Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis.
The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.


Children and adolescents cancer incidence, mortality and survival a population-based study in Midwest of Brazil.
To identify time trends in incidence, mortality and 5-year relative survival in children and adolescents with cancer in Goiania-Goias, Brazil, during the years of 1996-2012. Incidence and mortality age-standardized rates (ASR) were calculated, and trends were identified by determining the Average Annual Percentage Change (AAPC). Five-year relative survival were estimated. The overall incidence ASR (1996-2012) was 164.2/1,000,000 in both genders. In boys was 176.6/1,000,000, in girls it was 151.8/1,000,000. Overall mortality ASR for both gender were 69.3/1,000,000. Incidence rates (AAPC: -0.5; 95 %CI: -2.4;1.4) and mortality rates (AAPC: 0.0; 95 %CI: -2.6;2;7) were stable in the period. Five-year relative survival for all cancers were 63.9 %, with the highest survival rates for retinobastoma (83.5 %), germ cell tumors (79.8 %), and lymphomas (72.7 %). It was observed an increase in survival in the period from de 62.8 % (1996 a 2003) to 65.0 % from 2004 to 2012. Children and adolescent cancer incidence and mortality rates were higher in Goiania, but both are stable overall. The relative survival slighly improved in the period but remained lower mainly for leukemias.


Effects of three different sterilization methods on utero-ovarian Doppler blood flow and serum levels of ovarian hormones.
The aim of the study was to assess pre-operative and post-operative serum levels of ovarian hormones and changes in utero-ovarian arterial blood flow by Doppler ultrasonography in women in whom one of three different sterilization methods was applied. The Pomeroy method of tubal ligation, fimbriectomy, or laparoscopic bipolar coagulation were applied in 42 patients. Serum levels of sex hormones were checked, and utero-ovarian arterial Doppler measurements were performed pre-operatively and post-operatively. The presence or absence of dysmenorrhea was noted before and after the operations. We detected a significant increase in the average uterine arterial resistivity index (RI) and both ovarian arterial pulsatility index (PI) values in the Pomeroy method group (p<0.05). There was a significant increase in dysmenorrhea complaints in the total number of patients (p<0.05), particularly in the fimbriectomy group. The significant increase in uterine arterial Doppler measurements with the Pomeroy method may be due to the removal of a larger tubal segment. Even though the increase is not statistically significant, fimbriectomy should not be applied in young women, because it may increase dysmenorrhea and the procedure is not reversible.


Filling the gap: a series of 3D-printed titanium truss cages for the management of large, lower limb bone defects in a developing country setting.
Large segmental long bone defects are notoriously difficult to manage. Treatment is resource-intensive due to the complexity, cost, and specialized skills required. Truss designs are known for their triangular shapes organized in web configurations. This allows for maximal mechanical strength, the least mass, and a lattice that can be filled with bone graft. Using a truss cage combined with contemporary internal fixation provides immediate stability for bone ingrowth and long-term potential union. The implant is designed using virtual 3D modelling of the patient's bone defect based on a CT scan. The truss cage can be used in a staged procedure combined with Masquelet's induced membrane technique. This study aims to review the outcomes of patient-specific, locally designed 3D titanium truss cages packed with cancellous autograft in treating segmental, long bone defects in the lower limb in a developing country setting. This retrospective series reviewed cases performed at various institutions between January 2019 and March 2022. Parameters assessed included patient demographics, size and location of the defect, time to clinical and radiological union and complications. Nine cases were included for review, with a mean age of 36 years (range 19-52). Defects ranged from 60 to 205 mm, and eight cases were staged procedures. Eight cases used intramedullary reamings as bone graft. Contemporary intramedullary nails were used for fixation in all cases. No peri- or post-operative complications occurred. All cases progressed to functional union. 3D-printed titanium truss cages combined with bone graft appear to be an effective treatment of large bone defects in the lower limb in a developing country setting in the short term. No complications were encountered, but longer follow-up is needed before definitive recommendations can be made. Level IV (retrospective case series).


Sperm cryopreservation affects postthaw motility, but not embryogenesis or larval growth in the Brazilian fish Brycon insignis (Characiformes).
Sperm cryopreservation is an important method for preserving genetic information and facilitating artificial reproduction. The objective was to investigate whether the cryopreservation process affects postthaw sperm motility, embryogenesis, and larval growth in the fish Brycon insignis. Sperm was diluted in methyl glycol and Beltsville Thawing solution, frozen in a nitrogen vapor vessel (dry shipper) and stored in liquid nitrogen. Half of the samples were evaluated both subjectively (% of motile sperm and motility quality score-arbitrary grading system from 0 [no movement] to 5 [rapidly swimming sperm]) and in a computer-assisted sperm analyzer (CASA; percentage of motile sperm and velocity). The other half was used for fertilization and the evaluation of embryogenesis (cleavage and gastrula stages), hatching rate, percentage of larvae with normal development and larval growth up to 112 days posthatching (dph). Fresh sperm was analyzed subjectively (percentage of motile sperm and motility quality score) and used as the control. In the subjective analysis, sperm motility significantly decreased from 100% motile sperm and quality score of 5 in fresh sperm to 54% motile sperm and quality score of 3 after thawing. Under computer-assisted sperm analyzer evaluation, postthaw sperm had 67% motile sperm, 122 μm/sec of curvilinear velocity, 87 μm/sec of straight-line velocity and 103 μm/sec of average path velocity. There were no significant differences between progenies (pooled data) for the percentage of viable embryos in cleavage (62%) or gastrula stages (24%) or in the hatching rate (24%), percentage of normal hatched larvae (93%), larval body weight (39.8 g), or standard length (12.7 cm) at 112 days posthatching. Based on these findings, cryopreserved sperm can be used as a tool to restore the population of endangered species, such as B. insignis, as well as for aquaculture purposes, without any concern regarding quality of the offspring.


Methionine deficiency in rats fed soy protein induces hypercholesterolemia and potentiates lipoprotein susceptibility to peroxidation.
A number of studies have provided evidence that plant proteins, especially soy protein, have a cholesterol-lowering effect as compared with casein. However, dietary supply of sulfur amino acids may be deficient when soy protein is present in the diet at a suboptimal level, which could affect lipid metabolism. Accordingly, in rats fed 13% protein diets, soy protein feeding resulted in a cholesterol-increasing effect (+18%), which could be counteracted by methionine supplementation (0.4%). In contrast, soy protein was effective in decreasing plasma triglyceride, as compared with levels in rats fed casein; this triglyceride-lowering effect was entirely abolished by methionine supplementation. The hypercholesterolemic effect of soy protein was characterized by a higher cholesterol content in low-density lipoprotein (LDL) and high-density lipoprotein 1 (HDL1) fractions, together with a marked induction of hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase activity and to a lesser extent cholesterol 7 alpha-hydroxylase. There was practically no induction of these enzymes, as compared with levels in rats fed casein diets, when the soy protein diet was supplemented with methionine. Very-low-density lipoprotein (VLDL) plus LDL susceptibility to peroxidation was higher in rats fed soy protein than in casein-fed rats, which could reflect in part the lack of sulfur amino acid availability, since methionine supplementation led to a partial recovery of lipoprotein resistance to peroxidation. These findings suggest that amino acid imbalance could be atherogenic by increasing circulating cholesterol and leading to a higher lipoprotein susceptibility to peroxidation.


Granulomatous Diseases Affecting Jaws.
The common aspect of all granulomatous diseases is the typical form of chronic inflammatory response with distinct microscopic granulomas that are formed secondary to either definitive etiologic agents, like bacteria, fungal, or parasitic, or due to an unknown etiologic agent, such as trauma, autoimmune, or even neoplastic process. Although they can be histologically distinct, granulomatous diseases demonstrate a variety of clinical features that may not seem to be inflammatory. Two types of granulomas are typically encountered: foreign body granulomas and immune granulomas. The differences between the two types of granulomas lie in the pathogenesis.


In vivo platelet activation following myocardial infarction and acute coronary ischaemia.
Forty-seven patients presenting with acute chest pain had in vivo platelet activity assessed by measuring plasma levels of the platelet-specific protein beta thromboglobulin (BTG), and by screening for the presence of circulating platelet aggregates. Nineteen patients with transmural myocardial infarction (MI), 21 patients with acute coronary ischaemia (CI), and 7 patients with non-cardiac chest pain (NCCP) were investigated in a serial study and compared with a normal control group. The means of all BTG determinations in the MI (34, +/- SD = 21-57) and CI (33, +/- SD = 19-57) groups were significantly higher than those in the NCCP group (24, +/- SD equal 17-34; p less than 0.01) and normal subjects (22,5 +/- SD = 14-37; p less than 0.001). There was no difference in BTG between those with MI or CI, nor between the NCCP group and normal subjects. Raised numbers of circulating platelet aggregates could not be detected in either MI or CI. The mean BTG levels in both MI and CI patients were significantly raised, compared to normal subjects, on the first day of admission to hospital and remained so on each of the subsequent nine days. Neither heparin plus warfarin nor sulphinpyrazone had any significant effect in lowering BTG levels. 15/40 patients (37.5%) following MI and CI had repeatedly raised BTG levels throughout the study period, and it is suggested that these patients represent an "at risk" group that may benefit from anti-platelet therapy in secondary prevention studies.


Lockdown spillovers.
Lockdowns imposed to fight the Covid-19 pandemic have cross-border effects. In this paper, we estimate the empirical magnitude of lockdown spillovers in a set of panel local projections. We use daily indicators of economic activity such as stock returns, effective exchange rates, NO2 emissions, mobility and maritime container trade. Lockdown shocks originating in the most important trading partners have a strong and significant adverse effect on economic activity in the home economy. For stock prices and exports, the spillovers can even be larger than the effect of domestic lockdown shocks. The results are robust with respect to alternative country weights used to construct foreign shocks, i.e. weights based on foreign direct investment or the connectedness through value chains. We find that lockdown spillovers have been particularly strong during the first wave of the pandemic. Countries with a higher export share are particularly exposed to lockdown spillovers.


