significantly higher mechanical nociceptive thresholds, supporting the hypothesis of an antinociceptive action of CORT. Recorded GABAA IPSCs shortened during maturation in all strains while remaining larger in Fisher rats. Blocking the 5α-reduction of steroids in Fisher rats produced a further decrease of IPSC deactivation time constant. In contrast, GABAA tonic inhibition progressively increased during maturation, without any difference among strains. In conclusion, we show that both phasic and tonic GABAergic inhibitions undergo postnatal maturation in lamina II. Moreover spinal production of 3α5α-reduced steroids that presumably derive from plasma CORT is correlated to spinal GABAA phasic (but not tonic) inhibition and to mechanical nociceptive thresholds.


Concomitant Systemic Therapy: Current and Future Perspectives.
Chemotherapy in combination with radical cystectomy or radiotherapy has led to improved oncological outcomes in the definitive treatment of muscle-invasive bladder cancer (MIBC). Here we discuss the current role of chemotherapy and immunotherapy in the management of MIBC and discuss future directions of treatment.


Evidence for long-term seamount-induced chlorophyll enhancements.
Seamounts are ubiquitous global features often characterized by biological hotspots of diversity, biomass, and abundance, though the mechanisms responsible are poorly understood. One controversial explanation suggests seamount-induced chlorophyll enhancements (SICE) subsidize seamount ecosystems. Using a decade of satellite chlorophyll data, we report substantial long-term chlorophyll enhancements around 17% of Pacific seamounts and 45% of shallow (< 100 m) seamounts, with the highest probability of detection at shallow, low-latitude seamounts. SICE is shown to enhance chlorophyll concentrations by up to 56% relative to oceanic conditions, and SICE seamounts have two-fold higher fisheries catch relative to non-enhancing seamounts. Therefore, seamount-induced bottom-up trophic subsidies are not rare, occurring most often at shallow, heavily exploited seamounts, suggesting an important subset of seamounts experience fundamentally different trophic dynamics than previously thought.


[Solitary calcaneal cyst].
Differential diagnosis of solitary calcaneal cysts extends from benign cysts to malignant tumours. In all, 10-50% of these cysts are located at the centre of the calcaneal body in the form of intraosseous lipomas. Among our patients treated over a period of more than 20 years, there were four who underwent surgery for calcaneal cysts; the respective histological findings showed three lipomas and one tuberculoma. The average age of these patients corresponded to that of Milgram's study. It should also be remarked that all four patients came from a region in which mining was of central economic importance. Our experience has shown that such cysts should be surgically removed and filled with plastic spongiosa material in order both to check whether the cysts are benign or malignant and to avoid an imminent spontaneous fracture of the heel bone.


"I'm not here to push you:" raising adolescents' treatment engagement via autonomy support.
More than 45% of adolescents with aggressive behavior problems drop out of treatment prematurely. Building on insights from self-determination theory, we examined in three studies whether clinicians can raise adolescents' treatment engagement by supporting their autonomy. In an interview study (Study 1), clinicians (N = 16; 43.8% female; ages 30-57) spontaneously described 12 times more autonomy-supportive than controlling strategies to engage adolescents. In a preregistered experiment (Study 2), clinicians (N = 68; 88.2% female; ages 23-65) were confronted with videos of adolescents displaying resistance. We manipulated the DSM diagnosis of adolescents to indicate either aggressive behavior problems or other problems. We found that, regardless of diagnosis, clinicians used both autonomy-supportive strategies (57.7% of responses) and controlling strategies (39.3%), suggesting that applying autonomy support can be challenging with any adolescent displaying resistance. In an experimental study (Study 3), adolescents (N = 252; 50.0% female; ages 12-17) reported higher therapeutic alliance (d = 0.95, 95% CI [0.80, 1.10]) and treatment engagement (d = 0.77, 95% CI [0.63, 0.91]) after listening to audio-recorded autonomy-supportive versus controlling responses from clinicians, regardless of whether these adolescents had aggressive behavior problems. Overall, this research suggests that clinicians can raise adolescents' treatment engagement through autonomy support.


