[Recommendations on the use of 5-amino-levulinic acid in surgery of malignant gliomas. Consensus document. The Neuro-oncology Working Group of the Spanish Neurosurgical Society (SENEC)].
Among the prognostic factors when it comes to patients with high-grade gliomas, we find the radicality of the surgery performed. The limitations of this factor are caused by either the extension of the tumour or its location in an eloquent area. To achieve this goal, in the last few years we have developed several methods that allow us to maximise tumour resection, while always trying to cause the least possible co-morbidity. One of these methods includes the use of 5-amino-levulinic acid (5-ALA) and the development of fluorescence guided surgery. However, optimal performance requires knowledge of the product employed, the mode of administration and precautions to consider. Members of the neuro-oncology work group of the Spanish Neurosurgical Society (SENEC) have prepared this guideline or consensus document for anyone who wishes to become familiar with the use of 5-ALA fluorescence-guided surgery in the management of high-grade gliomas. For those who already utilise this technique, this document can be useful for consultation purposes.


Design, synthesis and SAR study of 2-aminopyrimidines with diverse Michael addition acceptors for chemically tuning the potency against EGFRL858R/T790M.
The covalent binding nature of irreversible kinase inhibitors potentially increases the severity of "off-target" toxicity. Based on our continual strategy of chemically tuning the Michael addition acceptors, herein, we further explore the relationship among the electronic nature of Michael addition acceptors and EGFRT790M mutation selectivity as well as "off-target" toxicity balance. By perturbing the electronic nature of acrylamide moiety, compound 8a with a chloro-group at the α-position of the Michael addition acceptor was identified. It was found that 8a retained the excellent EGFR L858R/T790M potency (IC50 = 3.9 nM) and exhibited good anti-proliferative activities against the gefitinib-resistant NCI-H1975 cells (IC50 = 0.75 μM). Moreover, 8a displayed a significant EGFRWT selectivity and much weaker inhibitory activity against non-EGFR dependent SW620 cell and COS7. Preliminary study showed that 8a could arrest NCI-H1975 cells in G0/G1 phase. This work provides a promising chemical tuned strategy for balancing the mutant-EGFR potency and selectivity as well as "off-target" toxicity.


Autologous epidermal cells can induce wound closure of neurotrophic ulceration caused by trigeminal trophic syndrome.
Trigeminal trophic syndrome is an extremely rare complication following surgical ablation of the trigeminal nerve or after alcohol injection or thermocoagulation of the Gasserian ganglion. These lesions show a poor healing tendency and sometimes persist for years. The therapeutic results of local wound care with ointments and wound dressings are often unsatisfactory, and those of plastic surgery are variable. In the case presented, the skin area affected by neurotrophic ulceration is successfully treated with autologous cultivated epidermal cells. This form of tissue engineering is already a clinically established procedure for treating burns and chronic wounds. The results show for the first time that transplantation of in vitro cultivated epidermal cells can induce tissue regeneration and may be an effective tool in the treatment of neurotrophic ulcerations in the facial region.


Policy implementation and priorities to create healthy food environments using the Healthy Food Environment Policy Index (Food-EPI): A pooled level analysis across eleven European countries.
Food environments have been recognised as highly influential on population diets. Government policies have great potential to create healthy food environments to promote healthy diets. This study aimed to evaluate food environment policy implementation in European countries and identify priority actions for governments to create healthy food environments. The Healthy Food Environment Policy Index (Food-EPI) was used to evaluate the level of food environment policy and infrastructure support implementation in Estonia, Finland, Germany, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Slovenia, and Spain in 2019-2021. Evidence of implementation of food environment policies was compiled in each country and validated by government officials. National experts evaluated the implementation of policies and identified priority recommendations. Finland had the highest proportion (32%, n = 7/22) of policies shaping food environments with a "high" level of implementation. Slovenia and Poland had the highest proportion of policies rated at very low implementation (42%, n = 10/24 and 36%, n = 9/25 respectively). Policies regarding food provision, promotion, retail, funding, monitoring, and health in all policies were identified as the most important gaps across the European countries. Experts recommended immediate action on setting standards for nutrients of concern in processed foods, improvement of school food environments, fruit and vegetable subsidies, unhealthy food and beverage taxation, and restrictions on unhealthy food marketing to children. Immediate implementation of policies and infrastructure support that prioritize action towards healthy food environments is urgently required to tackle the burden of obesity and diet-related non-communicable diseases in Europe. This project has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement No 774548 and from the Joint Programming Initiative "A Healthy Diet for a Healthy Life".


Clarifying the role of clinical research nurses working in Sweden, using the Clinical Trial Nursing Questionnaire - Swedish version.
To explore the role of CRNs in Sweden and differences in competences and tasks, using the Clinical Trial Nursing Questionnaire - Swedish version (CTNQ-SWE). A cross-sectional survey. Participants were identified through strategic sampling. Data were analysed by descriptive and comparative statistics. The respondents were experienced nurses who felt proficient in their role, they felt more acceptance by the principal investigators than by nursing colleagues. A majority of CRNs are involved in all procedures specified in the CTNQ-SWE. The most often performed tasks, also rated as the most important by the CRNs, concerned informed consent and management of investigational products. The education was often informal: with a lack of job descriptions and professional development plans. Need of formal specialist education was expressed. Knowledge about the role description can be used by clinical research enterprise internationally and healthcare organizations aiming to support CRNs in their role.


Acquired resistance to tyrosine kinase inhibitors during cancer therapy.
Selective tyrosine kinase inhibitors have emerged as important therapeutic agents in the treatment of a variety of human malignancies. Although several of these inhibitors have marked clinical activity, it is widely recognized that the overall value of these agents is substantially limited by the acquisition of drug resistance, which eventually arises in most, if not all treated patients. Mechanisms of drug resistance are beginning to be elucidated through the molecular analysis of clinical specimens as well as through cell culture modeling. By identifying resistance mechanisms, it should be possible to develop 'second-generation' inhibitors as well as rational drug combinations that can overcome or even prevent acquired resistance to kinase inhibitors, thereby enhancing clinical benefit.


Complement modulates the cutaneous microbiome and inflammatory milieu.
The skin is colonized by a plethora of microbes that include commensals and potential pathogens, but it is currently unknown how cutaneous host immune mechanisms influence the composition, diversity, and quantity of the skin microbiota. Here we reveal an interactive role for complement in cutaneous host-microbiome interactions. Inhibiting signaling of the complement component C5a receptor (C5aR) altered the composition and diversity of the skin microbiota as revealed by deep sequencing of the bacterial 16S rRNA gene. In parallel, we demonstrate that C5aR inhibition results in down-regulation of genes encoding cutaneous antimicrobial peptides, pattern recognition receptors, and proinflammatory mediators. Immunohistochemistry of inflammatory cell infiltrates in the skin showed reduced numbers of macrophages and lymphocytes with C5aR inhibition. Further, comparing cutaneous gene expression in germ-free mice vs. conventionally raised mice suggests that the commensal microbiota regulates expression of complement genes in the skin. These findings demonstrate a component of host immunity that impacts colonization of the skin by the commensal microbiota and vice versa, a critical step toward understanding host-microbe immune mutualism of the skin and its implications for health and disease. Additionally, we reveal a role for complement in homeostatic host-microbiome interactions of the skin.


Efficacy and safety of human umbilical cord-derived mesenchymal stem cells for COVID-19 pneumonia: a meta-analysis of randomized controlled trials.
Elevated levels of inflammatory factors are associated with poor prognosis in coronavirus disease-19 (COVID-19). However, mesenchymal stem cells (MSCs) have immunomodulatory functions. Accordingly, this meta-analysis aimed to determine the efficacy and safety of MSC-based therapy in patients with COVID-19 pneumonia. Online global databases were used to find relevant studies. Two independent researchers then selected and evaluated the studies for suitability while the Cochrane risk of bias tool determined the quality of all articles and Cochran's Q test and I2 index assessed the degree of heterogeneity in the principal studies. Statistical analysis was performed using Review Manager software, and the effect of each study on the overall estimate was evaluated by sensitivity analysis. Seven studies were included in the meta-analysis, and all MSCs used in the trials were acquired from the umbilical cord. The results of these studies (n = 328) indicated that patients with COVID-19 pneumonia who received MSCs had a 0.58 risk of death compared with controls (95% CI = 0.38, 0.87; P = 0.53; I2 = 0%). In terms of inflammatory biomarkers, MSCs reduced the levels of C-reactive protein (n = 88; MD = - 32.49; 95% CI = - 48.43, - 16.56; P = 0.46; I2 = 0%) and interferon-gamma (n = 44; SMD = - 1.23; 95% CI = - 1.89, - 0.57; P = 0.37; I2 = 0%) in severe COVID-19 patients but had no significant effect on interleukin-6 (n = 185; MD = - 0.75; 95% CI = - 7.76, 6.27; P = 0.57; I2 = 0%). A summary of the data revealed no significant differences in adverse events (n = 287) or serious adverse events (n = 229) between the MSC and control groups. Infusion of umbilical cord-derived MSCs is an effective strategy for treating patients with COVID-19 pneumonia, with no noticeable adverse effects.


Liver cytosol corticosteroid binder IB, a new binding protein.
A new binding protein named corticosteroid Binder IB elutes just after ligandin in DEAE-Sephadex chromatograms. It has been partially purified to about 2500-fold over cytosol proteins. Calculation of the number of steroid binding sites, assuming one site per molecule of Binder IB fraction after DEAE-Sephadex chromatography, suggests a concentration of the binding protein of about 0.0004% of cytosol proteins. Its pI value is judged to be 7.5 to 8 from it elution position on DEAE-Sephadex chromatograms. IB has an apparent molecular weight of 30,500 +/- 10% by gel filtration and a Stokes radius of 20 A. Binder IB binds radioactive dexamethasone, cortisol, and corticosterone in vitro with estimated KD values of 1, 13, and 25 nM, respectively. Saturation curves are abnormal, showing two phases. The saturation curves within the physiological range of concentrations of steroid are abnormal and suggestive of cooperativity. The second phase, at concentrations of glucocortidoids above saturation and physiological levels, shows extensive binding. After fractionation from other steroid binding proteins, the specificity of binding from competition studies in vitro is dexamethasone greater than or equal to cortisol = corticosterone = estradiol-17beta greater than or equal to deoxycorticosterone = dihydrotestosterone greater than aldosterone = cortexolone greater than testosterone. Other steroids tested are less efficient ligands. The binding is probably noncovalent, but strong; and the complex becomes more dissociable as purification proceeds, suggesting a conformational change in the protein. Storage and rebinding with steroid are possible throughout the purification process, although extensive ligand dissociation and denaturation of the protein occur after the final purification step. Binding in vitro is temperature-sensitive and binding is sharply pH dependent with an optimum at 7.5. The ligand is the unmetabolized steroid as judged by extraction of steroid-IB complex with methylene chloride and subsequent thin layer chromatography. The physiological function of this protein is unknown at present and purification fo the major corticosteroid hormone receptor to homogeneity may be required before the function of Binder IB is fully understood.