What's new in obstetric anesthesia? Focus on preeclampsia.
Recent advances in the diagnosis, pathogenesis, and understanding of preeclampsia-related morbidity provide opportunities to optimize clinical management of the mother and fetus. These discoveries are timely, as contemporary data suggest that the prevalence of preeclampsia, affecting 7.5% of pregnancies globally and 2-5% in the USA, has increased by up to 30% over the last decade. Managing pregnant patients with preeclampsia can be challenging for all members of the obstetric care team due to the disease's multi-organ system maternal and fetal effects. This review presents recent updates in the definition of preeclampsia, etiology, comorbidities and therapeutic interventions and discusses how they impact the care of these high-risk patients.


New AMP-forming acid:CoA ligases from Streptomyces lividans, some of which are posttranslationally regulated by reversible lysine acetylation.
In nature, organic acids are a commonly used source of carbon and energy. Many bacteria use AMP-forming acid:CoA ligases to convert organic acids into their corresponding acyl-CoA derivatives, which can then enter metabolism. The soil environment contains a broad diversity of organic acids, so it is not surprising that bacteria such as Streptomyces lividans can activate many of the available organic acids. Our group has shown that the activity of many acid:CoA ligases is posttranslationally controlled by acylation of an active-site lysine. In some cases, the modification is reversed by deacylases of different types. We identified eight new acid:CoA ligases in S. lividans TK24. Here, we report the range of organic acids that each of these enzymes can activate, and determined that two of the newly identified CoA ligases were under NAD+ -dependent sirtuin deacylase reversible lysine (de)acetylation control, four were not acetylated by two acetyltransferases used in this work, and two were acetylated but not deacetylated by sirtuin. This work provides insights into the broad organic-acid metabolic capabilities of S. lividans, and sheds light into the control of the activities of CoA ligases involved in the activation of organic acids in this bacterium.


Bismuth-dispersed xerogel-based composite films for trace Pb(II) and Cd(II) voltammetric determination.
We report for the first time the synthesis of bismuth-modified (3-mercaptopropyl) trimethoxysilane (MPTMS) and its application for the determination of lead and cadmium by anodic stripping voltammetry. Xerogels made from bismuth-modified MPTMS and mixtures of it with tetraethoxysilane, under basic conditions (NH3·H2O), were characterized with scanning electron microscopy, energy dispersive spectroscopy, infrared spectroscopy and electrochemical methods. Bismuth-modified xerogels were mixed with 1.5% (v/v) Nafion in ethanol and applied on glassy carbon electrodes. During the electrolytic reductive deposition step, the bismuth compound on the electrode surface was reduced to metallic bismuth. The target metal cations were simultaneously reduced to the respective metals and were preconcentrated on the electrode surface by forming an alloy with bismuth. Then, an anodic voltammetric scan was applied in which the metals were oxidized and stripped back into the solution; the voltammogram was recorded and the stripping peak heights were related to the concentration of Cd(II) and Pb(II) ions in the sample. Various key parameters were investigated in detail and optimized. The effect of potential interferences was also examined. Under optimum conditions and for preconcentration period of 4 min, the 3σ limit of detection was 1.3 μg L(-1) for Pb(II) and 0.37 μg L(-1) for Cd(II), while the reproducibility of the method was 4.2% for lead (n=5, 10.36 μg L(-1) Pb(II)) and 3.9% for cadmium (n=5, 5.62 μg L(-1) Cd(II)). Finally, the sensors were applied to the determination of Cd(II) and Pb(II) ions in water samples.


Morphometric spectral-domain optical coherence tomography features of epiretinal membrane correlate with visual acuity in patients with uveitis.
To identify visually significant spectral-domain optical coherence tomography (SD-OCT) features of epiretinal membranes (ERM) in patients with uveitis. Retrospective cohort and cross-sectional study. Eighty consecutive eyes with uveitis and SD-OCT-documented ERM were included. Clinical data were collected at the time of diagnosis of ERM and at the final visit. SD-OCT images at the last visit were evaluated to identify fovea and ERM configuration and structural changes. Changes of 10% and 20% in central subfield thickness between initial and last SD-OCT were calculated and correlated with visual acuity (VA). An ERM thickness map was created using validated SD-OCT grading software. VA improved significantly in eyes with more than 12 months of follow-up (P = .03). Although inflammation activity and medical treatment methods were no different in eyes with more or less than 12 months of follow-up, 16 eyes in the subset with longer follow-up underwent cataract extraction and intraocular lens implantation. Kaplan-Meier analysis demonstrated few vision losses during the follow-up period. Change in central subfield thickness did not correlate with VA. Foveal center involvement (P < .001), focal attachment of the ERM (P = .003), and foveal inner segment and outer segment junction disruption (P = .006) were associated independently with lower VA. ERM was thinner in eyes with 20/40 or better VA (4.6 ± 0.6 μm) compared with eyes with VA of less than 20/200 (P = .02). Longer duration of ERM was associated with thicker ERM (P < .05). In most eyes with uveitis and ERM, VA remains stable if ocular inflammation and comorbidities are addressed appropriately.


Recovery oriented psychotherapy.
Professionals disagree about the role of psychotherapy in the treatment of drug and alcohol problems. This paper defines psychotherapy in terms of the changing ways the professional can assist in the tasks of recovery. These are examined in an evolutionary sequence: dealing with the client in the active abuse cycle; breaking the addiction cycle; consolidating abstinence and changing life styles; addressing recovery-related psychological issues; and undertaking long term psychological exploration. Differing applications of behavior shaping and insight oriented techniques are discussed.


Bandgap Engineering of Melon using Highly Reduced Graphene Oxide for Enhanced Photoelectrochemical Hydrogen Evolution.
The uncondensed form of polymeric carbon nitrides (PCN), generally known as melon, is a stacked 2D structure of poly(aminoimino)heptazine. Melon is used as a photocatalyst in solar energy conversion applications, but suffers from poor photoconversion efficiency due to weak optical absorption in the visible spectrum, high activation energy, and inefficient separation of photoexcited charge carriers. Experimental and theoretical studies are reported to engineer the bandgap of melon with highly reduced graphene oxide (HRG). Three HRG@melon nanocomposites with different HRG:melon ratios (0.5%, 1%, and 2%) are prepared. The 1% HRG@melon nanocomposite shows higher photocurrent density (71 µA cm-2 ) than melon (24 µA cm-2 ) in alkaline conditions. The addition of a hole scavenger further increases the photocurrent density to 630 µA cm-2 relative to the reversible hydrogen electrode (RHE). These experimental results are validated by calculations using density functional theory (DFT), which revealed that HRG results in a significant charge redistribution and an improved photocatalytic hydrogen evolution reaction (HER).


Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.
Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.


Quantitative LSPR imaging for biosensing with single nanostructure resolution.
Localized surface plasmon resonance (LSPR) imaging has the potential to map complex spatio-temporal variations in analyte concentration, such as those produced by protein secretions from live cells. A fundamental roadblock to the realization of such applications is the challenge of calibrating a nanoscale sensor for quantitative analysis. Here, we introduce a new, to our knowledge, LSPR imaging and analysis technique that enables the calibration of hundreds of individual gold nanostructures in parallel. The calibration allowed us to map the fractional occupancy of surface-bound receptors at individual nanostructures with nanomolar sensitivity and a temporal resolution of 225 ms. As a demonstration of the technique's applicability to molecular and cell biology, the calibrated array was used for the quantitative LSPR imaging of anti-c-myc antibodies harvested from a cultured 9E10 hybridoma cell line without the need for further purification or processing.


On the use of the Stern-layer and the charged-layer formalisms for the interpretation of dielectric and electrokinetic properties of colloidal suspensions.
The classical description of colloidal suspensions is based on a series of assumptions that constitute the standard electrokinetic model: suspended particles are surrounded by a uniform surface density of fixed charge, the equilibrium ion density coincides with the Gouy-Chapman distribution, and the surface conductivity coincides with the conductivity of the diffuse double layer. Although highly versatile and relatively simple to compute, the classical model often fails to predict crucial experimental trends. Consequently, various attempts have been made to generalize the standard electrokinetic model in order to encompass a broader set of experimental data. Numerical results show that the Stern-layer formalism increases the conductivity and dielectric response but decreases the electrophoretic mobility, while the charged-layer approach leads to electrophoretic mobility values that can actually increase with the surface layer conductivity. Here we compare the predictions of these two surface layer models regarding the conductivity increment, the electrophoretic mobility, and the dielectric increment. We show that for high kappaa (kappa and a being the reciprocal Debye length and the particle radius, respectively) and intermediate electrophoretic mobility values as well as cases when the measured mobility is higher than the maximum value predicted by the standard electrokinetic model, the experimental data can only be interpreted using the charged-layer model.


Why people die of active tuberculosis in the era of effective chemotherapy in Southern Ethiopia: A qualitative study.
High TB mortality is increasingly understood as an indicator of different problems in the health system and community. Limited awareness of TB in the community, restricted accessibility and/or quality of health services can hamper survival. Exploration and analysis of death among TB patients can lead to a clearer and specific understanding of why the deaths happened and where interventions are likely to make a difference in a specific context. The study aimed to assess why people die of active tuberculosis in the era of effective chemotherapy. The study was conducted from October to December 2020 in Arba Minch Health and Demographic Surveillance System (AM-HDSS) by applying phenomenological study design. A total of 27 family members of people who had died of TB, 9 health extension workers (HEW) and 8 health care professionals working in TB clinics were participated in open in-depth interview. A total of 130 individuals participated in 16 focus group discussion which composed of patient survived from TB, religious leader, health development army (HAD) and HEWs. Adequacy of information (saturation) was considered as an adequate sample size to create the intended qualitative product. All the interviews and FGD were tape recorded and recordings were transcribed immediately. ATLAS TI 9 software was used to analyse and process qualitative data. From data set codes were created then by identifying pattern among them themes were created. Then, generated themes were compared and some of them were split, combined, discarded and new ones created after returning to data set. Finally, themes were defined and a concise and easily understandable name was given for each theme. Luck of sufficient knowledge about TB was considered to be a reason for cause of death. Most of the time, TB patients underestimate and ignore when the symptoms first emerge and will not relate it with any diseases. The low level of community awareness about the cause, transmission, treatment and prevention highly contributed to increased transmission rate and death due to TB. The study identified misconceptions in the community; they prefer traditional medicine to the scientific way. First, they try different herbal medicine to get relief from their illness. At the end, if the disease is getting worse, they visit health facilities. Participants mentioned high transportation cost, poor health seeking behaviours, inadequate food consumption and lack of TB awareness as reasons for low treatment adherence. The health facilities were inaccessible for the community. Most of them indicated that health facilities were too far to reach. In some health institution, right amount and combination of medication were not delivery on time and Diagnostic facilities for TB were reported to be inadequate. Poor treatment adherence, lack of TB awareness, stigma, inadequate food consumption, poor health care seeking behaviour and inaccessibility of health facility were identified as major reasons for death. To prevent death of TB patients all sectors such as education, health, and agriculture should work to address health education, infrastructures, nutritional supplementation needs of TB patients, caregivers and the community as a whole.