Pathogen inactivation of Trypanosoma cruzi in plasma and platelet concentrates using riboflavin and ultraviolet light.
Emigration of people infected with Trypanosoma cruzi to non-endemic areas has resulted in transfusion transmission to immunocompromised recipients. We studied the feasibility of inactivating T. cruzi using a new technology which utilizes riboflavin as a photosensitizer in combination with UV light, Mirasol PRT. One billion T. cruzi organisms and 30 mL of 500 microM riboflavin were added to each of six units of human plasma and six units of platelets. To determine the level of detection of organism, a sample of each unit was cultured in tenfold serial dilutions beginning with 100 billion/250 mL as the starting culture. After 30 min, each unit was illuminated with 5.9 J/cm(2) of UV light (6.24 J/mL). The units were then cultured again in tenfold serial dilutions post-treatment. A 6 log reduction of pathogens was demonstrated in 5 of 6 units of plasma, and a 7 log reduction of pathogens was demonstrated in one unit. A 6 log reduction of pathogens was demonstrated in 3 of 6 units of platelets, a 7 log reduction was demonstrated in 2 of 6 units of platelets, and an 8 log reduction of pathogens was demonstrated in 1 of 6 units. Mirasol PRT treatment demonstrated an ability to inactivate 5-7 logs of T. cruzi in plasma and platelets.


Genetic and epigenetic changes in vulvar squamous cell carcinoma and its precursor lesions: a review of the current literature.
Vulvar cancer is a relatively rare gynecologic malignancy with an annual incidence in developed countries of approximately 2 per 100,000 women. Vulvar squamous cell carcinoma (VSCC) has two etiological pathways: a high risk human papillomavirus (HPV)-dependent route, which has usual vulvar intraepithelial neoplasia (uVIN) as a precursor lesion, and an HPV-independent route, which is associated with differentiated VIN (dVIN), lichen sclerosus, and genetic alterations, such as TP53 mutations. Research on the molecular etiology of vulvar cancer has increased in the past years, not only regarding genetic alterations, but also epigenetic changes. In genetic alterations, a mutation irreversibly changes the nucleotide sequence of the DNA, or the number of copies of chromosomes per cell is altered. In epigenetics, the nucleotide sequence remains the same but genes can be 'switched' on or off by, for example, DNA methylation or histone modification. We searched the current literature on genetic and epigenetic alterations in VSCC and its precursor lesions. Many studies have reported a higher incidence of somatic mutations in HPV-negative tumors compared to HPV-positive tumors, with TP53 mutations being the most frequent. Allelic imbalances or loss of heterozygosity are more frequently found in higher stages of dysplasia and in invasive carcinomas, but it is not exclusive to HPV-negative tumors. A limited number of studies are available on epigenetic changes in vulvar lesions, with hypermethylation of CDKN2A being the most frequently investigated change. For most genes, hypermethylation occurs more frequently in vulvar squamous cell carcinomas than in precursor lesions. As most studies have focused on HPV infection and TP53 mutations, we suggest that more research should be performed using whole genome or next generation sequencing to determine the true landscape of genetic and epigenetic alterations in vulvar squamous cell carcinoma.


Effect of the polarity reversal frequency in the electrokinetic-biological remediation of oxyfluorfen polluted soil.
This work studies the feasibility of the periodic polarity reversal strategy (PRS) in a combined electrokinetic-biological process for the remediation of clayey soil polluted with a herbicide. Five two-weeks duration electrobioremediation batch experiments were performed in a bench scale set-up using spiked clay soil polluted with oxyfluorfen (20 mg kg-1) under potentiostatic conditions applying an electric field between the electrodes of 1.0 V cm-1 (20.0 V) and using PRS with five frequencies (f) ranging from 0 to 6 d-1. Additionally, two complementary reference tests were done: single bioremediation and single electrokinetic. The microbial consortium used was obtained from an oil refinery wastewater treatment plant and acclimated to oxyfluorfen degradation. Main soil conditions (temperature, pH, moisture and conductivity) were correctly controlled using PRS. On the contrary, the electroosmotic flow clearly decreased as f increased. The uniform soil microbial distribution at the end of the experiments indicated that the microbial activity remained in every parts of the soil after two weeks when applying PRS. Despite the adapted microbial culture was capable of degrade 100% of oxyfluorfen in water, the remediation efficiency in soil in a reference test, without the application of electric current, was negligible. However, under the low voltage gradients and polarity reversal, removal efficiencies between 5% and 15% were obtained, and it suggested that oxyfluorfen had difficulties to interact with the microbial culture or nutrients and that PRS promoted transport of species, which caused a positive influence on remediation. An optimal f value was observed between 2 and 3 d-1.