The prevalence of essential tremor in rural northern Tanzania.
Estimates of the prevalence of essential tremor (ET) vary widely but there are few existing data on the prevalence of ET in sub-Saharan Africa. A door-to-door community based prevalence study of ET was carried out in the Hai district of northern Tanzania (n = 161,071). The screening questionnaire was followed by examination of positive responders and backed up with other case finding methods. 222 patients responded positively to the screening questions and 43 were referred by village elders. 65 (38 men, 27 women) were diagnosed with ET. Mean age was 72 years and mean duration of symptoms was 11.3 years. The crude prevalence rate was 41/100,000 and age standardised prevalence compared with the UK population (2001) was 82/100,000. This is the first community based prevalence study of ET in sub-Saharan Africa. Previous data from community based neurological surveys showed lower prevalence rates of 5/100,000 in Ethiopia and 10/100,000 in Nigeria. Non-selective beta blockers are available locally and are affordable, yet none of these patients had previously been on any treatment.


Immunoassay Biosensing of Foodborne Pathogens with Surface Plasmon Resonance Imaging: A Review.
Surface plasmon resonance imaging (SPRi) has been increasingly used in the label-free detections of various biospecies, such as organic toxins, proteins, and bacteria. In combination with the well-developed microarray immunoassay, SPRi has the advantages of rapid detection in tens of minutes and multiplex detection of different targets with the same biochip. Both prism-based and prism-free configurations of SPRi have been developed for highly integrated portable immunosensors, which have shown great potential on pathogen detection and living cell imaging. This review summarizes the recent advances in immunoassay biosensing with SPRi, with special emphasis on the multiplex detections of foodborne pathogens. Additionally, various spotting techniques, surface modification protocols, and signal amplification methods have been developed to improve the specificity and sensitivity of the SPRi biochip. The challenges in multiplex detections of foodborne pathogens in real-world samples are addressed, and future perspectives of miniaturizing SPRi immunosensors with nanotechnologies are discussed.


Stimulatory and inhibitory effects of sulfhydryl reagent on p-aminohippuric acid transport by isolated renal tubules.
Isolated tubules from rabbit kidney cortex were treated with several different sulfhydryl reagents in an attempt to determine whether sulfhydryl groups are involved in organic acid transport. Disulfide reagents such as sodium tetrathionate and 6,6'-dithionicotinic acid were found to exert a biphasic effect on p-aminohippuric acid transport, i.e. transient stimulation followed by inhibition. In contrast, treatment of tubules with the mercaptide-forming reagent, p-chloromercuribenzoate, caused only inhibition of organic acid transport. Treatment of tubules with reductants such as dithiothreitol or mercaptoethanol blocked the stimulatory effect of tetrathionate without affecting the inhibitory effect of this oxidant. The inhibition caused by p-chloromercuribenzoate, however, was largely reversible when tubules were treated with reductants. The results suggest that the renal organic acid transport system contains sulfhydryl groups and that its activity is increased when some of these groups are oxidized.


New approaches to polysubstituted pyrroles and gamma-lactams based on nucleophilic addition of Ti(IV) enolates derived from alpha-diazo-beta-keto carbonyl compounds to N-tosylimines.
The Ti(IV) enolates derived from alpha-diazo-beta-keto esters or ketones efficiently add to TiCl4-activated N-tosylimines to give delta-N-tosylamino substituted alpha-diazo-beta-keto carbonyl compounds. The diazo decomposition of the addition products occurs under Rh2(OAc)4-catalyzed or photoinduced conditions to afford pyrrole or gamma-lactam derivatives, both in high yields.


Identification of Bombyx mori bidensovirus VD1-ORF4 reveals a novel protein associated with viral structural component.
Bombyx mori bidensovirus (BmBDV) VD1-ORF4 (open reading frame 4, ORF4) consists of 3,318 nucleotides, which codes for a predicted 1,105-amino acid protein containing a conserved DNA polymerase motif. However, its functions in viral propagation remain unknown. In the current study, the transcription of VD1-ORF4 was examined from 6 to 96 h postinfection (p.i.) by RT-PCR, 5'-RACE revealed the transcription initiation site of BmBDV ORF4 to be -16 nucleotides upstream from the start codon, and 3'-RACE revealed the transcription termination site of VD1-ORF4 to be +7 nucleotides downstream from termination codon. Three different proteins were examined in the extracts of BmBDV-infected silkworms midguts by Western blot using raised antibodies against VD1-ORF4 deduced amino acid, and a specific protein band about 53 kDa was further detected in purified virions using the same antibodies. Taken together, BmBDV VD1-ORF4 codes for three or more proteins during the viral life cycle, one of which is a 53 kDa protein and confirmed to be a component of BmBDV virion.


Experimental study of the inhibition of human hepatocarcinoma Bel7402 cells by the tripeptide tyroserleutide(YSL).
To investigate the antitumor effects of tyroserleutide (tyrosyl-seryl-leucine, YSL) on human Bel7402 hepatocarcinoma in vitro and in vivo, with preliminary exploration of its antitumor mechanism. MTT was used to observe the anticarcinogenic effects of YSL on human hepatocarcinoma Bel7402 cells in vitro. The ultrastructure of tumor cells was observed by electron microscopy. Nude mice bearing xenografts of human hepatocarcinoma Bel7402 were given daily i.p. injections of YSL or saline and an admixture of amino acids as controls, after tumor implantation. The inhibition of xenografts was determined by calculating the tumor volume and measuring tumor weight. The effects of YSL on the cell cycle and apoptosis of Bel7402 cells were determined by flow cytometry, and the effects on the ultrastructure of the cells by electron microscopy. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and proliferating-cell nuclear antigen (PCNA) immunohistochemical staining were used to investigate apoptosis in tumor tissue in nude mice. In vitro YSL inhibited the proliferation of human Bel7402 tumor cells and changed their ultrastructure, resulting in the necrosis and apoptosis of the tumor cells. YSL at 80, 160, or 320 microg/kg/d inhibited tumor growth in nude mice by 40.26, 64.17, and 59.19%, respectively, which are significantly lower than the inhibition exerted by saline and an admixture of YSL amino acids (P<0.05). The ultrastructure and cell cycle of human hepatocarcinoma Bel7402 cells were changed by treatment with YSL, with a rate of apoptosis higher than that of the control group. TUNEL and PCNA analysis showed that YSL inhibited the proliferation of tumor cells and induced apoptosis at the level of the cell. YSL significantly inhibited human hepatocarcinoma Bel7402 growth in vitro and in vivo. The growth inhibition of the tumor may involve necrosis and apoptosis of the tumor induced by YSL.


Quality of Intervention Reporting in Randomized Clinical Trials Published in Urology Journals.
We used the Template for Intervention Description and Replication (TIDieR) to find evidence that intervention reporting in urology randomized controlled trials is suboptimal. Action to improve intervention reporting is warranted and we advise extending TIDieR into Consolidated Standards for Reporting Trials guidelines.


Axonal Protection by Nicotinamide Riboside via SIRT1-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.
Nicotinamide adenine dinucleotide (NAD+) synthesis pathway has been involved in many biological functions. Nicotinamide riboside (NR) is widely used as an NAD+ precursor and known to increase NAD+ level in several tissues. The present study aimed to examine the effect of NR on tumor necrosis factor (TNF)-induced optic nerve degeneration and to investigate whether it alters SIRT1 expression and autophagic status in optic nerve. We also examined the localization of nicotinamide riboside kinase 1 (NRK1), which is a downstream enzyme for NR biosynthesis pathway in retina and optic nerve. Intravitreal injection of TNF or TNF plus NR was performed on rats. The p62 and LC3-II protein levels were examined to evaluate autophagic flux in optic nerve. Immunohistochemical analysis was performed to localize NRK1 expression. Morphometric analysis showed substantial axonal protection by NR against TNF-induced axon loss. TNF-induced increment of p62 protein level was significantly inhibited by NR administration. NR administration alone significantly increased the LC3-II levels and reduced p62 levels compared with the basal levels, and upregulated SIRT1 levels in optic nerve. Immunohistochemical analysis showed that NRK1 exists in retinal ganglion cells (RGCs) and nerve fibers in retina and optic nerve. NR administration apparently upregulated NRK1 levels in the TNF-treated eyes as well as the control eyes. Pre-injection of an SIRT1 inhibitor resulted in a significant increase of p62 levels in the NR plus TNF treatment group, implicating that SIRT1 regulates autophagy status. In conclusion, NRK1 exists in RGCs and optic nerve axons. NR exerted protection against axon loss induced by TNF with possible involvement of upregulated NRK1 and SIRT1-autophagy pathway.


Control of renin synthesis and secretion.
The aspartyl protease renin is the rate limiting activity of the renin-angiotensin-aldosterone system (RAAS). Renin is synthesized as an enzymatically inactive proenzyme which is constitutively secreted from several tissues. Only renin-expressing cells in the kidney are capable of generating active renin from prorenin, which is stored in prominent vesicles and which is released into the circulation upon demand. The acute release of renin is controlled by cyclic adenosine monophosphate (cAMP) and by calcium signaling pathways, which in turn are activated by a number of systemic and local factors. Longer lasting challenges of renin secretion lead to changes in the number of renin-producing cells, which occur by a metaplastic transformation of renin cell precursors such as preglomerular vascular smooth muscle or extraglomerular mesangial cells. This review aims to briefly address the state of knowledge of these various aspects of renin synthesis and secretion and attempts to relate them to the in vivo situation, in particular in men.