Immune modulation of vascular resident cells by Axl orchestrates carotid intima-media thickening.
Cellular mechanisms of carotid intima-media thickening (IMT) are largely unknown. The receptor tyrosine kinase Axl is essential for function of both bone marrow (BM) and non-BM cells. We studied the mechanisms by which Axl expression in BM-derived cells (compared with non-BM-derived cells) mediates carotid IMT. Partial ligation of the left carotid artery resulted in a similar carotid blood flow reduction in Axl chimeras. Neither irradiation nor bone marrow transplantation had any effect on the 40% difference in carotid IMT between Axl genotypes. Axl-dependent survival is very important for intimal leukocytes; however, Axl expression in BM cells contributes to <30% of carotid IMT. Axl in non-BM cells has a greater effect on carotid remodeling. Expression of Axl in non-BM cells is crucial for the up-regulation of several key proinflammatory signals (eg, IL-1) in the carotid. We found that Axl is involved in immune activation of cultured smooth muscle cells and in immune heterogeneity of medial cells (measured by major histocompatibility complex class II) after carotid injury. Finally, a lack of Axl in non-BM cells increased collagen Iα expression, which may play a critical role in carotid remodeling. Our data suggest that Axl contributes to carotid remodeling not only by inhibition of apoptosis but also via regulation of immune heterogeneity of vascular cells, cytokine/chemokine expression, and extracellular matrix remodeling.


Role of the implantation site on metastatic ability of the murine MBT-2 transitional cell carcinoma.
The influence of implantation site on the metastatic behavior of a murine transitional cell carcinoma line (MBT-2) was examined. MBT-2 cells were injected into one of four anatomic sites; subcutaneously, intramuscularly, intravenously or into the footpad, to evaluate the influence of implantation site on the formation and number of metastases. The MBT-2 cell line produced a low incidence of lung metastases after intravenous injection with a mean of 1.1 lung tumors per mouse. Injection of MBT-2 cells into the footpad or subcutaneously did not produce metastases from the primary tumor. Intramuscular implantation, however, resulted in a sixty percent incidence of metastasis with a mean of 8.2 lung nodules per mouse. This study demonstrated a definite implantation site influence on the metastatic ability of the MBT-2 line.


Risk Factors for Red Blood Cell Transfusions in Children Undergoing Cardiac Catheterization.
To identify risk factors associated with risk of red blood cell transfusions (RBCTs) following pediatric cardiac catheterizations. We performed a review of all pediatric cardiac catheterizations from 2012 to 2017. The primary endpoint was RBCT within 72 hours of pediatric cardiac catheterization. Patient and procedural factors were reviewed. Generalized linear modelling was performed to describe interactions among relevant risk factors. In total, 831 RBCTs occurred within 72 hours of 6028 pediatric cardiac catheterizations (13.8%). Univariate analysis revealed that the prevalence of RBCT was highest among infants (37.6% incidence of RBCT) and among those with higher estimated blood loss as a percent of blood volume (P = .03). Among infants, multivariate analysis revealed that weight (OR 0.72; 95% CI 0.63-0.81), complex 2-ventricle (OR 3.14, 95% CI 2.18-4.57), and single ventricle status (OR 5.21, 95% CI 3.42-8.01) were associated with risk of RBCT. Inpatient infants from intensive care (OR 4.74; 95% CI 3.49-6.49) or stepdown units (OR 2.33; 95% CI 1.58-3.46) were at higher risk. Length of procedure (OR 2.57; 95% CI 2.03-3.26) and oxygen saturation (OR 0.98; 95% CI 0.97-0.99; P < .01) were also associated with RBCTs. Hospitalized infants with single ventricle or complex 2-ventricle anatomy are at highest risk of RBCT. Length of procedure, blood loss, and oxygen saturations are additional risk factors associated with RBCT. Operators should consider these factors when planning pediatric cardiac catheterizations, particularly when exposure to RBCT is undesirable.


Vitamin D regulation of cathelicidin in the skin: toward a renaissance of vitamin D in dermatology?
1,25-Dihydroxyvitamin D(3), the active form of vitamin D, is a major regulator of the expression of the cationic antimicrobial peptide cathelicidin, not only in monocytes but also in epidermal keratinocytes. The involvement of cathelicidin in wound healing and skin diseases as diverse as psoriasis, rosacea, and atopic dermatitis may create new opportunities for the use of vitamin D in dermatology.


Radiation-induced rhombencephalopathy.
We report the case of a patient who underwent radiotherapy of the neck because of an epidermoid carcinoma in Rosenmuller's fossa. Eleven months later, T1-weighted brain magnetic resonance imaging (MRI) revealed a bulbo-pontine lesion, and the clinical course and sequential MRI results led to a diagnosis of radionecrosis-induced rhombencephalopathy. At a distance of more than three years, the lesion is no longer visible on MRI images but the severe neurological deficits remain. The clinical picture has not been improved by treatment with prednisone, hyperbaric oxygen, symptomatic therapies or anticoagulants.


Laparoscopic ultrasonography for abdominal tumor staging.
In recent years, laparoscopic ultrasonography has been introduced as an adjunct to diagnostic laparoscopy for staging of tumors of the upper gastrointestinal tract, liver, biliary tree, and pancreas. It has proved feasible to visualize most anatomic structures in the upper abdomen consistently and in detail with laparoscopic ultrasonography. Recent publications indicate that laparoscopic ultrasonography may be useful for detecting small liver metastases, lymph node metastases, small primary tumors of the pancreas and bile ducts, and for the assessment of the local extension of tumors of the pancreas and stomach. The ongoing improvements in US technology and the results of larger studies will in the near future determine the precise place of this new imaging modality for staging of abdominal tumors.


Author Correction: Matrix metalloproteinase-9 activity and a downregulated Hedgehog pathway impair blood-brain barrier function in an in vitro model of CNS tuberculosis.
A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.


Hierarchical deep reinforcement learning reveals novel mechanism of cell movement.
Time-lapse images of cells and tissues contain rich information of dynamic cell behaviors, which reflect the underlying processes of proliferation, differentiation and morphogenesis. However, we lack computational tools for effective inference. Here, we exploit Deep Reinforcement Learning (DRL) to infer cell-cell interactions and collective cell behaviors in tissue morphogenesis from 3D, time-lapse images. We used Hierarchical DRL (HDRL), known for multiscale learning and data efficiency, to examine cell migrations based on images with ubiquitous nuclear label and simple rules formulated from empirical statistics of the images. When applied to C. elegans embryogenesis, HDRL reveals a multi-phase, modular organization of cell movement. Imaging with additional cellular markers confirms the modular organization as a novel migration mechanism, which we term sequential rosettes. Furthermore, HDRL forms a transferable model that successfully differentiates sequential rosettes-based migration from others. Our study demonstrates a powerful approach to infer the underlying biology from time-lapse imaging without prior knowledge.


Structure of the metazoan Rab7 GEF complex Mon1-Ccz1-Bulli.
The endosomal system of eukaryotic cells represents a central sorting and recycling compartment linked to metabolic signaling and the regulation of cell growth. Tightly controlled activation of Rab GTPases is required to establish the different domains of endosomes and lysosomes. In metazoans, Rab7 controls endosomal maturation, autophagy, and lysosomal function. It is activated by the guanine nucleotide exchange factor (GEF) complex Mon1-Ccz1-Bulli (MCBulli) of the tri-longin domain (TLD) family. While the Mon1 and Ccz1 subunits have been shown to constitute the active site of the complex, the role of Bulli remains elusive. We here present the cryo-electron microscopy (cryo-EM) structure of MCBulli at 3.2 Å resolution. Bulli associates as a leg-like extension at the periphery of the Mon1 and Ccz1 heterodimers, consistent with earlier reports that Bulli does not impact the activity of the complex or the interactions with recruiter and substrate GTPases. While MCBulli shows structural homology to the related ciliogenesis and planar cell polarity effector (Fuzzy-Inturned-Wdpcp) complex, the interaction of the TLD core subunits Mon1-Ccz1 and Fuzzy-Inturned with Bulli and Wdpcp, respectively, is remarkably different. The variations in the overall architecture suggest divergent functions of the Bulli and Wdpcp subunits. Based on our structural analysis, Bulli likely serves as a recruitment platform for additional regulators of endolysosomal trafficking to sites of Rab7 activation.


Two new species of Prochas Walkley from Brazil (Hymenoptera, Ichneumonidae, Campopleginae).
Two new species of the monotypic genus Prochas Walkley from Brazil, P. brasiliensis sp. nov. and P. shimborii sp. nov., are described and illustrated. A key to species is also provided.


Specific purification of glyceraldehyde-3-phosphate dehydrogenase by hydrophobic chromatography on immobilized colchicine.
Hydrophobic column chromatography of bovine brain extracts (40-80% ammonium sulfate fraction) on immobilized colchicine resulted in the selective elution of one major protein with decreasing ionic strength of medium. This protein was identified as glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 188.8.131.52) on the basis of its biochemical properties, N-terminal amino-acid sequence and enzymatic activity. The present method enabled GAPDH to be isolated with a high recovery (80%; 184 mg/kg brain) and could be of potential use for the purification of GAPDH from various tissues.