Effects of supplemented mode of emulsifier on growth performance, serum biochemical index, quality of meat and skin fat, and nutrient utilization in Pekin ducks.
In our previous experiment, we found that fats with pre-emulsification (PreE), a new supplemented mode of emulsifier, had an improved bioavailability for Pekin ducks than fats without PreE based on dietary EE utilization. Therefore, this study was conducted to investigate the effects of the supplemented mode of emulsifier (PreE vs. emulsifier direct supplementation) on the growth performance, serum biochemical index, quality of meat and skin fat, and nutrient utilization in Pekin ducks. A total of 640 healthy 10-day-old Pekin male ducks (408.65 ± 12.00 g) were randomly allocated into 4 treatments with 16 replicates of 10 birds each. The 4 dietary treatments were as follows: the positive control group (PC; the oil supplemented amount of 6%), the negative control group (NC; the oil supplemented amount of 5.4%), the emulsifier group (E; NC diet with an emulsifier added directly), and the oil pre-emulsification group (PreE; NC diet with oil PreE). The results showed reducing the amount of fat in the diet (NC vs. PC) significantly decreased growth performance and quality of skin fat, and affected serum lipid metabolism (P < 0.05). Interestingly, the body weight (BW), body weight gain (BWG), and the shear force of skin fat were increased, but the feed to gain ratio (F/G) was markedly decreased in the PreE group (P < 0.05) compared to those in the NC group, and these levels were similar to those in the PC group (P > 0.05). Additionally, the utilization of dietary dry matter (DM), ether extract (EE), and total phosphorous (TP) were increased, but the activity of aspartate aminotransferase (AST) in serum was decreased in the PreE group compared to those in the NC group (P < 0.05). Furthermore, compared to the E group, the F/G was decreased (P < 0.05), and the utilization of dietary EE, the shear force of skin fat and content of collagen in skin fat were markedly increased (P < 0.05) in the PreE group. However, no differences were observed (P > 0.05) in growth performance between the group administered a direct supplementation of emulsifier and the control groups (PC and NC). These results indicate that the negative effect of reducing the oil supplementation amount (-0.6%) in the diet can be restored by supplementation with emulsifier, especially by oil with PreE.


Neuronal tachykinin NK2 receptors mediate release of non-adrenergic non-cholinergic inhibitory transmitters in the circular muscle of guinea-pig colon.
The aims of this study were: (i) verify the usefulness of the recently described non-peptide antagonist, SR 142801, for blocking tachykinin NK3 receptors in the circular muscle of the guinea-pig colon and (ii) after occlusion of NK3 receptors by SR 142801, test the hypothesis that tachykinins may activate non-adrenergic non-cholinergic inhibitory neurons via non-NK3 receptors. In sucrose gap, we found that SR 142801 (0.1 microM) time-dependently inhibited the senktide-induced atropine (1 microM)-sensitive depolarization, action potentials and contractions of circular muscle of guinea-pig colon without affecting the cholinergic excitatory junction potential and contraction produced by single pulse electrical field stimulation. Likewise, SR 142801 (0.1 microM) time-dependently inhibited the senktide-induced non-adrenergic non-cholinergic hyperpolarization and relaxation of the circular muscle, without affecting the non-adrenergic non-cholinergic inhibitory junction potentials and relaxation produced by single pulse electrical field stimulation. Therefore, SR 142801 is a suitable tool to occlude neuronal NK3 receptors in guinea-pig colon. In the presence of SR 142801 (0.1 microM), atropine (1 microM), guanethidine (3 microM), indomethacin (3 microM) and nifedipine (1 microM) superfusion with neurokinin A (0.3 microM) produced depolarization on which a series of inhibitory junction potentials were superimposed. The incidence, number and amplitude of the inhibitory junction potentials evoked by neurokinin A was partly reduced by pretreatment with either apamin (0.1 microM) or L-nitroarginine (30 microM) and was totally blocked by pretreatment with apamin plus L-nitroarginine or by tetrodotoxin (1 microM). None of these treatments affected the depolarization and contraction produced by neurokinin A. The NK1 receptor selective antagonist, GR 82,334 (3 microM), did not affect the responses to neurokinin A, which were abolished by the NK2 receptor-selective antagonist GR 94,800 (0.1 microM). Substance P (0.3 microM) produced a large depolarization of the membrane but was poorly effective in producing superimposed inhibitory junction potentials. The NK1 receptor-selective agonist [Sar9]substance P sulfone (0.3 microM) produced large depolarization without inducing superimposed inhibitory junction potentials, while the NK2 receptor-selective synthetic agonist [beta-Ala8]neurokinin A(4-10) (0.3 microM) produced depolarization and superimposed inhibitory junction potentials. We conclude that neurokinin A, in addition to direct excitation and contraction of circular muscle activates, via neuronal NK2 receptors, inhibitory non-adrenergic non-cholinergic motorneurons. Thus, neuronal NK2 receptors should be considered as targets for endogenous tachykinins in enteric circuitries leading to descending relaxation in guinea-pig colon.