Prioritizing organic chemicals for long-term air monitoring by using empirical monitoring data--application to data from the Swedish screening program.
This paper illustrates a step-by-step approach for evaluating chemical monitoring data in air and deposition and for prioritizing chemicals to be included in long-term air monitoring programs. The usability of the method is shown by application to data generated within the Swedish screening program. The suggested prioritization approach uses a novel methodology by combining empirical data on occurrence in air and deposition with publicly available quantitative structure activity relationship estimation tools that predict atmospheric persistence and bioaccumulation. A selection tree is presented, which may be used by regulatory bodies to prioritize chemicals for long-term air monitoring. A final ranking list is presented proposing a prioritization order for inclusion in monitoring programs. Based on the suggested strategy, the chemicals identified as most relevant to include in Swedish long-term monitoring programs were short-chain chlorinated paraffins(C10-C13), perfluorooctane sulfonate, octachlorostyrene, hexabromocyclododecane, hexachlorobenzene, pentachloroanisole, decamethylcyclopentasiloxane, octamethylcyclotetrasiloxane, pentachlorobenzene, 1,2,3,4-tetrachlorobenzene, hexachlorobutadiene, dodecamethylcyclohexasiloxane, perfluorodecane sulfonate, 1,2,4,5-tetrachlorobenzene, and pentabromophenol.


Beneficial effect of Bradycardia Tachycardia Response (BTR) algorithm on VT detection in the presence of rate smoothing.
Rate smoothing algorithms, while known to help prevent ventricular tachyarrhythmias in some patients, have been shown to result in underdetection of ventricular tachycardia (VT) due to interaction between bradycardia pacing and tachycardia detection parameters. A new algorithm named Bradycardia Tachycardia Response (BTR) has been developed in order to prevent rate smoothing-induced underdetection. The efficacy of BTR is not known. The aim of this study was to assess the effectiveness of BTR in preventing VT underdetection due to rate smoothing. Two ICD models (TELIGEN and VITALITY AVT, Boston Scientific, St. Paul, MN, USA) bearing identical rate smoothing algorithms were connected to a VT simulator. Devices were programmed similarly except for the BTR feature that exists in TELIGEN only. The detection performance of both devices was tested using varying combinations of AV delay, rate smoothing down, and upper rate limit and compared between the two models. VT underdetection (delay or nondetection) occurred during pacing in 62% of the VT episodes with VITALITY AVT. In TELIGEN, all simulated VT episodes were detected appropriately as soon as their rates exceeded the programmed VT detection rate. Detection tended to be affected by higher upper rate, longer AV delays, and more aggressive rate smoothing. The BTR algorithm effectively counteracts VT detection delay caused by the interaction of rate smoothing with VT detection parameters, thus enabling safe use of the rate smoothing feature.


Evaluation of the toxicity of nickel nanowires to freshwater organisms at concentrations and short-term exposures compatible with their application in water treatment.
In order to understand the potential impacts of nickel nanowires (Ni NWs) after reaching the aquatic environment, this research evaluated the toxicity of Ni NWs with different lengths (≤ 1.1, ≤11 and ≤ 80 μm) for several floating, planktonic and nektonic freshwater organisms. In this work, Ni NWs were synthesized by electrodeposition using anodized aluminum oxide (AAO) membranes. The toxicity of the NWs was assessed using a battery of aquatic species representative of key functions at the ecosystem level: the bacterium Aliivibrio fischeri, the algae Raphidocelis subcapitata, the macrophyte Lemna minor, the crustacean Daphnia magna and the zebrafish Danio rerio. Results indicated that for the concentrations tested (up to 2.5 mg L-1) the synthesized Ni NWs showed low toxicity. And although no lethal toxicity was observed for D. magna, at a sublethal level the feeding activity of the freshwater cladoceran was severely affected after exposure to Ni NWs. These findings showed that NWs can be accumulated in the gut of D. magna, even during a short exposure (24 h) directly impairing Daphnia nutrition and eventually populations growth. Consequently, this can also contribute to trophic transfer of NWs along the food chain. According to our results the toxicity of Ni NW may be mainly attributed to physical effects rather than chemical effects of Ni ions, considering that the concentrations of Ni NWs tested in this study were well below the toxicity thresholds reported in the literature for Ni ions and for Ni NMs.


Seven cases of gastric perforation in Roux-en-Y gastric bypass patients: what lessons can we learn?
Patients undergoing Roux-en-Y gastric bypass for the resolution of morbid obesity have significant medical sequelae related to their weight. One of the most common comorbid conditions is joint pain requiring the use of non-steroidal anti-inflammatory medications (NSAIDs). In addition to NSAIDs, patients may engage in behaviors such as smoking and alcohol misuse that increase the risk of long-term postoperative complications to include gastric perforation. Data on 1,690 patients undergoing gastric bypass surgery were collected prospectively and reviewed retrospectively. We identified seven patients who presented to an emergency room and subsequently required emergent surgical intervention for repair of gastric perforation. Six of the seven cases involved use or abuse of NSAIDs. Important characteristics were identified including the use of NSAIDs, alcohol use, and non-compliance with routine long-term postoperative follow-up. Identifying those patients at high risk may decrease the incidence of this potentially life-threatening complication.


Metaflammatory responses during obesity: Pathomechanism and treatment.
Obesity induced inflammation acts as a reflex produced due to altered metabolic homeostasis in accordance to the nutrient overload on the metabolic cells. It involves up-regulation of the genes encoding for cytokines, chemokines and other inflammatory mediators through activated transcription factors - nuclear factor-kB, activator protein-1, nuclear factor of activated T cells and signal transducer and activator of transcription 3. These execute macromolecular innate immune cell sensor - inflammasome to activate caspase-1 pathway resulting in proteolytic maturation. Secretion of pro-inflammatory cytokines including TNF-α, IL-6, CRP, IL-1β, etc. from the M1 macrophages of white adipose tissue is increased, whereas there occurs a steep decline in the production of anti-inflammatory cytokines like IL-10, IL-Ra, adiponectin. Not only the adipose tissue, but also the immune cells, liver, brain, muscles and pancreas suffers from the inflammatory insult during obese condition and are exaggeratedly affected. The inflammatory kinases like JNK and IKK apart from inhibiting insulin action and glucose uptake, down-regulate transcriptional process resulting in increased expression of pro-inflammatory cytokines. Macrophage-like Kupffer cells initiate the inflammatory process in the liver preceding the inflammatory signals produced by the white adipose tissue which may further lead to hepatic-necro-inflammation. The muscle-fibre is affected by the cytokines and therefore results in decreased glycogen synthesis. The triggered hypothalamic-pituitary-adrenal axis further affects the expression of inflammatory cytokines thus altering insulin homeostasis and initiating glucose intolerance. Anti-inflammatory treatment so as to curb the severity of inflammatory responses includes administration of synthetic drugs to target the actual inflammatory molecules and various therapeutic interventions.


Mycoplasma genitalium lipoproteins induce human monocytic cell expression of proinflammatory cytokines and apoptosis by activating nuclear factor kappaB.
This study was designed to investigate the molecular mechanisms responsible for the induction of proinflammatory cytokines gene expression and apoptosis in human monocytic cell line THP-1 stimulated by lipoproteins (LPs) prepared from Mycoplasma genitalium. Cultured cells were stimulated with M. genitalium LP to analyze the production of proinflammatory cytokines and expression of their mRNA by ELISA and RT-PCR, respectively. Cell apoptosis was also detected by Annexin V-FITC-propidium iodide (PI) staining and acridine orange (AO)-ethidium bromide (EB) staining. The DNA-binding activity of nuclear factor-kappaB (NF-kappaB) was assessed by electrophoretic mobility shift assay (EMSA). Results showed that LP stimulated THP-1 cells to produce tumor necrosis factor-alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in a dose-dependent manner. The mRNA levels were also upregulated in response to LP stimulation. LPs were also found to increase the DNA-binding activity of NF-kappaB, a possible mechanism for the induction of cytokine mRNA expression and the cell apoptosis. These effects were abrogated by PDTC, an inhibitor of NF-kappaB. Our results indicate that M. genitalium-derived LP may be an important etiological factor of certain diseases due to the ability of LP to produce proinflammatory cytokines and induction of apoptosis, which is probably mediated through the activation of NF-kappaB.


Cross-cultural adaptation to the Thai language of the neuropathic pain diagnostic questionnaire (DN4).
To cross-culturally adapt the neuropathic pain diagnostic questionnaire (DN4) to Thai language Phase 1: Forward and backward translation followed by assessment of semantic equivalence. Phase 2: Testing of the questionnaire in 30 neuropathic pain patients who were seen and diagnosed by experts, followed by modifications to produce a final version. All the Thai translated pain descriptors except 'tingling' got high percentages of understanding among neuropathic pain patients in the first round of testing. After some adaptation of the Thai word for 'tingling' had been made, the new translated word was retested, and all subjects doing the retest understood the word very well. The Thai DN4 questionnaire was systematically translated and validated. This offers a simple Thai neuropathic pain diagnostic tool for clinical use.


Laboratory-confirmed bloodstream infections in two large neonatal units in sub-Saharan Africa.
Epidemiological data on neonatal bloodstream infections (BSI) in sub-Saharan Africa are extremely limited. A comparative analysis of laboratory-confirmed neonatal BSI episodes was conducted retrospectively in two large neonatal units in Botswana and South Africa (January 1 to December 31, 2017). Routine laboratory and ward register data were used to determine BSI rates, the pathogen spectrum, and BSI outcomes. In 2017, the Princess Marina Hospital (PMH) and Tygerberg Hospital (TBH) neonatal units admitted 1187 and 2826 neonates, respectively. The BSI incidence rate was 12.1/1000 patient-days (95% confidence interval (CI) 10.2-14.3) at PMH and 3.5/1000 patient-days (95% CI 2.9-4.1) at TBH (p < 0.0001). Most BSI episodes were hospital-acquired (260/284; 91.6%). The blood culture contamination rate was substantially higher at PMH than TBH (152/1116 (13.6%) vs 122/2559 (4.8%); p < 0.001). The crude mortality rate in neonates with BSI was 21.2% (53/250) and significantly higher at TBH than PMH (38/128 (29.7%) vs 15/122 (12.3%), p = 0.001). Factors independently associated with death were birth weight <1500 g (adjusted odds ratio (aOR) 2.8, 95% CI 1.3-6.4; p = 0.02) and male sex (aOR 2.1, 95% CI 1.1-3.7; p = 0.01). Klebsiella pneumoniae was the dominant BSI pathogen in both units, accounting for two-thirds of BSI, and was associated with a large infection outbreak at PMH. Antibiotic resistance rates were substantial in both neonatal units, particularly for K. pneumoniae (98/122 (80.3%), extended-spectrum beta-lactamase (ESBL)-producers) and Staphylococcus aureus (22/33 (66.7%), methicillin-resistant). BSI rates and associated mortality were substantial in these two neonatal units in sub-Saharan Africa. ESBL-producing K. pneumoniae remains a leading BSI and outbreak pathogen.