Recovery of human immunodeficiency virus type 1 from supernatant fluid of routine viral cultures.
Peripheral blood mononuclear cell samples from human immunodeficiency virus (HIV) antibody-positive subjects were inoculated into cell cultures used for routine viral isolation to determine if HIV could survive in them. HIV was recovered from 5 (19%) of 26 day 1 supernatants and from four of the five samples in all three types of cell cultures. We conclude that HIV may survive for at least 24 h in standard virology cell culture systems and therefore is a potential risk for laboratory personnel.


Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It is known that a prostate cancer gene 3 (PCA3) urine assay is superior to serum PSA level or PSA-related indices for predicting a positive biopsy result in European and US men. This is the first report on PCA3 in a large cohort of Japanese men. The diagnostic value of the PCA3 score in Japanese men was similar to those reported in European and US men. The study concludes that a combination of PSA density and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy. To examine the diagnostic performance of the prostate cancer gene 3 (PCA3) score for prostate cancer in Japanese men undergoing prostate biopsy. This Japanese, multicentre study included 647 Asian men who underwent extended prostate biopsy with elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Urine samples were collected after DRE. The PCA3 score was determined using a PROGENSA PCA3 assay and correlated with biopsy outcome. Its diagnostic accuracy was compared with that of serum PSA level, prostate volume (PV), PSA density (PSAD), and free/total PSA ratio (f/t PSA). A total of 633 urine samples were successfully analysed (the informative rate was 98%). Median PSA was 7.6 ng/mL. Biopsy revealed cancer in 264 men (41.7%). The PCA3 score for men with prostate cancer was significantly higher than that for men with negative biopsies (median PCA3 score: 49 vs. 18; P < 0.001). The rate of positive biopsy was 16.0% in men with a PCA3 score of <20 and 60.6% in those with a PCA3 score of ≥50. Using a PCA3 score threshold of 35, sensitivity and specificity were 66.5 and 71.6%, respectively. The area under the curve of the PCA3 score was significantly higher than that of the f/t PSA in men with PSA 4-10 ng/mL (0.742 vs 0.647; P < 0.05). In men with PSAD < 0.15 and PCA3 < 20, only three (4.2%) out of 72 men had prostate cancer. The PCA3 score was significantly superior to f/t PSA in predicting a positive biopsy result for prostate cancer in Japanese men with PSA 4-10 ng/mL. The combination of PSAD and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy.


The ontogenesis of skin and organ characteristics in the Syrian golden hamster. II. Body and organ weights as well as blood glucose and plasma insulin levels.
The ontogenesis of the organ weights of the liver, kidneys, adrenals, testes and ovaries as well as the blood glucose and plasma insulin levels were studied in a total of 464 golden hamsters of both sexes of the acromelanic white inbred strain Bio 1.5 and agouti coloured outbred strain Han:AURA. Familial and seasonal influences were excluded by means of randomisation (25 groups from 1-365 days of life). Body weight development was found to be sigmoid and showed significant differences in terms of age, sex, and strain. Liver and kidney weights developed in parallel. Here, too, strain differences (agoutis greater than acromelanics) were seen, and sex differences were observed in the case of the kidneys (females greater than males). The increased adrenal weight in male hamsters compared to females was in accordance with species- but not rodent-typical behaviour. Both the testes and ovarian weights varied considerably. Age as well as, in part, strain differences were seen in the case of the blood glucose and insulin levels. The continual development of body and organ weight could be explained in terms of physiological changes.


Anticoagulant plus antiplatelet therapy for atrial fibrillation : Cost-utility of combination therapy with non-vitamin K oral anticoagulants vs. warfarin.
Emerging evidence indicates combination therapy with anticoagulants and antiplatelet agents for atrial fibrillation (AF) will be increasingly required. Numerous studies compare the efficacy and cost-effectiveness of anticoagulation alone in AF, i. e., non-vitamin K oral anticoagulants (NOACs) vs. warfarin. However, the addition of antiplatelet agents with their potential for decreasing thromboembolic stroke counter-balanced by an increased bleeding risk has received less attention. Thus, we evaluated the cost-utility of this combination therapy. We obtained event estimates from our recent meta-analysis of four randomized clinical trials designed to compare NOACs with warfarin in patients with AF. We examined patient subgroups within each trial that received antiplatelet therapy in addition to anticoagulation. Utilities were derived from the literature and cost estimates from the German health-care system. A decision tree was constructed and populated with these parameters. We used a 1-year time horizon because combination therapy is not recommended beyond this time. We calculated the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). The derived ICER was 13,168.50 € per QALY. NOAC prices exerted considerable influence on the calculation. Nevertheless, there is potential for ICER shifts in favor of warfarin, e.g., if warfarin-mediated anticoagulation control is improved and thereby adverse events decrease. Conversely, if NOAC adherence decreases, adverse events could increase. The derived ICER was 13,168.50 € per QALY, consistent with NOACs being cost-effective vs. warfarin when anticoagulation is used with antiplatelet agents. Nevertheless, country-, practice-, and patient-related factors influence the ICER. Our cost-utility calculation should be used a starting point for decision-making.


Associations between aerobic exercise and dopamine-related reward-processing: Informing a model of human exercise engagement.
Endurance or aerobic exercise has many physical and mental health benefits, but less is known about the specific impact that cardiovascular activity may have on dopamine-associated brain circuits involved in reward processing and mood regulation in humans. Understanding such effects will help to explain individual differences in both exercise uptake and maintenance. This study evaluated neural response to a classical taste-conditioning reward prediction error task with the use of functional magnetic resonance imaging, along with data on self-reported aerobic exercise among healthy young adult females (N = 111). Results indicated positive associations between reported aerobic exercise and regional brain response that remained significant after multiple comparison correction for the right medial orbital frontal cortex response to unexpected sucrose receipt (r = 0.315, p = .0008). The medial orbitofrontal cortex is implicated in reward and outcome value computation and the results suggest that aerobic exercise may strengthen this circuitry, or reciprocally, higher orbitofrontal cortical activity may reinforce exercise behavior. The findings aid in developing a model of how exercise engagement can modify reward-circuit function and could be used therapeutically in conditions associated with altered brain salience response.


Low-Temperature Growth of Hydrogenated Amorphous Silicon Carbide Solar Cell by Inductively Coupled Plasma Deposition Toward High Conversion Efficiency in Indoor Lighting.
A p-a-SiC:H window layer was used in amorphous Si thin film solar cells to boost the conversion efficiency in an indoor lighting of 500 lx. The p-a-SiC:H window layer/p-a-Si:H buffer layer scheme moderates the abrupt band bending across the p/i interface for the enhancement of VOC, JSC and FF in the solar spectra of short wavelengths. The optimized thickness of i-a-Si:H absorber layer is 400 nm to achieve the conversion efficiency of ~9.58% in an AM1.5 G solar spectrum. However, the optimized thickness of the absorber layer can be changed from 400 to 600 nm in the indoor lighting of 500 lx, exhibiting the maximum output power of 25.56 μW/cm2. Furthermore, various durability tests with excellent performance were investigated, which are significantly beneficial to harvest the indoor lights for applications in the self-powered internet of thing (IoT).


A radioimmunoassay program for Lotus 1-2-3.
Spreadsheet programs have become very popular as convenient ways of performing mathematical operations, as well as entering and organizing data. This paper describes how Lotus 1-2-3 can be used to calculate the results of a radioimmunoassay, a widely used technique in biomedical laboratories.


Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells.
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths. Unfortunately, there is still no completely effective treatment. Ferroptosis could affect the development of HCC by regulating the level of glutathione (GSH), intracellular lipid peroxidation, and other related substances. This paper introduced a new one-pot reaction for the synthesis of manganese doped mesoporous silica nanoparticles (manganese-silica nanoparticles, MMSNs) which could induce ferroptosis of the tumor cells through the consumption of intracellular GSH caused by the degradation of MMSNs. The more amount of MnCl2 added during the preparation, the larger doping amount of manganese presented in MMSNs. When the molar ratio of TEOS to MnCl2 was 5:1, the prepared MMSNs had a small size (102.6 ± 3.06 nm), uniform structure (pore sizes of 3.67 nm) and large pore volume. Manganese-oxidation bonds of MMSNs could break in high GSH concentration, which in turn consume GSH in the environment rapidly. Sorafenib (SO), an inhibitor of Xc- transport system was loaded in the MMSNs (MMSNs@SO) with a drug loading rate of 2.68 ± 0.32%. MMSNs@SO achieved on-demand drug release in the tumor microenvironment due to the degradation of MMSNs. Subsequently, a significant tumor cell (HepG2) suppression effect of MMSNs@SO was achieved through the consumption of GSH and synthesis inhibition of intracellular GSH. The depletion of GSH led to the inactivity of glutathione peroxidase 4 and increase of intracellular lipid peroxide, which could induce the ferroptosis of HCC cells. In summary, such dual GSH-exhausting nanodrugs have a great potential to induce ferroptosis of HCC cells.


The decomposition and ecological risk of DDTs and HCHs in the soil-water system of the Meijiang River.
This research project was designed to study the residues of OCPs (organochlorine pesticides) in the sediments of the Meijiang River Basin. Samples from the Meijiang River Basin were analyzed by gas chromatography-mass spectrometry after being pretreated by Soxhlet extraction, and their compositions, distributions and sources were evaluated. The current study presents the distribution of OCPs in the soils and sediments of the Meijiang River Basin. The results demonstrate that OCPs contamination is an important environmental concern due to the excessive use of these compounds in the agricultural and industrial sectors. The ratios of α-HCH/γ-HCH, (DDE + DDD)/∑DDTs, p,p-DDT/o,p-DDT, and DDD/DDE were used as indices for identifying the possible pollution sources and assessing the decomposition of the parent compounds and the recent γ-HCH and DDT inputs. At the XY (Xiyang) and DSGYY (Dongshenggongyeyan) sites, the pollutants had industrial origins. At other sites (QTH (Qutianhu), LXC (Longxichun), ZJC (Zhenjiaochun), HKC (Hekouchun), GS (Guangshan) and RGQ (Raogongqiao)), the pollution was caused by dissolved organic matter. The SHB site was polluted by transportation and upstream pollutants. At the SXC (Shixichun), YZX (Youzhihe), DSH (Dongshihe) and ZGG (Zhegupai) sites, the metabolite was p,p'-DDD and was produced in an environment with anaerobic conditions. At the FJC (Fujiangkou), QTH (Qiutianhu), GS (Guangshang) and MX (Meixi) sites, the metabolite was DDE and was produced under aerobic conditions. In view of the health risks, the risk quotients for these contaminants were evaluated, and all risk quotients were less than 1 under the best-case scenario. This result suggests that the investigated pollutants may pose little hazard to the local ecosystem. The sediments containing toxic pesticides had a less than 55% ecological risk, indicating that the ecological risk of HCHs in the soils from the Meijiang River Basin is low.