Can plantar fibroblast implantation protect amputees from skin injury? A recipe for skin augmentation.
Skin injuries remain a persistent problem for users of lower-limb prostheses despite sustained progress in prosthesis design. One factor limiting the prevention of skin injuries is that skin on the residual limb is not suited to bear the mechanical loads of ambulation. One part of the body that is suited to this task is the sole of the foot. Here, we propose a novel strategy to actively augment skin's tolerance to load, increasing its resistance to mechanically induced injuries. We hypothesise that the load tolerance of skin can be augmented by autologous transplantation of plantar fibroblasts into the residual limb dermis. We expect that introducing plantar fibroblasts will induce the overlying keratinocytes to express plantar-specific keratins leading to a tougher epidermis. Using a computational finite element model of a weight-bearing residual limb, we estimate that skin deformation (a key driver of pressure ulcer injuries) could be halved by reprogramming skin to a plantar-like phenotype. We believe this strategy could yield new progress in pressure ulcer prevention for amputees, facilitating rehabilitation and improving quality of life for patients.


Molecular evolution of the modulator of chloroplast ATP synthase: origin of the conformational change dependent regulation.
Chloroplast ATP synthase synthesizes ATP by utilizing a proton gradient as an energy supply, which is generated by photosynthetic electron transport. The activity of the chloroplast ATP synthase is regulated in several specific ways to avoid futile hydrolysis of ATP under various physiological conditions. Several regulatory signals such as Delta mu H(+), tight binding of ADP and its release, thiol modulation, and inhibition by the intrinsic inhibitory subunit epsilon are sensed by this complex. In this review, we describe the function of two regulatory subunits, gamma and epsilon, of ATP synthase based on their possible conformational changes and discuss the evolutionary origin of these regulation systems.


Factors Associated With Readmission in the United States Following Hospitalization With Coronavirus Disease 2019.
Patients hospitalized for coronavirus disease 2019 (COVID-19) may experience complications following hospitalization and require readmission. In this analysis, we estimated the rate and risk factors associated with COVID-19-related readmission and inpatient mortality. In this retrospective cohort study, we used deidentified chargemaster data from 297 hospitals across 40 US states on patients hospitalized with COVID-19 from 15 February 2020 through 9 June 2020. Demographics, comorbidities, acute conditions, and clinical characteristics of first hospitalization are summarized. Multivariable logistic regression was used to measure risk factor associations with 30-day readmission and in-hospital mortality. Among 29 659 patients, 1070 (3.6%) were readmitted. Readmitted patients were more likely to have diabetes, hypertension, cardiovascular disease (CVD), or chronic kidney disease (CKD) vs those not readmitted (P < .0001) and to present on first admission with acute kidney injury (15.6% vs 9.2%), congestive heart failure (6.4% vs 2.4%), or cardiomyopathy (2.1% vs 0.8%) (P < .0001). Higher odds of readmission were observed in patients aged >60 vs 18-40 years (odds ratio [OR], 1.92; 95% confidence interval [CI], 1.48-2.50) and those admitted in the Northeast vs West (OR, 1.43; 95% CI, 1.14-1.79) or South (OR, 1.28; 95% CI, 1.11-1.49). Comorbidities including diabetes (OR, 1.34; 95% CI, 1.12-1.60), CVD (OR, 1.46; 95% CI, 1.23-1.72), CKD stage 1-5 (OR, 1.51; 95% CI, 1.25-1.81), and CKD stage 5 (OR, 2.27; 95% CI, 1.81-2.86) were associated with higher odds of readmission; 12.3% of readmitted patients died during second hospitalization. Among this large US population of patients hospitalized with COVID-19, readmission was associated with certain comorbidities and acute conditions during first hospitalization. These findings may inform strategies to mitigate risks of readmission due to COVID-19 complications.