CDH1 germline variants are enriched in patients with colorectal cancer, gastric cancer, and breast cancer.
CDH1 germline variants have been linked to heritability in diffuse gastric (DGC) and lobular breast cancer (LBC). Studies have not yet assessed whether CDH1 is a cancer-susceptibility gene in other cancers. Herein, we mapped the landscape of pathogenic and likely pathogenic (P/LP) germline variants in CDH1 across various cancers and ethnicities. We evaluated CDH1 germline P/LP variants in 212,944 patients at one CLIA-certified laboratory (Invitae) and described their frequency in 7 cancer types. We screened for CDH1 variant enrichment in each cancer relative to a cancer-free population from The Genome Aggregation Database version 3 (gnomADv3). CDH1 P/LP variants were identified in 141 patients, most commonly in patients with DGC (27/408, 6.6%) followed by colorectal signet-ring cell cancer (CSRCC; 3/79, 3.8%), gastric cancer (56/2756, 2%), and LBC (22/6809, 0.3%). CDH1 P/LP variants were enriched in specific ethnic populations with breast cancer, gastric cancer, CRC, LBC, DGC, and CSRCC compared to matched ethnicities from gnomADv3. We report for the first time the prevalence of P/LP CDH1 variants across several cancers and show significant enrichment in CDH1 P/LP variants for patients with CSRCC, DGC, and LBC across various ethnicities. Future prospective studies are warranted to validate these findings.


LISREL analysis of twin data with structured means.
A method is introduced to test the hypothesis that both the phenotypic means and the phenotypic covariances can be modeled with the same common genetic and environmental factors. LISREL can be used to implement the method. An illustration is given with simulated twin data.


Clinical and anatomical characteristics associated with obstructive sleep apnea severity in children.
To determine the clinical and anatomical characteristics associated with obstructive sleep apnea severity in children with adenotonsillar hypertrophy. The authors conducted a cross-sectional multidisciplinary survey and selected 58 Brazilian children (4‒9 years old) with adenotonsillar hypertrophy, parental complaints of snoring, mouth-breathing, and witnessed apnea episodes. The authors excluded children with known genetic, craniofacial, neurological, or psychiatric conditions. Children with a parafunctional habit or early dental loss and those receiving orthodontic treatment were not selected. All children underwent polysomnography, and three were excluded because they showed an apnea-hypopnea index lower than one or minimal oxygen saturation higher than 92%. The sample consisted of 55 children classified into mild (33 children) and moderate/severe (22 children) obstructive sleep apnea groups. Detailed clinical and anatomical evaluations were performed, and anthropometric, otorhinolaryngological, and orthodontic variables were analyzed. Sleep disorder symptoms were assessed using the Sleep Disturbance Scale for Children questionnaire. All children also underwent teleradiography exams and Rickett's and Jarabak's cephalometric analyses. The mild and moderate/severe obstructive sleep apnea groups showed no significant differences in clinical criteria. Facial depth angle, based on Ricketts cephalometric analysis, was significantly different between the groups (p = 0.010), but this measurement by itself does not express the child's growth pattern, as it is established by the arithmetic mean of the differences between the obtained angles and the normal values of five cephalometric measurements. The clinical criteria and craniofacial characteristics evaluated did not influence the disease severity.


Evidence for the involvement of HLA-DR antigens in restricted cytotoxicity by fetal calf serum-specific human T cells.
Fetal calf serum (FCS) generated at least two distinct populations of human cytotoxic cells in vitro. One population expressed natural killer (NK) cell-like activity and lysed K562 and HSB-2 targets more effectively than autologous or allogeneic lymphoblastoid cell lines (LCLs). The other population contained FCS-specific cytotoxic T cells which preferentially lysed the autologous LCLs and showed minimal lysis of K562. E-rosette separation and cold target competition experiments clearly established that NK cells were not involved in the self-reactive lysis. Moreover, the lytic activity of the E-rosetted T cells was reduced by up to 95% when autologous target cells were grown in human AB serum rather than FCS, showing that FCS-associated determinants on targets were essential in the cytolytic phase. Autologous LCLs grown in FCS were also considerably stronger competitors than human serum-grown LCLs. The consistent self-preferred lysis suggested that HLA antigen-related restriction was involved, but the patterns of lysis did not implicate HLA-A or B antigens, and monoclonal antibody (W6/32) to an A, B, and C monomorphic determinant failed to block FCS-specific lysis. In contrast, monoclonal antibody (DA.2) to a monomorphic determinant of DR effectively blocked FCS-specific lysis. Cytotoxicity tests with a small panel of DR-typed donors indicated that strong cross-reactions were invariably associated with sharing of DR antigens, particularly DR2, and to a lesser but significant extent DR7. Although DR antigen sharing did not always result in lysis of allogeneic targets, the overall evidence strongly suggests that FCS-specific T-cell cytotoxicity in humans is restricted by products encoded by or associated with the DR genes.


Phytanic acid-derived peroxisomal lipid metabolism in porcine oocytes.
Lipid metabolism plays an important role in oocyte maturation. The peroxisome is the fundamental mediator for this mechanism. In this study, we investigated the peroxisomal lipid metabolism in porcine oocytes. Phytanic acid (PA) was chosen as an activator of alpha-oxidation in peroxisomes. Oocyte maturation, embryo development, immunocytochemistry of peroxisomal lipid activities, and staining of mitochondrial potentials were assessed. We found that 40 μM PA not only increased porcine oocyte maturation and embryonic development, but also upregulated the expression of genes and proteins related to activities of the peroxisomal lipid metabolism (PHYH, PEX19, and PEX subfamilies) and mitochondrial potentials (NRF1 and PGC1α). Moreover, PA upregulated the lipid droplet and fatty acid content in the oocytes. Moreover, mitochondria were activated and the mitochondrial membrane potential was increased after PA treatment, resulting in the production of more ATPs in the oocytes. Our findings suggest that the degradation of PA via alpha-oxidation in the peroxisome may potentiate oocyte maturation processes, peroxisomal lipid oxidation, and mitochondria activities.


Living with phenylketonuria: perspectives of patients and their families.
This study surveyed PKU patients and their primary caretakers to assess their current management practices, the barriers to effective management, and the potential utility of a home monitor in managing PKU. A survey instrument was mailed to caretakers of all 50 patients with PKU in Utah between the ages of 2 and 18 years in 1997 (response rate 64%). It included separate components for caretakers and patients aged 10 to 18 years. Although there was uneven compliance with recommended practices, caretakers universally recognized the negative consequences of not adhering to the low-protein diet. There was, however, disagreement regarding such consequences among the older children surveyed. The primary obstacles cited to better adherence were time constraints and stress associated with food preparation and record-keeping, and the restrictions imposed on social life. Phenylalanine test results were regarded as the principal signal for the need for dietary adjustment. Despite the facts that obstacles to dietary adherence are multifaceted and that no single intervention would therefore serve as a panacea, a large majority of respondents believed a home monitor would facilitate better management of PKU through more regular and timely feedback.


Toxinogenicity ofMicrodochium nivale (Fusarium nivale) isolates from cereals in Poland.
Microdochium nivale (Fusarium nivale) was found to be frequently occuring in Poland pathogen of small grain cereals heads, causing symptoms similar to those observed after infection ofFusarium species. In consecutive years since 1985 till 1989 the following percentage of wheat and rye ears infected withM. Nivale and withFusarium head blight symptoms was found: 34%, 21%, 42%, 9%, 46% (wheat) and 57%, 43%, 65%, 4%, 47% (rye) heads.However, in naturally infected rye and wheat samples (kernels and chaff), we did not detect toxins usually present in samples infected with fungi of genusFusarium - such as deoxynivalenol and derivatives. TypicalFusarium trichothecene metabolites were also not present in cultures of 11M. nivale strains, growing 3-5 weeks on rice (45% water content) at 20°C. Cultures of two typical isolates on wheat grain (strain KF 1124) and on rice (KF 245) were found to be non toxic to broiler chickens when present in amount 20-40% in their diet. It can be concluded thatM. nivale (F. nivale) representatives in Poland did not produce toxic metabolites neither under laboratory condition nor after cereal ears infection under field conditions.


Managing perinatal outcomes: the clinical benefit and cost-effectiveness of pharmacologic treatment of recurrent preterm labor.
To compare the clinical benefit and cost-effectiveness of utilizing continuous subcutaneous terbutaline versus oral tocolytics following recurrent preterm labor. Retrospective, 1:1 matched cohort. From prospectively collected data in a nationwide, perinatal database of women receiving outpatient services, we identified singleton gestations having recurrent preterm labor, stabilized during hospitalization, and subsequently treated with oral tocolytics (PO group) or continuous subcutaneous terbutaline infusion (SQ group). Those without medically indicated delivery were eligible for inclusion. Each woman in the PO group was matched 1:1 by gestational age at recurrent preterm labor to a woman in the SQ group. A standardized cost model was applied to compare total antepartum hospital, nursery, and outpatient charges. Wilcoxon Signed Rank, paired t, and McNemar's C2 test statistics were used for comparisons. 558 women were studied (279 per group). The PO group had less gestational gain following recurrent preterm labor than the SQ group (28.4 +/- 19.8 days vs. 33.9 +/- 19.0 days, respectively, P < .001). The SQ group had less per patient charges ($) for antepartum hospitalization (3,986 +/- 6,895 vs. 5,495 +/- 7,131, P = .009), and nursery (7,143 +/- 20,048 vs. 15,050 +/- 32,648, P < .001). Outpatient charges were less for the PO group (1,390 +/- 1,152 vs. 5,520 +/- 3,292, P < .001). Overall costs for those in the SQ group were $5,286 less per pregnancy compared to the PO group. In this population, continuous subcutaneous terbutaline infusion was both a clinically beneficial and cost-effective treatment following recurrent preterm labor.