Herpes simplex encephalitis: the role of surgical decompression.
The role of acyclovir for the treatment of herpes simplex encephalitis has been well documented, but the role of surgical decompression for herpes simplex encephalitis has only rarely been mentioned. The authors report two cases of herpes simplex encephalitis that involved surgical decompression. In the first case, a therapeutic regimen of acyclovir was begun on the 11(th) day of the clinical course, and surgical decompression was performed because of impending uncal herniation on the 13(th) day. In the second case, a therapeutic regimen of acyclovir was begun on the third day of the disease's clinical course, and surgical decompression was performed because of impending uncal herniation on the 11(th) day. Both patients had good neurological outcomes and were seizure-free 12 months after their surgical procedures. We conclude that, for patients with herpes simplex encephalitis, it is important for the clinician to detect deterioration of consciousness because of the mass effect caused by the disease-associated inflammatory process as early as is possible. Surgical decompression is indicated for impending uncal herniation or intolerable increased intracranial pressure. Such surgery can contribute to an improved outcome for patients with herpes simplex encephalitis.


Distal gangrene in a polycythemic recipient fetus in twin-twin transfusion.
Gangrene of an extremity in a twin pregnancy has been attributed to the release of thromboplastin from a dead fetus or to a combination of polycythemia and anomalous vasculature. It has not been described in a situation where both twins survived. In a pregnancy complicated by twin-twin transfusion syndrome and managed with repeated amniocenteses, both twins survived. The recipient twin had necrosis of the left lower leg, which had appeared in the antenatal period and was associated with polycythemia, but not anomalous vasculature. Antenatally, polycythemia alone may cause necrosis of an extremity. Necrosis could be detected with ultrasound examination and may be an additional argument for laser photocoagulation of the chorioangiopagus.


Urinary vanadium as a biological indicator of exposure to vanadium.
Vanadium was determined in urine and blood of two workers (Worker Nos. 1 and 2 with direct exposure to vanadium pentoxide) and 13 fellow workers (with indirect or no vanadium exposure), and the results were compared by means of personal and stationary sampling of vanadium in air. Worker No. 1, a foreman with the heaviest exposure to vanadium, had a green tongue, complained of frequent productive coughing, and excreted 47 to 124 ng/ml vanadium in his late morning and mid-afternoon urine. Worker No. 2, a helper to the foreman with less exposure, had no green tongue or subjective complaints, and excreted no vanadium at a measurable level even in his mid-shift urine. No vanadium was detected in urine samples from other workers, nor in blood from all workers including Worker Nos. 1 and 2. Application of inductively coupled plasma emission spectrometry to measurement of vanadium in biological materials is discussed.


Contribution to catalysis of ornithine binding residues in ornithine N5-monooxygenase.
The SidA ornithine N5-monooxygenase from Aspergillus fumigatus is a flavin monooxygenase that catalyzes the NADPH-dependent hydroxylation of ornithine. Herein we report a mutagenesis study targeting four residues that contact ornithine in crystal structures of SidA: Lys107, Asn293, Asn323, and Ser469. Mutation of Lys107 to Ala abolishes activity as measured in steady-state oxygen consumption and ornithine hydroxylation assays, indicating that the ionic interaction of Lys107 with the carboxylate of ornithine is essential for catalysis. Mutation of Asn293, Asn323, or Ser469 individually to Ala results in >14-fold increases in Km values for ornithine. Asn323 to Ala also increases the rate constant for flavin reduction by NADPH by 18-fold. Asn323 is unique among the four ornithine binding residues in that it also interacts with NADPH by forming a hydrogen bond with the nicotinamide ribose. The crystal structure of N323A complexed with NADP(+) and ornithine shows that the nicontinamide riboside group of NADP is disordered. This result suggests that the increase in flavin reduction rate results from an increase in conformational space available to the enzyme-bound NADP(H). Asn323 thus facilitates ornithine binding at the expense of hindering flavin reduction, which demonstrates the delicate balance that exists within protein-ligand interaction networks in enzyme active sites.


Antileishmanial effect of rapamycin as an alternative approach to control Leishmania tropica infection.
Cutaneous leishmaniosis (CL) is a parasitic disease in animals and human with no satisfactory treatments and vaccination. Rapamycin is a potent inhibitor of mammalian target of rapamycin (mTOR) with various applications. Here, the effect of rapamycin alone or in combination with two other drugs, namely amphotericin B (AmB) and glucantime, was investigated against Leishmania tropica infection. In vitro viability and electron microscopy evaluation of the parasites showed detrimental changes in their appearance and viability. Treatment with clinically relevant dose of rapamycin (10.2 μg/dose) is able to control the parasite load in BALB/c mice infected with L. tropica. Furthermore, the cytokine profiles showed significant polarization towards Th1 immune response. Surprisingly, combination therapy with either AmB or glucantime was not efficient. Rapamycin is showed an effective alternative therapy against leishmaniosis caused by L. tropica.


Binding of amino beta-lactam antibiotics to soluble protein from rat intestinal mucosa--II. Mutual inhibition of binding among amino beta-lactam antibiotics and binding characteristics.
The characteristics of binding of amino beta-lactam antibiotics including ampicillin, amoxicillin, cephalexin and cephradine to fraction b obtained from the 105,000 g supernatant of rat small intestinal mucosa was investigated. The mutual inhibition of binding among these antibiotics was observed, and these were dependent on the concentration of inhibitors. It was found that dipeptides such as L-carnosine and glycylglycine significantly reduced the binding of cephalexin to fraction b, but the binding of cephradine was only slightly decreased by these dipeptides. Furthermore, the binding of cephalexin and cephradine was not influenced by amino acids (L-phenylalanine, glycine). Although ANS(1-anilino-8-naphthalenesulfonic acid magnesium salt), which is a hydrophobic probe, bound to the fraction b, there was no competitive inhibition in binding between ANS and amino beta-lactam antibiotics. The Scatchard plot of binding data of cephalexin gave two dissociation constant (Kd) values (1.37 and 15.7 microM). On the other hand, one Kd value (11.2 microM) was obtained for ampicillin.


Is a Single-Item Operative Performance Rating Sufficient?
A valid measure of resident operative performance ability requires direct observation and accurate rating of multiple resident performances under the normal range of operating conditions. The challenge is to create an operative performance rating (OPR) system that: is easy to use, encourages completion of many ratings immediately after performances and minimally disrupts supervising surgeons' work days. The purpose of this study was to determine whether a score based on a single-item overall OPR provides a valid and stable appraisal of resident operative performances. A retrospective comparison of a single-item OPR with a gold-standard rating based on multiple procedure-specific and general OPR items. Data were collected in the general surgery residency program at Southern Illinois University from 2001 through 2012. Assessments of 1033 operative performances (3 common procedures, 2 laparoscopic, and 1 open) by general surgery residents were collected. OPRs based on single-item overall performance scale scores were compared with gold-standard ratings for the same performances. Differences in performance scores using the 2 scales averaged 0.02 points (5-point scale). Correlations of the single-item and gold-standard scale scores averaged 0.95. Based on generalizability analyses of laparoscopic cholecystectomy ratings, each instrument required 5 observations to achieve reliabilities of 0.80 and 11 observations to achieve reliabilities of 0.90. Only 4.4% of single-item ratings misclassified the performance when compared with the gold-standard rating and all misclassifications were near misses. For 80% of misclassified ratings, single-item ratings were lower. Single-item operative performance measures produced ratings that were virtually identical to gold-standard scale ratings. Misclassifications occurred infrequently and were minor in magnitude. Ratings using the single-item scale: take less time to complete, should increase the sample of procedures rated, and encourage attending surgeons to complete ratings immediately after observing performances. Face-to-face and written comments and suggestions should continue to be used to provide the granular feedback residents need to improve subsequent performances.


A Rare Case of an Asymmetric Overgrowth Syndrome in a Kenyan African Child: A Case Report and Review of Literature.
Body overgrowth may be generalized or may affect certain areas. We present a seven-year-old African male with progressive, asymmetric, postnatal overgrowth of the left side of his face and left upper limb. The impression of proteus syndrome (PS) was made based on established clinical diagnostic criteria presented in the literature. Our objective is to highlight the diagnosis based on clinical features, investigations, and a multidisciplinary approach to the management of proteus syndrome.