HPLC separated fractions of 99mTc(NaBH4)-HEDP as myocardial infarct imaging agents.
Component fractions of 99mTc(NaBH4)-HEDP mixtures, isolated by anion exchange high performance liquid chromatography (HPLC), have been evaluated as myocardial infarct imaging agents in two animal models. Results from both the isoproterenol-induced myocardial infarction model, and the heat-induced myocardial necrosis model, show that the several HPLC isolated components exhibit significantly different abnormal/normal heart uptake ratios. In addition, the HPLC isolated component of shortest chromatographic retention time exhibits a higher abnormal/normal heart uptake ratio than does 99mTc(Sn)-PyP, the current agent of choice for clinical myocardial infarct imaging.


Reliability of Office, Home, and Ambulatory Blood Pressure Measurements and Correlation With Left Ventricular Mass.
Determining the reliability and predictive validity of office blood pressure (OBP), ambulatory BP (ABP), and home BP (HBP) can inform which is best for diagnosing hypertension and estimating risk of cardiovascular disease. This study aimed to assess the reliability of OBP, HBP, and ABP and evaluate their associations with left ventricular mass index (LVMI) in untreated persons. The Improving the Detection of Hypertension (IDH) study, a community-based observational study, enrolled 408 participants who had OBP assessed at 3 visits, and completed 3 weeks of HBP, 2 24-h ABP recordings, and a 2-dimensional echocardiogram. Mean age was 41.2 ± 13.1 years, 59.5% were women, 25.5% African American, and 64.0% Hispanic. The reliability of 1 week of HBP, 3 office visits with mercury sphygmomanometry, and 24-h ABP were 0.938, 0.894, and 0.846 for systolic and 0.918, 0.847, and 0.843 for diastolic BP, respectively. The correlations among OBP, HBP, and ABP, corrected for regression dilution bias, were 0.74 to 0.89. After multivariable adjustment including OBP and 24-h ABP, 10 mm Hg higher systolic and diastolic HBP were associated with 5.07 (standard error [SE]: 1.48) and 3.92 (SE: 2.14) g/m2 higher LVMI, respectively. After adjustment for HBP, neither systolic or diastolic OBP nor ABP was associated with LVMI. OBP, HBP, and ABP assess somewhat distinct parameters. Compared with OBP (3 visits) or 24-h ABP, systolic and diastolic HBP (1 week) were more reliable and more strongly associated with LVMI. These data suggest that 1 week of HBP monitoring may be the best approach for diagnosing hypertension.


Protective potential of an attenuated Pasteurella multocida, which expresses only the N-terminal truncated fragment of P. multocida toxin.
Pasteurella multocida serogroup D causes progressive atrophic rhinitis in pigs and produces a potent, intracellular, mitogenic toxin known as P. multocida toxin (PMT), which is encoded by the toxA gene. Highly toxic to cells, PMT is a poor antigen and becomes more immunogenic after its native structure has been destroyed. Previously, we found that the N-terminal fragment of PMT (N-PMT) can induce a strong immune response that is protective against wild-type challenge. Here, an attenuated P. multocida mutant expressing only N-PMT was developed and its protective effect was evaluated. The mutant provides protective immune responses against bacterial and toxin challenges, and so is a good live vaccine candidate.


Electrocardiographic diagnosis of acute myocardial infarction in a pacemaker patient: a case report.
The electrocardiographic diagnosis of acute myocardial infarction (AMI) in the setting of cardiac pacing is often challenging. The original Sgarbossa criteria proposed in 1996 were demonstrated to be valid for diagnosis of AMI in both ventricular paced rhythm and left bundle branch block. To improve accuracy, the modified Sgarbossa criteria (MSC) were proposed. We presented a case of electrocardiographic diagnosis of AMI in a pacemaker patient. The Electrocardiogram (ECG) was false negative by using the original Sgarbossa criteria, whereas true positive by the MSC at a ratio of - 0.20. The application of MSC using an appropriate ratio (- 0.20 or - 0.25) may facilitate a timely diagnosis of AMI. Physicians should carefully choose the appropriate cutoff in a case-by-case basis.


Unique canal communicating between both maxillary sinuses through the palatine recess with hypertrophy of sinuses.
The result of an inappropriate growth of the jaws is in many cases related to abnormalities in the rest of the facial skeleton. We present a 21-year-old patient with a possibly unique anomaly of the maxillary sinus in skeletal class III dentofacial deformity. This anatomical variant has not to our knowledge been previously reported and all clinicians should be aware of it. It presented not only as hypertrophy of the sinuses but also as a communication between the two maxillary sinuses, and might be associated with a severe III class deformity with an extremely narrow maxilla. We describe this as a narrowed maxillary canal with no septum or membrane.