Characterization of the Peri-Membrane Fluorescence Phenomenon Allowing the Detection of Urothelial Tumor Cells in Urine.
Urine cytology is non-invasive, easy to collect, with medium sensitivity and a high specificity. It is an effective way to detect high-grade bladder cancer (BC), but it is less effective on low-grade BC because the rate of equivocal results is much higher. Recently, the fluorescent properties of plasma membranes of urothelial tumor cells (UTC) found in urine cytology have been shown to be useful in improving the early detection of BC. This phenomenon is called peri-membrane fluorescence (PMF). Based on previous studies that have identified the PMF on UTCs, the main objective was to characterize this phenomenon. For this study, a software was specially created to quantify the PMF of all tested cells and different treatments performed. PMF was not found to be a morphological and discriminating feature of UTCs, all cells in shape and not from urine show PMF. We were able to highlight the crucial role of plasma membrane integrity in the maintenance of PMF. Finally, it was found that the induction of a strong cellular stress induced a decrease in PMF, mimicking what was observed in non-tumor cells collected from urine. These results suggest that PMF is found in cells able to resist this stress, such as tumor cells.


Machine-learning analysis of contrast-enhanced CT radiomics predicts recurrence of hepatocellular carcinoma after resection: A multi-institutional study.
Current guidelines recommend surgical resection as the first-line option for patients with solitary hepatocellular carcinoma (HCC); unfortunately, postoperative recurrence rate remains high and there is no reliable prediction tool. We explored the potential of radiomics coupled with machine-learning algorithms to improve the predictive accuracy for HCC recurrence. A total of 470 patients who underwent contrast-enhanced CT and curative resection for solitary HCC were recruited from 3 independent institutions. In the training phase of 210 patients from Institution 1, a radiomics-derived signature was generated based on 3384 engineered features extracted from primary tumor and its periphery using aggregated machine-learning framework. We employed Cox modeling to build predictive models. The models were then validated using an internal dataset of 107 patients and an external dataset of 153 patients from Institution 2 and 3. Using the machine-learning framework, we identified a three-feature signature that demonstrated favorable prediction of HCC recurrence across all datasets, with C-index of 0.633-0.699. Serum alpha-fetoprotein, albumin-bilirubin grade, liver cirrhosis, tumor margin, and radiomics signature were selected for preoperative model; postoperative model incorporated satellite nodules into above-mentioned predictors. The two models showed superior prognostic performance, with C-index of 0.733-0.801 and integrated Brier score of 0.147-0.165, compared with rival models without radiomics and widely used staging systems (all P < 0.05); they also gave three risk strata for recurrence with distinct recurrence patterns. When integrated with clinical data sources, our three-feature radiomics signature promises to accurately predict individual recurrence risk that may facilitate personalized HCC management.


[GC-MS analysis on volatile components of wild Trogopterus faeces from Laishui county of Hebei province].
To analysis the volatile components of Trogopterus faeces. The volatile components of Trogopterus faeces was extracted by steam distillation and analyzed by GC-MS. Eighty-five volatile components were identified and the main components are cedrol (12.31%) and caryophyllene (7.5%). The volatile components of the samples are originated from the ingredients or other chemical compositions with similar basic structure of the fodders.


Novel Foscan®-derived ring-fused chlorins for photodynamic therapy of cancer.
Photodynamic therapy (PDT) is an established anticancer treatment that combines the use of a photosensitiser (PS) and a light source of a specific wavelength for the generation of reactive oxygen species (ROS) that are toxic to the tumour cells. Foscan® (mTHPC) is a clinically-approved chlorin used for the PDT treatment of advanced head and neck, prostate and pancreatic cancers but is characterized by being photochemically unstable and associated with prolonged skin photosensitivity. Herein, we report the synthesis of new 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused chlorins, having the meso-tetra(3-hydroxyphenyl)macrocycle core of mTHPC, by exploring the [8π + 2π] cycloaddition of a meso-tetra(3-hydroxyphenyl)porphyrin derivative with diazafulvenium methides. These chlorins have photochemical properties similar to Foscan® but are much more photostable. Among the novel compounds, two chlorins with a hydroxymethyl group and its azide derivative present in the 4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-fused system, are promising photodynamic agents with activity in the 100 nM range against triple-negative breast cancer cells and, in the case of azidomethyl chlorin, a safer phototherapeutic index compared to Foscan®.


Rational decision making based on history: adult sore throats.
Primary care physicians are often required to make preliminary evaluations based only on the patient's history, especially during telephone encounters about sore throats. The authors studied adults with sore throats to determine whether patients can be stratified into higher and lower risks of strep throat by history alone. They first obtained data from 517 patients seen in an emergency room. Providers graded symptoms on a four-point scale (absent, mild, moderate, or severe). Initial analyses showed that prediction based on history should include three variables: fever, difficulty in swallowing, and cough. For ease of computation, these were consolidated into one score, "history" (= fever history + difficulty in swallowing - cough). This score was used to develop a model that predicts the probability of infection with group A beta-hemolytic streptococcus, and the model's performance was tested in two additional patient groups. The predictive accuracy of the "history" score was confirmed in all patient groups, despite differences in providers and disease prevalences. Primary care physicians may use this model to help them make decisions in situations such as telephone encounters without using additional data.


A new surgical procedure for treatment of complete rectal prolapse: preliminary report.
A new technique is reported for treatment of massive rectal prolapse, combining: mobilization of the rectum, colorectal fixation to the promontory and sacrum, "hammock-like" peritoneal autosuspension and obliteration of Douglas's pouch. The technique was successfully performed in six cases, with a follow-up ranging from one to six years; anal continence was satisfactory in four and fair in two.


Image guidance based on prostate position for prostate cancer proton therapy.
To determine the target coverage for proton therapy with and without image guidance and daily prebeam reorientation. A total of 207 prostate positions were analyzed for 9 prostate cancer patients treated using our low-risk prostate proton therapy protocol (University of Florida Proton Therapy Institute 001). The planning target volume was defined as the prostate plus a 5-mm axial and 8-mm superoinferior extension. The prostate was repositioned using 5- and 10-mm shifts (anteriorly, inferiorly, posteriorly, and superiorly) and for Points A-D using a combination of 10-mm multidimensional movements (anteriorly or inferiorly; posteriorly or superiorly; and left or right). The beams were then realigned using the new prostate position. The prescription dose was 78 Gray equivalent (GE) to 95% of the planning target volume. For small movements in the anterior, inferior, and posterior directions within the planning target volume (< or =5 mm), treatment realignment demonstrated small, but significant, improvements in the clinical target volume (CTV) coverage to the prescribed dose (78 GE). The anterior and posterior shifts also significantly increased the minimal CTV dose (Delta +1.59 GE). For prostate 10-mm movements in the inferior, posterior, and superior directions, the beam realignment produced larger and significant improvements for both the CTV V(78) (Delta +6.4%) and the CTV minimal dose (Delta +8.22 GE). For the compounded 10-mm multidimensional shifts, realignment significantly improved the CTV V(78) (Delta +11.8%) and CTV minimal dose (Delta +23.6 GE). After realignment, the CTV minimal dose was >76.6 GE (>98%) for all points (A-D). Proton beam realignment after target shift will enhance CTV coverage for different prostate positions.


Tumor and local lymphoid tissue interaction determines prognosis in high-grade serous ovarian cancer.
Tertiary lymphoid structure (TLS) is associated with prognosis in copy-number-driven tumors, including high-grade serous ovarian cancer (HGSOC), although the function of TLS and its interaction with copy-number alterations in HGSOC are not fully understood. In the current study, we confirm that TLS-high HGSOC patients show significantly better progression-free survival (PFS). We show that the presence of TLS in HGSOC tumors is associated with B cell maturation and cytotoxic tumor-specific T cell activation and proliferation. In addition, the copy-number loss of IL15 and CXCL10 may limit TLS formation in HGSOC; a list of genes that may dysregulate TLS function is also proposed. Last, a radiomics-based signature is developed to predict the presence of TLS, which independently predicts PFS in both HGSOC patients and immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients. Overall, we reveal that TLS coordinates intratumoral B cell and T cell response to HGSOC tumor, while the cancer genome evolves to counteract TLS formation and function.


Differentiated neuroblastoma cells are more susceptible to aluminium toxicity than developing cells.
The influence of aluminium (20-50 micrograms/ml) on neuronal function was examined using electrophysiological techniques and neuroblastoma clone cells which offer a convenient model of differentiating and fully active neurons. Two specific questions were addressed: 1) Can differentiated cells maintain their normal excitable function when exposed to aluminium? 2) Can proper development of electrophysiological properties be achieved in its presence? We report that aluminium caused premature onset of deterioration in fully differentiated cells. Within 4-6 days they depolarized from -29.3 +/- 0.9 mV to levels lower than -15 mV; compound polyphasic action potentials were gradually replaced by slow monophasic spikes before the final loss of excitable properties and structural deformations was noticed. Developing cells followed the normal pattern of differentiation in the presence of aluminium: within 7 days they extended neurites, hyperpolarized and exhibited polyphasic spikes. These results show that neuroblastoma cells are apparently less susceptible to aluminium's toxicity during the process of development than after differentiation. Possible mechanisms by which aluminium may exert its effects are discussed in view of these observations.


The basolateral limbic circuit and self-stimulation of the medial prefrontal cortex in the rat.
The effects of lesions of the basolateral nucleus of the amygdala (ABL) and the mediodorsal nucleus of the thalamus (MD) on self-stimulation (SS) of the medial prefrontal cortex (MPC) were investigated. Spontaneous motor activity (SMA) was measured as a control for possible non-specific effects of the lesions. Bilateral electrolytic lesions of ABL or MD produced a parallel transient decrease of SS and SMA. However, combined lesion of ABL and MD produced clearly different effects on both parameters. SMA decreased during the 1st day post-lesion and recovered to control levels by the 3rd day post-lesion. SS, on the contrary, was significantly decreased during the first five days post-lesion and after that time SS rate recovered to control levels. These results suggest the involvement of the basolateral limbic circuit in the neural substate underlying SS behavior of the MPC.