The jugular venous-to-arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during rebreathing and end-tidal forcing: Relationship with cerebral perfusion.
We examined two assumptions of the modified rebreathing technique for the assessment of the ventilatory central chemoreflex (CCR) and cerebrovascular CO2 reactivity (CVR), hypothesizing: (1) that rebreathing abolishes the gradient between the partial pressures of arterial and brain tissue CO2 [measured via the surrogate jugular venous P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and arterial P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference (Pjv-a CO2 )] and (2) rebreathing eliminates the capacity of CVR to influence the Pjv-a CO2 difference, and thus affect CCR sensitivity. We also evaluated these variables during two separate dynamic end-tidal forcing (ETF) protocols (termed: ETF-1 and ETF-2), another method of assessing CCR sensitivity and CVR. Healthy participants were included in the rebreathing (n = 9), ETF-1 (n = 11) and ETF-2 (n = 10) protocols and underwent radial artery and internal jugular vein (advanced to jugular bulb) catheterization to collect blood samples. Transcranial Doppler ultrasound was used to measure middle cerebral artery blood velocity (MCAv). The Pjv-a CO2 difference was not abolished during rebreathing (6.2 ± 2.6 mmHg; P < 0.001), ETF-1 (9.3 ± 1.5 mmHg; P < 0.001) or ETF-2 (8.6 ± 1.4 mmHg; P < 0.001). The Pjv-a CO2 difference did not change during the rebreathing protocol (-0.1 ± 1.2 mmHg; P = 0.83), but was reduced during the ETF-1 (-3.9 ± 1.1 mmHg; P < 0.001) and ETF-2 (-3.4 ± 1.2 mmHg; P = 0.001) protocols. Overall, increases in MCAv were associated with reductions in the Pjv-a CO2 difference during ETF (-0.095 ± 0.089 mmHg cm-1 s-1 ; P = 0.001) but not during rebreathing (-0.028 ± 0.045 mmHg · cm-1 · s-1 ; P = 0.067). These findings suggest that, although the Pjv-a CO2 is not abolished during any chemoreflex assessment technique, hyperoxic hypercapnic rebreathing is probably more appropriate to assess CCR sensitivity independent of cerebrovascular reactivity to CO2 . KEY POINTS: Modified rebreathing is a technique used to assess the ventilatory central chemoreflex and is based on the premise that the rebreathing method eliminates the difference between arterial and brain tissue P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ . Therefore, rebreathing is assumed to isolate the ventilatory response to central chemoreflex stimulation from the influence of cerebral blood flow. We assessed these assumptions by measuring arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ and middle cerebral artery blood velocity during modified rebreathing and compared these data against data from another test of the ventilatory central chemoreflex using hypercapnic dynamic end-tidal forcing. The difference between arterial and jugular venous bulb P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ remained present during both rebreathing and end-tidal forcing tests, whereas middle cerebral artery blood velocity was associated with the P C O 2 ${P_{{\mathrm{C}}{{\mathrm{O}}_{\mathrm{2}}}}}$ difference during end-tidal forcing but not rebreathing. These findings offer substantiating evidence that clarifies and refines the assumptions of modified rebreathing tests, enhancing interpretation of future findings.


Serine carboxypeptidases from the carnivorous plant Nepenthes mirabilis: Partial characterization and heterologous expression.
This study aimed to partially characterize the three main serine carboxypeptidases (SCP3, SCP20, and SCP47) from Nepenthes mirabilis. Furthermore, one peptidase (SCP3) was chosen for further heterologous expression in Escherichia coli Shuffle®T7. SCP3 also was characterized in terms of its allergenic potential using bioinformatics tools. SCP3, SCP20, and SCP47 showed very similar 3D structures and mechanistic features to other plant serine peptidases belonging to clan SC and family S10. Although SCP3 was obtained in its soluble form, using 1% ethanol during induction with 0.5 mM IPTG at 16 °C for 18 h, it did not show proteolytic activity by zymography or in vitro analysis. SCP3 presented a few allergenic peptides and several cleavage sites for digestive enzymes. This work describes additional features of these enzymes, opening new perspectives for further studies for characterization and analysis of heterologous expression, as well as their potential biotechnological applications.


Impact of Cultural and Linguistic Maintenance on Mental Health Outcomes in Migrant Adolescents: Protocol for a Scoping Review.
There is no consensus on how the disruption or maintenance of heritage culture and language affect mental health outcomes in adolescents with a migrant (also known as "immigrant" or "international migrant") background. Even though previous literature reviews have investigated the association between acculturation and mental health in migrants, none have explicitly focused on adolescents. The aim of the scoping review described in this protocol is to understand (1) the focus, scope, and nature of quantitative empirical research investigating heritage cultural maintenance, including linguistic maintenance, and mental health outcomes in adolescents with a migrant background worldwide and (2) the potential effects of cultural and linguistic maintenance or disruption on migrant adolescent mental health outcomes. A total of 11 key electronic health, medical, social science, and language databases (APA PsycArticles Full Text; Embase Classic+Embase; Ovid MEDLINE All and Epub Ahead of Print, In-Process, In-Data-Review and Other Non-Indexed Citations and Daily; Ovid MEDLINE All; APA PsycInfo; University of Melbourne full-text journals; Science Citation Index Expanded; Social Sciences Citation Index; Arts & Humanities Citation Index; Scopus; Linguistics and Language Behavior Abstracts) were searched. Databases were searched without time restrictions from the beginning of their coverage. Publication date, location, and quantitative study design (except for literature reviews) were not restricted; however, the search was only conducted in English. Data from included studies will be extracted using a template with predefined data items, and results will be summarized in a structured, narrative summary. A search was conducted on April 20, 2021, returning 2569 results. We are currently at the final stages of screening titles and abstracts of our search results, which will be followed by a full-text review and the data extraction of included studies. We expect to submit the full review for publication by the end of 2023. The scoping review aims to provide a better understanding of existing research on the association between cultural (including linguistic) maintenance and mental health in migrant adolescents. It will help identify gaps in the existing literature and develop hypotheses that could inform future research, eventually facilitating the development of targeted prevention initiatives and improving migrant adolescents' well-being. DERR1-10.2196/40143.


Reduction of clinically irrelevant alarms in patient monitoring by adaptive time delays.
The problem of high rates of false alarms in patient monitoring in anesthesiology and intensive care medicine is well known but remains unsolved. False alarms desensitize the medical staff, leading to ignored true alarms and reduced quality of patient care. A database of intra-operative monitoring data was analyzed to find characteristic alarm patterns. The original data were re-evaluated to find relevant events and to rate the severity of these events. Based on this analysis an adaptive time delay was developed that individually delays the alarms depending on the grade of threshold deviation. The conventional threshold algorithm led to 4893 alarms. 3515 (71.84 %) of these alarms were annotated as clinically irrelevant. In total 81.0 % of all clinically irrelevant alarms were caused by only mild and/or brief threshold violations. We implemented the new algorithm for selected parameters. These parameters equipped with adaptive validation delays led to 1729 alarms. 931 (53.85 %) alarms were annotated as clinically irrelevant. 632 alarms indicated the 645 clinically relevant events. The positive predictive value of occurring alarms improved from 28.16 % (conventional algorithm) to 46.15 % (new algorithm). 13 events were missed. The false positive alarm reduction rate of the algorithm ranged from 33 to 86.75 %. The overall reduction was 73.51 %. The implementation of this algorithm may be able to suppress a large percentage of false alarms. The effect of this approach has not been demonstrated but shows promise for reducing alarm fatigue. Its safety needs to be proven in a prospective study.


Comparison of the effects of ketamine and fentanyl-midazolam-medetomidine for sedation of rhesus macaques (Macaca mulatta).
This study assessed the effects of sedation using a combination of fentanyl, midazolam and medetomidine in comparison to ketamine. Rhesus Macaques (Macaca mulatta), (n = 16, 5 males and 3 females randomly allocated to each treatment group) received either ketamine (KET) (10 mg.kg(-1)) or fentanyl-midazolam-medetomidine (FMM) (10 μg/kg(-1); 0.5 mg.kg(-1); 20 μg.kg(-1)) both IM. Oxygen (100%) was provided by mask and heart rate, blood pressure, respiratory rate, EtCO2 and depth of sedation were assessed every 5 min for 20 min. After the last time point, FMM monkeys were reversed with atipamezole-naloxone (0.2 mg.kg(-1); 10 μg.kg(-1)). Recovery was scored using clinical scoring scheme. Differences in physiological parameters and quality of sedation were compared using Area Under the Curve (AUC) method and either Mann-Witney or t-student tests. Heart rate (beats/min) (Ket = 119 ± 18; FMM = 89 ± 17; p = 0.0066), systolic blood pressure (mmHg) (Ket = 109 ± 10; FMM = 97 ± 10; p = 0.0313), and respiratory rate (breaths/min) (Ket = 39 ± 9; FMM = 29 ± 10; p = 0.0416) were significantly lower in the FMM group. End-tidal CO2 (mmHg) did not differ between the groups (KET = 33 ± 8; FMM = 42 ± 11; p = 0.0462). Although some depression of physiological parameters was seen with FMM, the variables all remained within the normal ranges in both groups. Onset of a sufficient degree of sedation for safe handling was more rapid with ketamine (KET = 2.9 ± 1.4 min; FMM = 7.9 ± 1.2 min; p = 0.0009), but FMM recovery was faster (KET = 21.4 ± 13.4 min; FMM = 9.1 ± 3.6 min; p = 0.0379) and of better quality (KET = 1.3 ± 0.9; FMM = 7.4 ± 1.9; p = 0.0009) most probably because of the effectiveness of the reversal agents used. FMM provides an easily reversible immobilization with a rapid and good recovery quality and may prove a useful alternative to ketamine.


Linking global top-down views to first-person views in the brain.
Humans and other animals have a remarkable capacity to translate their position from one spatial frame of reference to another. The ability to seamlessly move between top-down and first-person views is important for navigation, memory formation, and other cognitive tasks. Evidence suggests that the medial temporal lobe and other cortical regions contribute to this function. To understand how a neural system might carry out these computations, we used variational autoencoders (VAEs) to reconstruct the first-person view from the top-down view of a robot simulation, and vice versa. Many latent variables in the VAEs had similar responses to those seen in neuron recordings, including location-specific activity, head direction tuning, and encoding of distance to local objects. Place-specific responses were prominent when reconstructing a first-person view from a top-down view, but head direction-specific responses were prominent when reconstructing a top-down view from a first-person view. In both cases, the model could recover from perturbations without retraining, but rather through remapping. These results could advance our understanding of how brain regions support viewpoint linkages and transformations.


Sentinel Node Identification in Melanoma: Current Clinical Impact, New Emerging SPECT Radiotracers and Technological Advancements. An Update of the Last Decade.
Melanoma is the most lethal skin cancer with a mortality rate of 262 cases per 100.000 cases. The sentinel lymph node (SLN) is the first lymph node draining the tumor. SLN biopsy is a widely accepted procedure in the clinical setting since it provides important prognostic information, which helps patient management, and avoids the side effects of complete lymph node dissection. The rationale of identifying and removing the SLN relies on the low probability of subsequent metastatic nodes in case of a negative histological exam performed in the SLN. Recently, new analytical approaches, based on the evaluation of scintigraphic images are also exploring the possibility to predict the metastatic involvement of the SLN. 99mTc-labeled colloids are still the most commonly used radiotracers but new promising radiotracers, such as 99mTc- Tilmanocept, are now on the market. In the last decades, single photon emission computed tomography- computerized tomography (SPECT/CT) has gained wider diffusion in clinical departments and there is large evidence about its superior diagnostic accuracy over planar lymphoscintigraphy (PL) in the detection of SLN in patients with melanoma. Scientists are also investigating new hybrid techniques combining functional and anatomical images for the depiction of SLN but further evidence about their value is needed. This review examined the predictive and prognostic factors of lymphoscintigraphy for metastatic involvement of SLN, the currently available and emerging radiotracers and the evidence of the additional value of SPECT/CT over PL for the identification of SLN in patients with melanoma. Finally, the review discussed the most recent technical advances in the field.