Differential effects of naloxone and diprenorphine on defensive behaviour in rats.
Two opiate antagonists, naloxone and diprenorphine, were used to examine the proposed involvement of endogenous opioid mechanisms in the modulation of shock-induced defensive behaviour patterns in rats. Naloxone was found to exert a biphasic influence on defensive fighting, with small dose (0.1 mg/kg) facilitation and large dose (10 mg/kg) inhibition. This compound also induced a dose-dependent inhibitory effect on shock-elicited threat whilst facilitated escape/avoidance behaviour was observed with the largest doses only. None of these influences could be attributed to alterations in electric shock thresholds. In contrast to the effects of naloxone, diprenorphine (0.1-10 mg/kg) was largely ineffective in modifying shock-induced defensive behaviour. These data suggest that endogenous opioid mechanisms may not be involved in the effects of naloxone on defensive fighting and cast some doubt upon the general hypothesis of the involvement of endorphins in the regulation of innate defence patterns.


"Nonalcoholic steatohepatitis" induced by massive doses of synthetic estrogen.
We have noticed that functional disorders of the liver characterized by hepatomegaly and an increase in serum gamma-glutamyl transpeptidase develop in patients with prostatic cancer who are placed under longterm therapy with massive doses of estrogen after castration. We performed laparoscopy in six cases of prostatic cancer with hepatomegaly so that we could study the morphology of the liver. Our findings were as follows. In five, the histological features of the liver biopsies were very similar to those seen in alcoholic hepatitis. In spite of this fact, two of the five had no history of alcohol consumption. Furthermore, in one other case, liver damage resembling alcoholic hepatitis developed during abstinence. The findings in these three cases suggested that long-term, massive doses of synthetic estrogen may lead to liver injury similar to alcoholic hepatitis in nonalcoholics. The ultrastructural findings of the liver cells were also suggestive of the adverse effect of treatment. All cases were negative for hepatitis B surface antigen. Recent reports have demonstrated some nonalcoholics with histological features of the liver indicative of alcoholic hepatitis. This particular condition was termed "nonalcoholic steatohepatitis" by Ludwig et al. It is quite likely that synthetic estrogen is also responsible for "nonalcoholic steatohepatitis" when it is used in massive doses.


Reversible conduction block in human ischemic neuropathy after ergotamine abuse.
Conduction block [a significant reduction in compound muscle action potential (CMAP) amplitude after proximal compared to distal stimulation] is often found in demyelinating neuropathies, including inflammatory neuropathies and degenerative neuropathies, such as "liability to pressure neuropathy." There is experimental evidence that a transient conduction block can occur in rats after ischemic lesions of peripheral nerves are induced either by ligation of arterial vessels supplying nerve trunks, or by injection of arachidonic acid into peripheral arterial vessels. Conduction block has also recently been described in cases with necrotizing vasculitis. To date, however, no example of a reversible conduction block has been reported in human ischemic neuropathy.


Enzyme histochemistry of glutamate dehydrogenase in ageing rat cerebellar cortex.
The influence of ageing on glutamate dehydrogenase activity was studied in the cerebellar cortex of 3-month-old (young), 12-month-old (adult) and 26-month-old (aged) male Sprague-Dawley rats by using an enzyme histochemical technique. In young rats the enzyme reactivity was observed in the neuropil of the molecular layer as well as in the perikarya of basket cells and of stellate cells; within the cytoplasm of Purkinje neurons and in synaptic glomeruli of the granular layer. Glutamate dehydrogenase activity was significantly increased in the cerebellar cortex of adult rats and decreased in old animals. The synaptic glomeruli of the granular layer were the structures of the cerebellar cortex more remarkably affected by age-related changes. The possibility that decreased glutamate catabolism occurring in the ageing cerebellar cortex may result in an excess of the amino acid and may contribute to the nerve cell loss occurring in the cerebellum of old rats is discussed.


Rational polytherapy with lacosamide in clinical practice: results of a Spanish cohort analysis RELACOVA.
There has been little long-term success with polytherapy for patients with refractory partial-onset epilepsy. The rational combination of antiepileptic drugs based on their mechanism of action may help improve treatment efficacy and tolerability. Lacosamide, a novel sodium channel blocker (SCB), was investigated in 158 patients with partial-onset epilepsy in the prospective, multicenter, observational, RELACOVA cohort study conducted in Spain. After 12 months' treatment with lacosamide, 47% of patients were responders (≥50% reduction in seizure frequency) and 24% were seizure free. Lacosamide was well tolerated; dizziness was the most frequent adverse event. Efficacy was better (responder rate, 65% vs 38%; seizure free rate, 35% vs 17%) and there was a lower adverse event rate (33% vs 58%) in patients receiving non-SCBs (n=49) versus those receiving SCBs (n=104) as concomitant therapy at baseline. Further investigation of lacosamide combination therapy is warranted.


Neuroendocrine appendiceal tumor and endometriosis of the appendix: a case report.
Endometriosis of the appendix is very uncommon, accounting for only about 1% of all cases of endometriosis. However, endometriosis is found in the appendix in approximately 8-13% of patients with deep infiltrating endometriosis and is particularly common in patients with severe forms of deep infiltrating endometriosis. Neuroendocrine tumors are the most common neoplasms of the appendix and may be misdiagnosed when there are multiple endometriosis lesions in the pelvis. We describe a case of a Caucasian patient with deep infiltrating endometriosis with rectal involvement, retrocervical lesions, and a right ovarian endometrioma with no suspected lesions in the appendix. She underwent laparoscopy and, after a systematic intraoperative evaluation, suspected involvement of the appendix was observed. The patient underwent ovarian cystectomy, excision of the pelvic endometriosis lesions, appendectomy, and anterior stapler discoid resection. Histopathological analysis of the appendix revealed endometriosis and a well-differentiated neuroendocrine carcinoma at the appendix tip. Our patient's case emphasizes the need to approach these lesions carefully and strengthens the indication for appendectomy when the appendix is affected in the setting of endometriosis. Despite the more likely diagnosis of appendiceal endometriosis, neuroendocrine tumors cannot be ruled out by imaging examinations, and both conditions can occur in the same patient.


Fenretinide cytotoxicity is independent of both constitutive and pharmacologically modulated glutathione levels in pediatric acute lymphoblastic leukemia cells cultured at hypoxia.
Fenretinide (4-HPR) cytotoxicity relative to glutathione levels in pediatric acute lymphoblastic leukemia cell lines cultured at bone marrow level hypoxia (5% O2) is evaluated. 4-HPR cytotoxicity correlated with reactive oxygen species generation (P < 0.001),but not with levels of intracellular glutathione, g-glutamylcysteine synthase, or glutathione peroxidase. Buthionine sulfoximine (BSO)reduced glutathione levels in 10 cell lines (P < 0.001), but 4-HPR þ BSO was markedly synergistic in only 1 of 10 lines. Pretreatment with N-acetylcysteine increased glutathione (P < 0.02)but did not alter 4-HPR cytotoxicity. Our data suggest that 4-HPR cytotoxicity is independent of glutathione under physiologic oxygen tension.


Neuromuscular blockade of slow twitch muscle fibres elevates muscle oxygen uptake and energy turnover during submaximal exercise in humans.
We tested the hypothesis that a greater activation of fast-twitch (FT) fibres during dynamic exercise leads to a higher muscle oxygen uptake (VO2 ) and energy turnover as well as a slower muscle on-kinetics. Subjects performed one-legged knee-extensor exercise for 10 min at an intensity of 30 W without (CON) and with (CUR) arterial injections of the non-depolarizing neuromuscular blocking agent cisatracurium. In CUR, creatine phosphate (CP) was unaltered in slow twitch (ST) fibres and decreased (P < 0.05) by 28% in FT fibres, whereas in CON, CP decreased (P < 0.05) by 33% and 23% in ST and FT fibres, respectively. From 127 s of exercise, muscle VO2 was higher (P < 0.05) in CUR compared to CON (425 +/- 25 (+/- S.E.M.) versus 332 +/- 30 ml min(-1)) and remained higher (P < 0.05) throughout exercise. Using monoexponential fitting, the time constant of the exercise-induced muscle VO2 response was slower (P < 0.05) in CUR than in CON (55 +/- 6 versus 33 +/- 5 s). During CUR and CON, muscle homogenate CP was lowered (P < 0.05) by 32 and 35%, respectively, and also muscle lactate production was similar in CUR and CON (37.8 +/- 4.1 versus 35.2 +/- 6.2 mmol). Estimated total muscle ATP turnover was 19% higher (P < 0.05) in CUR than in CON (1196 +/- 90 versus 1011 +/- 59 mmol) and true mechanical efficiency was lower (P < 0.05) in CUR than in CON (26.2 +/- 2.0 versus 30.9 +/- 1.5%). In conclusion, the present findings provide evidence that FT fibres are less efficient than ST fibres in vivo at a contraction frequency of 1 Hz, and that the muscle VO2 kinetics is slowed by FT fibre activation.


Estradiol reduced 5-HT reuptake by downregulating the gene expression of Plasma Membrane Monoamine Transporter (PMAT, Slc29a4) through estrogen receptor β and the MAPK/ERK signaling pathway.
Estrogen deficiency-induced female depression is closely related to 5-hydroxytriptamine (5-HT) deficiency. Estradiol (17β-estradiol, E2) regulates the monoamine transporters and acts as an antidepressant by affecting 5-HT clearance through estrogen receptors and related signaling pathways at the genomic level, although the specific mechanisms require further exploration. The brain expresses higher levels of plasma membrane monoamine transporter (PMAT, involved in 5-HT reuptake of the uptake 2 system) than other uptake transporters. In this study, we found that estrogen-deficient ovariectomized (OVX) rats had high PMAT mRNA and protein expression levels in the hippocampus and estradiol significantly reduced these levels. Furthermore, estradiol inhibited PMAT expression and reduced 5-HT reuptake in neurons and astrocytes and estradiol regulated the PMAT expression mainly by affecting estrogen receptor β (ERβ) at the genomic level in astrocytes. Further experiments showed that estradiol also regulated PMAT expression through the MAPK/ERK signaling pathway and not through the PI3K/AKT signaling pathway. In conclusion, estradiol inhibited 5-HT reuptake by regulating PMAT expression at the genomic level through ERβ and the MAPK/ERK signaling pathway, highlighting the importance of PMAT in the antidepressant effects of estradiol through 5-HT clearance reduction.