The Diesel Exhaust in Miners Study (DEMS) II: Temporal Factors Related to Diesel Exhaust Exposure and Lung Cancer Mortality in the Nested Case-Control Study.
The Diesel Exhaust in Miners Study (DEMS) was an important contributor to the International Agency for Research on Cancer reclassification of diesel exhaust as a Group I carcinogen and subsequent risk assessment. We extended the DEMS cohort follow-up by 18 y and the nested case-control study to include all newly identified lung cancer deaths and matched controls (DEMS II), nearly doubling the number of lung cancer deaths. Our purpose was to characterize the exposure-response relationship with a focus on the effects of timing of exposure and exposure cessation. We conducted a case-control study of lung cancer nested in a cohort of 12,315 workers in eight nonmetal mines (376 lung cancer deaths, 718 controls). Controls were selected from workers who were alive when the case died, individually matched on mine, sex, race/ethnicity, and birth year (within 5 y). Based on an extensive historical exposure assessment, we estimated respirable elemental carbon (REC), an index of diesel exposure, for each cohort member. Odds ratios (ORs) were estimated by conditional regression analyses controlling for smoking and other confounders. To evaluate time windows of exposure, we evaluated the joint OR patterns for cumulative REC within each of four preselected exposure time windows, <5, 5-9, 10-19, and ≥20 y prior to death/reference date, and we evaluated the interaction of cumulative exposure across time windows under additive and multiplicative forms for the joint association. ORs increased with increasing 15-y lagged cumulative exposure, peaking with a tripling of risk for exposures of ∼950 to<1,700 μg/m3-y [OR=3.23; 95% confidence interval (CI): 1.47, 7.10], followed by a plateau/decline among the heavily exposed (OR=1.85; 95% CI: 0.85, 4.04). Patterns of risk by cumulative REC exposure varied across four exposure time windows (phomogeneity<0.001), with ORs increasing for exposures accrued primarily 10-19 y prior to death (ptrend<0.001). Results provided little support for a waning of risk among workers whose exposures ceased for ≥20 y. DEMS II findings provide insight into the exposure-response relationship between diesel exhaust and lung cancer mortality. The pronounced effect of exposures occurring in the window 10-19 y prior to death, the sustained risk 20 or more years after exposure ceases, and the plateau/decline in risk among the most heavily exposed provide direction for future research on the mechanism of diesel-induced carcinogenesis in addition to having important implications for the assessment of risk from diesel exhaust by regulatory agencies. https://doi.org/10.1289/EHP11980.


Surface marker analysis of acute lymphocytic leukaemia in Taiwan, Republic of China.
Acute lymphocytic leukaemia (ALL) is heterogeneous in clinical characteristics and immunological properties. Standard surface marker analysis has enabled us to subclassify 121 cases of ALL into four subtypes, i.e. T-ALL, common ALL, null ALL and B-ALL. We have also tried to correlate these subtypes with their clinical characteristics. Our patients had younger ages with a mean age of 13.75. A slight male predominance was observed. There were consistently higher incidences in northern Taiwan in each subtype, but no significant differences in incidences between rural and urban areas. Although there were high incidences of L1 type cell in each immunological subtype, there was no correlation between FAB classification and each subtype, nor did morphologic features relate to cellular origins. Clinical manifestations revealed significantly high incidence of CNS involvement and thymic mass in T-ALL. Hepatosplenomegaly was more common and complete remission rate was higher in children with ALL than in adults.


Notch signalling and voltage-gated Na+ channel activity in human prostate cancer cells: independent modulation of in vitro motility.
This study tested the possible functional relationship of two signalling mechanisms shown previously to be involved in human prostate cancer (PCa), Notch and voltage-gated sodium channel. Notch1 and Notch2 were differentially expressed in PCa cell lines of varying metastatic potential (LNCaP, PC-3, PC-3M) in comparison to a normal prostate cell line (PNT2), whereas Notch3 and Notch4 were not expressed. The Notch ligand Jagged1, but not Jagged2, was increased in all cell lines, whereas the Notch downstream target Deltex was not expressed. In comparison to the LNCaP cell line, Hes1, another downstream target, showed elevated expression in the metastatic PC-3 and PC-3M cells and promoted lateral motility. In contrast, the Notch ligand Delta-like1 (Dll1) levels were higher in LNCaP compared with PC-3 and PC-3M cells. Importantly, decreasing Dll1 expression increased the lateral motility of PC-3 cells, whereas blocking voltage-gated Na(+) channel activity with tetrodotoxin decreased motility. However, the effect of Dll1 was independent of Notch signalling through Hes1 and voltage-gated Na(+) channel expression/activity.


Tissue- and development-specific expression of the human phenylalanine hydroxylase/chloramphenicol acetyltransferase fusion gene in transgenic mice.
Human phenylalanine hydroxylase (PAH) catalyzes the conversion of L-phenylalanine to L-tyrosine. Deficiency of this enzyme results in phenylketonuria, a common genetic disorder of amino acid metabolism that causes severe mental retardation. In primates, PAH is expressed specifically in the liver, while in rodents PAH activity is also present in kidney, although at a much lower level. A 9-kilobase genomic DNA fragment at the 5' end of the hPAH gene (hPAH) was fused to the bacterial chloramphenicol acetyltransferase (CAT) gene. The hPAH/CAT minigene was used to generate multiple transgenic mouse lines. In all expressing lines, CAT activity was detected predominantly in the liver and at much lower levels in the kidney. By immunohistochemical staining, CAT expression was localized to hepatocytes and renal epithelial cells, both of which also express the endogenous mouse PAH enzyme. Furthermore, both the transgene and the endogenous mouse PAH were activated at about the same stage of embryonic development in the mouse liver. These results suggest that the 9-kilobase DNA fragment flanking the 5' end of the human PAH gene contains all the necessary cis-acting elements to direct tissue- and developmental-specific expression in vivo.


Placing Bundled Payments in Perspective: A Survey of the New England Ophthalmological Society.
To determine ophthalmologists' views on the Medicare bundled payment model for specialty physicians in the outpatient setting. The New England Ophthalmology Society (NEOS) was emailed an anonymous survey. Views of bundled payments and demographic characteristics were analyzed. Of responding members, 72% (115/160) strongly opposed bundled payments; 68% (108/160) believed bundled payments will lead to financial losses, and the majority did not support including costs of prescription drugs (69%, 109/159) or preoperative (77%, 123/159) or postoperative complications (59%, 94/159) in the bundle. Respondents who held office in a medical society, were in private practice, solely billed for income, and had mostly conservative political views were significantly more likely to oppose bundling. The majority of NEOS ophthalmologists were opposed to bundled payments. Personal beliefs and practice type may influence the level of ophthalmologist support of bundled payments.


A new approach for increasing ascorbyl palmitate stability by addition of non-irritant co-antioxidant.
The aim of this work was to test innovative approach for enhancing ascorbyl palmitate stability in microemulsions for topical application by addition of newly synthesized co-antioxidant 4-(tridecyloxy)benzaldehyde oxime (TDBO) and to investigate its antioxidant activity and finally to evaluate cytotoxicity of TDBO-loaded microemulsions on keratinocyte cells. TDBO significantly increased ascorbyl palmitate stability in oil-dispersed-in-water (o/w) microemulsions, most presumably due to reduction of ascorbyl palmitate radical back to ascorbyl palmitate, since TDBO free-radical scavenging activity was confirmed. Cytotoxicity experiments demonstrated no significant change in cell viability or morphology in the presence of TDBO-loaded microemulsions regarding unloaded microemulsions, although greater cytotoxicity was observed with increased microemulsion concentrations. Therefore, the incorporation of TDBO as non-cytotoxic co-antioxidant in o/w microemulsions is a promising new strategy for enhancing ascorbyl palmitate stability that could be used to support antioxidant network in the skin.


Characterization of Single Amino Acid Variations in an EDTA-Tolerating Non-specific Nuclease from the Ice-Nucleating Bacterium Pseudomonas syringae.
Non-specific nuclease (NSN) can be applied in industrial downstream processing to remove nucleic acids from crude protein extracts or in cell-sorting systems to degrade nucleic acids derived from lysed cells. PsNuc from the ice-nucleating bacterium Pseudomonas syringae has the ability to decompose double- and single-stranded DNA in linear or circular form and RNA. It is not affected by the presence of metal-ion chelators such as EDTA and tolerates several protease inhibitors and reducing agents. A multiple sequence alignment of PsNuc with closely related enzymes (97-99% identity on the protein level) within the family Pseudomonaceae revealed the presence of only six amino acid residues that are variable in putative NSN from different members of the genus Pseudomonas. Single amino acid variants were produced in recombinant form in Escherichia coli, purified, and characterized. They showed similar activity compared to PsNuc, but a single variant even displayed an improved performance with an activity of > 20,000 U/mg at 35 °C, while amino acid residues S148 and V161 were found to be essential for enzymatic functionality. These results suggest that homologous nucleases from Pseudomonaceae display high activity levels in a metal-ion-independent manner and are therefore of interest for applications in biotechnology.