Determination of enzyme thermal parameters for rational enzyme engineering and environmental/evolutionary studies.
Of the two independent processes by which enzymes lose activity with increasing temperature, irreversible thermal inactivation and rapid reversible equilibration with an inactive form, the latter is only describable by the Equilibrium Model. Any investigation of the effect of temperature upon enzymes, a mandatory step in rational enzyme engineering and study of enzyme temperature adaptation, thus requires determining the enzymes' thermodynamic parameters as defined by the Equilibrium Model. The necessary data for this procedure can be collected by carrying out multiple isothermal enzyme assays at 3-5°C intervals over a suitable temperature range. If the collected data meet requirements for V max determination (i.e., if the enzyme kinetics are "ideal"), then the enzyme's Equilibrium Model parameters (ΔH eq, T eq, ΔG (‡) cat, and ΔG (‡) inact) can be determined using a freely available iterative model-fitting software package designed for this purpose.Although "ideal" enzyme reactions are required for determination of all four Equilibrium Model parameters, ΔH eq, T eq, and ΔG (‡) cat can be determined from initial (zero-time) rates for most nonideal enzyme reactions, with substrate saturation being the only requirement.


The association of serum Klotho concentrations with hyperlipidemia prevalence and lipid levels among US adults: a cross-sectional study.
Klotho has anti-oxidative and anti-inflammatory properties. However, little is known about whether high Klotho concentrations were associated with reduced hyperlipidemia risk and improved plasma lipid levels. Participants with complete data on serum Klotho and plasma lipid concentrations from the 2007-2016 National Health and Nutrition Examination Survey were included. Weighted regression models were fitted to explore the association of Klotho concentrations with hyperlipidemia risk and plasma lipid levels while restricted cubic spline models were applied to explore the dose-response relationship. Additionally, we assessed the mediating effects of C-reaction protein (CRP) on the foregoing association. Individuals in the fourth and fifth quintile of serum Klotho had an adjusted odds ratio (OR) of 0.77 (95%CI: 0.65, 0.93) and 0.67 (95%CI: 0.65, 0.93) for hyperlipidemia. Doubling of serum Klotho concentrations was associated with decreased hyperlipidemia risk (OR = 0.81; 95%CI: 0.68, 0.95) and triglyceride levels (13.25 mg/dL; 95%CI: 4.02, 22.47), with a monotonic dose-response relationship. Individuals in the fourth and fifth quintile of serum Klotho had a 0.07 (95%CI: 0.002, 0.13), 0.08 (95%CI: 0.02, 0.15) and 0.05 (95%CI: -0.03, 0.12) mg/dL decreased CRP levels, with a marginally significant trend (Ptrend = 0.05). Higher Klotho concentrations were associated with reduced hyperlipidemia risk and triglyceride levels. Klotho supplementation maybe a promising method to intervene and prevent hyperlipidemia, but the underlying mechanism should be further explored.


Tight glycemic control by insulin, started in the preischemic, but not postischemic, period, protects against ischemic spinal cord injury in rabbits.
It is not well established whether insulin protects against ischemic spinal cord injury. We examined the effects of a single dose of insulin that corrects mild hyperglycemia on the outcome after transient spinal cord ischemia in rabbits. We assigned rabbits to four groups (n = 8 in each); untreated control (C) group, preischemic insulin (Pre-I) group, preischemic insulin with glucose (GI) group (glucose concentrations were maintained at levels similar to the C group by the administration of glucose), and postischemic insulin (Post-I) group. Insulin (0.5 IU/kg) was administered 30 min before ischemia in the Pre-I and GI groups, and just after reperfusion in the Post-I group. Spinal cord ischemia was produced by occluding the abdominal aorta for 13 min. Neurologic and histopathologic evaluations were performed 7 days after ischemia. The mean blood glucose concentration before ischemia in the Pre-I group (118 mg/dL) was significantly lower than in the other three groups (158-180 mg/dL) and those of 30 min after reperfusion in the Pre-I (92 mg/dL) and Post-I (100 mg/dL) groups were significantly lower than in the C (148 mg/dL) and GI (140 mg/dL) groups. The motor function score and number of normal neurons in the anterior lumbar spinal cord in the Pre-I group were significantly greater than in the other three groups. These results suggest that a relatively small dose of preischemic insulin protects against ischemic spinal cord injury, and that the protective effects result from tight glycemic control before ischemia.


Processing, characterisation and biocompatibility of iron-phosphate glass fibres for tissue engineering.
Iron-phosphate glass fibres based on the CaO-Na2O-Fe2O3-P2O5 system have been processed and characterised via thermal, XRPD, dissolution rates, diameter and biocompatibility studies. The compositions investigated were fixed at 50mol% P2O5, and the CaO content was varied between 30, 35 and 40mol%. The Fe2O3 was added in low amounts from 1-5mol%, substituting it for the Na2O mol%. The number of Tc (crystallisation temperature) peaks detected from the thermal analysis traces only showed correlation with XRPD analysis, for five out of the 15 compositions investigated. It has been suggested that either the crystalline phases had very similar Tc temperatures or that the other phase(s) were present in very small quantities. There was a good match seen with number of Tm (melting temperature) peaks picked up from the DTA traces, with the number of phases identified from XRPD analysis. The main phases identified from XRPD were NaCa(PO3)3, CaP2O6 and NaFeP2O7. Using network connectivity (NC), predictions on Qn species present within the compositions investigated were made. The predicted species (metaphosphates) matched with phases identified from XRPD analysis. A decrease in dissolution rates for the bulk glass and glass fibres was seen with an increase in CaO mol%, along with an increase in Fe2O3 mol%. An increase in fibre dissolution rates was seen with a decrease in diameter size. The biocompatibility studies were conducted using a conditionally immortal muscle precursor cell line derived from the H-2Kb-tsA58 immortomouse. It was found that iron-phosphate glass fibres containing 4-5mol% Fe2O3 was sufficient for cell attachment and differentiation. It was seen that myotubes formed along the axis of the fibres (which was indicative of differentiation). The biocompatibility of these compositions was attributed to the enhanced chemical durability of the glass fibres.


HEXOKINASE1 forms a nuclear complex with the PRC2 subunits CURLY LEAF and SWINGER to regulate glucose signaling.
The glucose sensor HEXOKINASE1 (HXK1) integrates myriad external and internal signals to regulate gene expression and development in Arabidopsis thaliana. However, how HXK1 mediates glucose signaling in the nucleus remains unclear. Here, using immunoprecipitation-coupled mass spectrometry, we show that two catalytic subunits of Polycomb Repressive Complex 2, SWINGER (SWN) and CURLY LEAF (CLF), directly interact with catalytically active HXK1 and its inactive forms (HXK1G104D and HXK1S177A ) via their evolutionarily conserved SANT domains. HXK1, CLF, and SWN target common glucose-responsive genes to regulate glucose signaling, as revealed by RNA sequencing. The glucose-insensitive phenotypes of the Arabidopsis swn-1 and clf-50 mutants were similar to that of hxk1, and genetic analysis revealed that CLF, SWN, and HXK1 function in the same genetic pathway. Intriguingly, HXK1 is required for CLF- and SWN-mediated histone H3 lysine 27 (H3K27me3) deposition and glucose-mediated gene repression. Moreover, CLF and SWN affect the recruitment of HXK1 to its target chromatin. These findings support a model in which HXK1 and epigenetic modifiers form a nuclear complex to cooperatively mediate glucose signaling, thereby affecting the histone modification and expression of glucose-regulated genes in plants.


When technologies makes good people do bad things: another argument against the value-neutrality of technologies.
Although many scientists and engineers insist that technologies are value-neutral, philosophers of technology have long argued that they are wrong. In this paper, I introduce a new argument against the claim that technologies are value-neutral. This argument complements and extends, rather than replaces, existing arguments against value-neutrality. I formulate the Value-Neutrality Thesis, roughly, as the claim that a technological innovation can have bad effects, on balance, only if its users have "vicious" or condemnable preferences. After sketching a microeconomic model for explaining or predicting a technology's impact on individuals' behavior, I argue that a particular technological innovation can create or exacerbate collective action problems, even in the absence of vicious preferences. Technologies do this by increasing the net utility of refusing to cooperate. I also argue that a particular technological innovation can induce short-sighted behavior because of humans' tendency to discount future benefits too steeply. I suggest some possible extensions of my microeconomic model of technological impacts. These extensions would enable philosophers of technology to consider agents with mixed motives-i.e., agents who harbor some vicious preferences but also some aversion to acting on them-and to apply the model to questions about the professional responsibilities of engineers, scientists, and other inventors.


Ground beetles (Coleoptera: Carabidae) of rice field banks and restored habitats in an agricultural area of the Po Plain (Lombardy, Italy).
An entomological investigation was carried out in an agricultural area, mainly rice fields, of the Po river plain, located in the municipalities of Lacchiarella (MI) and Giussago (PV) (Lombardy, Italy). In 2009 and 2010, ground beetles (Coleoptera: Carabidae) were sampled along rice field banks and in restored habitats, by means of pitfall traps. The area appeared as species-rich, compared to other anthropogenic habitats in the Po river pain. Most of the collected Carabids were species with a wide distribution in the Paleartic region, eurytopic and common in European agroecosystems. The assemblages were dominated by small-medium, macropterous species, with summer larvae. No endemic species were found. Species with southern distribution, rarely found north of the Po river, were also sampled. Amaralittorea is recorded for the first time in Italy.


Assessment of vertebral fracture using densitometric morphometry.
Diagnosis of vertebral fracture is critical for management of osteoporosis, as existence of such deformities substantially increases the risk of subsequent fracture. Thus, accurate and precise techniques allowing detection of such deformities are essential to clinicians. So far, this detection has been performed by spinal lateral X-rays. More advanced techniques have recently been developed, based on dual energy X-ray absorptiometry (DXA). This review describes these different techniques and discusses the effectiveness of the DXA technique to assess vertebral deformities compared to X-ray. The use of DXA detection of vertebral fracture for clinical practice and clinical trials is discussed. Specifically, vertebral morphometry using DXA provides an excellent specificity, with moderate sensitivity. The major limitation of the DXA vertebral assessment is the poor quality of images of thoracic vertebrae. The clinical utility of vertebral morphometry using densitometry may help screening patients with vertebral fracture, but technological improvements are necessary to improve image quality.