Lithium usage and renal function testing in a large UK community population; a case-control study.
This study investigates the prevalence of lithium use, monitoring practice and associated effects on renal function in a large UK community sample. A large population-based renal function database was cross-referenced with a general practitioner database of 404,673 patients. The renal function of patients prescribed lithium during the 2-year period was compared with that of matched controls. The renal monitoring patterns of these cases were investigated in a naturalistic observational study. Data underwent parametric testing - continuous variables by analysis of variance, with appropriate adjustment, and categorical outcomes by χ(2) testing. Block analysis of variance was undertaken on case-control data. A total of 422 patients in the database were prescribed lithium. Renal function monitoring in accordance with published guidelines occurred in 69% of patients. Patients taking lithium had a significantly higher serum creatinine (5.8 μmol/L, P<.001) and lower glomerular filtration rate (5.9 ml/min, P<.001) when compared to matched controls. This is the first study carried out in a large community sample. Lithium remains widely prescribed in the community setting. The study confirms that lithium has a statistically and clinically significant negative effect on renal function. Despite published guidelines and recognition of the importance of serial measurements, monitoring of renal function is inconsistent.


Pathogenesis, Clinical Features and Treatment of Diabetic Cardiomyopathy.
Patients with type 1 and type 2 diabetes mellitus (T1D and T2D) show an increased incidence of heart failure (HF) even after adjustment for well established risk factors for HF such as hypertension and ischaemic heart disease. The resulting specific form of cardiomyopathy is known as diabetic cardiomyopathy" (DCM). Pathogenetic mechanisms underlying DCM are likely to be multifactorial, from altered myocardial metabolism (hyperglycaemia, hyperinsulinaemia, increased circulating fatty acids and trglycerides) to microvascular disease, autonomic neuropathy, and altered myocardial structure with fibrosis. Current medical treatment recommendations from scientific societies on HF in patients with diabetes mellitus (DM) do not differ from those for patients without DM. Regarding the effect of different hypoglycaemic drugs on HF in patients with DM, and considering the best available current evidence, the sodium-glucose-co-transporter 2 inhibitors and metformin seem to be especially advantageous regarding the effects in patients with T2D and HF.


Intralesional and topical chemotherapy and immunotherapy.
Surgery is the mainstay of treatment for equine tumors. Conservative treatment approaches which preserve function and appearance are increasingly used in clinical practice. This article covers the principles and applications of two conservative treatment modalities including local chemotherapy and immunotherapy. The therapeutic benefit of local chemotherapy is based on the direct drug delivery to tumor tissue, i.e., topical and intratumoral administration of cytotoxic agents in slow release formulation. This treatment modality is very effective for cutaneous tumors and does not result in any permanent damage to normal tissue. Immunotherapy produces antitumor effects primarily through the action of natural host defense mechanisms against tumor cells. Although the use of immunotherapy is still under investigation there are many examples of its successful application to treatment of selected equine tumors.


[Effect of danazol on the function of the estrogen and progesterone receptor systems of the human endometrium].
Quantity of estrogen- and progesterone-specific binding sites was measured in endometrial tissues of 10 females treated with danazol during 3 month in a dose of 400 mg per day after surgical treatment for endometriosis. It was demonstrated that the amount of estrogen receptors in endometrium of the patients was the same as in endometrial tissue of healthy females but the quantity of nuclear progesterone receptors was markedly increased.


Dermal dendrocytes FXIIIA+ phagocytizing extruded mast cell granules in drug-induced acute urticaria.
Few authors have been attempting between mast cells and dermal dendrocytes interactions on urticaria. To describe the extruded mast cell granules and dermal dendrocytes in drug-induced acute urticaria. Seven patients with drug-induced acute urticaria were enrolled in the study. We token skin biopsies of urticaria lesion and perilesional skin. The 14 fragments collected were processed to immunogold electron microscopy using single stains to tryptase and FXIIIa, besides double immunogold labeling with both. Some sections demonstrated mast cells in degranulation process, both in anaphylactic and piecemeal degranulation types. After double immunogold staining, 10 nm (FXIIIa) and 15 nm (Tryptase) gold particles were present together over the granules in mast cells indicating that tryptase and FXIIIa are each localized within the granules of these cells. Interestingly, we found a strong evidence of than the exocytosed mast cell granules contents both FXIIIa and tryptase immunolabeled are phagocytized by dermal dendrocytes. The current observations provide morphological evidence that the exocytosis-phagocytosis mechanisms of mast cell granules represents one pathophysiological example of mast cells-dermal dendrocytes interactions in urticaria.


The Road from Mouse to Human ILCs: A Perspective of Understanding the Roles of ILCs in Disease.
The chapters of this book give a comprehensive overview of the current state of knowledge of ILCs. Most of this knowledge stems from studies in mouse models. Translation to the human situation is not always straightforward because of differences between human and mouse ILCs and the microenvironments in which these ILCs are operating. Nonetheless, these mouse studies formed the basis for investigations in human diseases using state-of-the art technologies which are beginning to provide an understanding of the role of ILCs in inflammatory diseases in humans. This perspective discusses gaps in our knowledge about human ILCs and what type of studies may be done to resolve these.


The surface antigen (HBsAg) and the e-antigen (HBeAg) in Somalian patients with acute viral hepatitis.
Serum samples from 55 Somalian patients with acute viral hepatitis were examined for the presence of the surface antigen (HBsAG) and the e-antigen (HBeAg) and the corresponding antibodies (anti-HBs and anti-e). No e-antigen was detected in patients with viral hepatitis or in controls (47 cases); anti-e was found in 23.6% of hepatitis cases, all of whom were HBsAg carriers, and in 10% of the controls. The HBsAg was found in 60% of cases with hepatitis and 34% of controls; the anti-HBs was detected in 18% of the patients with hepatitis, all except one of whom were negative for HBsAg; in the one exception the HBsAg and anti-HBs were present simultaneously; the anti-HBs was found in 44.6% of controls. The frequency of serological evidence of hepatitis B infection (HBV) based on the presence of antigen/antibody HBs was 78.2% among patients with acute viral hepatitis; only 30% of these patients showed evidence of anti-e antibody.


Associations between living in localities with e-cigarette sales restrictions and e-cigarette use change among young adults in Los Angeles County.
Local e-cigarette sales restrictions (ESRs) may impact e-cigarette use. This study examined the associations between living in localities with various ESR policies and changes in e-cigarette use among young adults in Los Angeles (LA) County, California, USA. Data were from a cohort of LA County young adults (18-21 years; n=2100) who completed two waves of surveys (Fall 2018-Summer 2019 and Summer-Fall 2020). Local flavoured (n=9) and comprehensive (n=2) ESRs in LA County implemented between June 2019 and May 2020 were identified, coded and merged with the baseline data. Multivariable logistic regressions were used to examine the associations between living in ESR localities and e-cigarette use at follow-up, controlling for covariates and stratified by cigarette smoking at baseline. Overall, 20.9% and 14.3% of participants lived in localities with flavoured and comprehensive ESRs, respectively. Participants who were non-Hispanic, had higher socioeconomic statuses and were currently using e-cigarettes were generally more likely to live in ESR localities than their counterparts. The associations between living in ESR localities and e-cigarette use at follow-up were not found among baseline non-e-cigarette users regardless of their cigarette smoking status; a positive relationship was found among baseline e-cigarette users who also smoked cigarettes but not among non-smokers. Participants who lived in localities with various ESR policies were different in their baseline e-cigarette use and socioeconomic backgrounds. Future research examining the potential impact of ESRs on e-cigarette use change should consider the localities' overall sociodemographic and tobacco-using characteristics and individuals' cigarette smoking histories.


Early recognition and aggressive treatment of gastroesophageal reflux following repair of esophageal atresia.
Twelve patients with gastroesophageal reflux following repair of esophageal atresia are presented. Reflux produced recurrent stricture, failure to thrive, repeated pneumonitis, and in one patient, respiratory arrest and nearly death. Treatment consists of positional therapy or fundoplication operation both of which seem less successful in this combination of lesions than with GER and a normal esophagus. There was one death as a late postoperative complication of fundoplication.


Isolation of the constitutive heterochromatin from mouse liver nuclei.
A method for isolation of constitutive heterochromatin (chromocenters) from nuclei of mouse liver cells is described. This method is based on the higher resistance of chromocenters to low ionic strength treatment as compared with that of nucleoli and euchromatin. The method allows separation of chromocenters that are essentially free of nucleoli and other nuclear contaminants. In contrast to nuclei and nucleoli, isolated chromocenters are characterized by a simpler protein composition and contain a smaller number of proteins (especially of high molecular weight proteins). They possess telomeric DNA and telomerase activity that suggests a tight association of chromocenters with the telomerase complex in mouse hepatocyte nuclei.


Retrieval of the retracted flexor tendon.
A reliable method of atraumatic retrieval of the retracted proximal end of a flexor tendon of finger or thumb is described. The technique is to pass a catheter through the sheath from proximal to distal alongside the tendons, without removing them from the sheath. The catheter and tendon are stitched side-to-side. The tendon can be advanced by traction on the catheter.


Steady-state serum concentrations of dothiepin and northiaden after two dosage regimens of dothiepin hydrochloride (Prothiaden).
Five healthy volunteers took part in a crossover study which examined the serum concentrations of dothiepin and northiaden after a 25 mg three times a day and a 75 mg once a day dosage regimen of Prothiaden. The inter-individual variation of serum levels was large after either schedule which is to be expected with this group of drugs. The minimum steady-state level of dothiepin tended to be lower after the single daily dose, but the differences were small and not statistically significant. The approximate maximum steady-state levels of dothiepin showed large intra-and inter-subject variation and no obvious trend. The values of the desmethylated metabolite, norhiaden, tended to follow the dothiepin concentrations but were lower than the parent drug. Average steady-state levels tended, with one exception, to be very similar after both regimens with no evidence with no evidence fo any trend when comparing the two regiments. The study showed that the two regimens yielded similar steady-state serum concentrations both of drug and metabolite but inter-individual differences were large.


Online learning and stimulus-driven responses of neurons in visual cortex.
In understanding how visual scene is processed in visual cortex, it has been an intriguing problem for theoretical and experimental neuroscientists to examine the relationship between visual stimuli and the induced responses of visual cortex. In particular, it is less explored whether and how the collective responses of visual neurons are patterned to reflect the geometrical regularities. In this paper, through a computation model and statistical analysis, we show that the orientation preference maps induced from correlated visual stimuli exhibit geometrical regularities similar as observed in natural images.