Production of D-amino acid using whole cells of recombinant Escherichia coli with separately and coexpressed D-hydantoinase and N-carbamoylase.
We developed a fully enzymatic process employing D-hydantoinase and N-carbamoylase for the production of D-amino acid from 5'-monosubstituted hydantoin. For the comparison of the reaction systems using two sequential enzymes, D-hydantoinase of Bacillus stearothermophilus SD1 and N-carbamoyl-D-amino acid amidohydrolase (N-carbamoylase) of Agrobacterium tumefaciens NRRL B11291 were separately expressed in each host cell and coexpressed in the same host cell. A high level and constitutive expression of both enzymes in Escherichia coli in a soluble form was achieved using a promoter derived from B. stearothermophilus SD1. The expression levels of both enzymes ranged from 17% to 23% of the total soluble protein, depending on the expression system. In the case of employing separately expressed enzymes, the product yield of D-hydroxyphenylglycine from D,L-p-hydroxyphenylhydantoin and productivity were 71% and 2.57 mM/g-cell/h in 15 h, respectively. The accumulation of N-carbamoyl-D-hydroxyphenylglycine was significant over the reaction time. On the other hand, use of coexpressed enzymes resulted in 98% product yield of D-hydroxyphenylglycine in 15 h, minimizing the level of intermediates in the reaction mixture. The productivity of coexpressed whole cell reaction was estimated to be 6.47 mM/g-cell/h in 15 h. The coexpressed system was tested for an elevated concentration of D,L-p-hydroxyphenylhydantoin, and efficient production can be achieved.


Inhibition of tumor-promoting effects by poricoic acids G and H and other lanostane-type triterpenes and cytotoxic activity of poricoic acids A and G from Poria cocos.
The structures of two novel 3,4-seco-lanostane-type triterpenes isolated from the sclerotium of Poria cocos were established to be 16alpha-hydroxy-3,4-seco-lanosta-4(28),8,24-triene-3,21-dioic acid (1; poricoic acid G) and 16alpha-hydroxy-3,4-seco-24-methyllanosta-4(28),8,24(24(1))-triene-3,21-dioic acid (2; poricoic acid H) on the basis of spectroscopic methods. These two, and eight other known compounds isolated from the sclerotium, poricoic acid B (3), poricoic acid A (4), tumulosic acid (5), dehydrotumulosic acid (6), 3-epidehydrotumulosic acid (7), polyporenic acid C (8), 25-hydroxy-3-epidehydrotumulosic acid (9), and dehydroabietic acid methyl ester (10), showed potent inhibitory effects on Epstein-Barr virus early antigen (EBV-EA) activation induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Evaluation of the cytotoxicity of compounds 1 and 4 against human cancer cell lines revealed that 1 was significantly cytotoxic to leukemia HL-60 cells [GI(50) (concentration that yields 50% growth) value 39.3 nM], although it showed only moderate cytotoxicity to the other cells. Compound 4 exhibited moderate cytotoxicity to all of the cancer cell lines tested.


A Comparison of Volume of Tissue Removed and Biomechanical Analysis of Different Access Cavity Designs in 2-rooted Mandibular First Molars: A Multisample 3-dimensional Finite Element Analysis.
The aim of this study was to compare the biomechanical properties and the amount of coronal tissue removed among the different access cavities with a multisample 3-dimensional finite element analysis in the mandibular first molar. The correlation between the amount of tissue removed and the fracture resistance of the teeth was also analyzed. Micro-computed tomography data from 20 2-rooted mandibular first molars were included in this study as 3-dimensional modeling prototypes. Models of untreated molars and molars treated with the traditional access cavity (TradAC), the conservative access cavity (ConsAC), and the straight-line minimally invasive endodontic access cavities (SMIAC) were created. Each model was loaded in 3 ways to simulate the functional conditions of occlusion. The amount of tissue removed and the maximum stress in the cervical region were recorded and analyzed, and the correlation between them was also analyzed. The amount of coronal tissue and pericervical dentin (PCD) removed in SMIAC and ConsAC was less than that of TradAC. The mean maximum stress in the cervical region was significantly smaller in SMIAC and ConsAC than in TradAC. The amount of hard tissue and PCD loss was positively correlated with the maximum stress in the cervical region of the tooth. In mandibular first molars, it could be beneficial to improve the fracture resistance of the tooth after endodontic treatment by the minimally invasive access cavity to reduce the loss of coronal tooth tissue and PCD. The SMIAC may be an option balancing biomechanical properties and clinical convenience.


[Susceptibility of Bithynia inflata mollusks from discrete populations for Opisthorchis felineus infestation from different foci of opisthorchiasis].
Experiments were conducted on crossed infection of the specific intermediate host of Opisthorchis, molluscs of Bithynia inflata from different and remote populations, with eggs of O. felineus from different nidi of the disease. The strains of the agent were found to be heterogeneous that is expressed in different degree of compatibility with the intermediate host.


Exact nonstationary probabilities in the asymmetric exclusion process on a ring.
The complete solution of the master equation for a system of interacting particles of finite density is presented. By using a new form of the Bethe ansatz, the totally asymmetric exclusion process on a ring is solved for arbitrary initial conditions and time intervals.


A Prospective Study of Chin Bone Graft Harvesting for Unilateral Maxillary Alveolar Cleft During Mixed Dentition.
The chin is a common donor site for alveolar cleft bone grafting. The amount of bone available at this site can be limited, because conservative harvesting with mixed dentition must consider the incisive nerve, the unerupted mandibular canine, and the integrity of the inferior mandibular border. Patients with nonsyndromic unilateral alveolar cleft in the mixed dentition stage were selected for this study. The volume of bone obtained from the mandibular symphysis (symphysis menti), degree of alteration in lower lip sensation, anterior tooth vitality, remaining bone in the alveolar cleft, and bone defects at the donor site 1 year after surgery were evaluated. Eighteen patients were enrolled in this study. The mean volume of bone harvested from the symphysis was 2.1 mL (range, 1.6 to 2.3 mL). For all cases, the bone volume harvested from the symphysis was insufficient to fill the alveolar cleft defect, and allograft had to be added to completely fill the cleft. Allograft was admixed in the range of 0.5 to 1 mL with autogenous bone harvested from the mandible. Lower lip sensation and vitality of the anterior teeth of the mandible were within the normal range 1 year after surgery in all cases. Fourteen of 18 patients (77.8%) had normal bone height or bone height at least three fourths of the expected height in the grafted alveolar cleft after 1 year; only 10% of the defect remained in the mandible. The amount of bone yielded by conservative monocortical bone harvest from the mandibular symphysis during the mixed dentition stage for unilateral alveolar cleft bone grafting is not sufficient in volume and should be mixed with allograft. However, donor site morbidity is low with this approach.


Short-Term Circulating Tumor Cell Dynamics in Mouse Xenograft Models and Implications for Liquid Biopsy.
Circulating tumor cells (CTCs) are widely studied using liquid biopsy methods that analyze fractionally-small peripheral blood (PB) samples. However, little is known about natural fluctuations in CTC numbers that may occur over short timescales in vivo, and how these may affect detection and enumeration of rare CTCs from small blood samples. We recently developed an optical instrument called "diffuse in vivo flow cytometry" (DiFC) that uniquely allows continuous, non-invasive counting of rare, green fluorescent protein expressing CTCs in large blood vessels in mice. Here, we used DiFC to study short-term changes in CTC numbers in multiple myeloma and Lewis lung carcinoma xenograft models. We analyzed CTC detections in over 100 h of DiFC data, and considered intervals corresponding to approximately 1%, 5%, 10%, and 20% of the PB volume. In addition, we analyzed changes in CTC numbers over 24 h (diurnal) periods. For rare CTCs (fewer than 1 CTC per ml of blood), the use of short DiFC intervals (corresponding to small PB samples) frequently resulted in no detections. For more abundant CTCs, CTC numbers frequently varied by an order of magnitude or more over the time-scales considered. This variance in CTC detections far exceeded that expected by Poisson statistics or by instrument variability. Rather, the data were consistent with significant changes in mean numbers of CTCs on the timescales of minutes and hours. The observed temporal changes can be explained by known properties of CTCs, namely, the continuous shedding of CTCs from tumors and the short half-life of CTCs in blood. It follows that the number of cells in a blood sample are strongly impacted by the timing of the draw. The issue is likely to be compounded for multicellular CTC clusters or specific CTC subtypes, which are even more rare than single CTCs. However, we show that enumeration can in principle be improved by averaging multiple samples, analysis of larger volumes, or development of methods for enumeration of CTCs directly in vivo.


Aberrant CD200/CD200R1 expression contributes to painful synovium hyperplasia in a patient with primary hypertrophic osteoarthropathy.
We present a case of hypertrophic osteoarthropathy (PHO), with painful synovium hyperplasia involving both knees that was refractory to corticosteroid treatment. His rheumatoid factor and anti-CCP antibody was negative, and his serum ESR and CRP level was within normal range. Histological examination of the synovium obtained from his right knee revealed endothelial hyperplasia and vascular thickening without inflammation that was in association with aberrant expression of CD200/CD200R1, which highlighted the importance of aberrant CD200/CD200R1 in the regulation of the endothelial activation that contributed to the development of synovium hyperplasia in this PHO patient.


Are the metabolic alterations associated with critical illness related to the hormonal environment?
The hormonal environment has a direct effect on mediating the catabolic response to critical illness. Administering hormones to normal volunteers simulated many, but not all, of the alterations observed in patients following injury or severe injection. The administration of an inflammatory agent, etiocholanolone, initiated a variety of acute phase responses and interacted with hormonally mediated changes to elicit a variety of responses commonly observed in critically ill patients. Further studies have manipulated the hormone environment in critically ill patients by administering anabolic factors or blocking catabolic hormone elaboration. These investigations have demonstrated a marked attenuation of many of the catabolic responses to critical illness. Such manipulations give some insight into the potential for patient care in the future, where catabolic responses could be successfully blunted, and anabolic hormones administered so as to prevent the marked wasting and tissue disruption that heretofore have commonly been associated with catabolic disorders.


Clinical and prognostic implications of CD47 and PD-L1 expression in surgically resected small-cell lung cancer.
Pharmacological inhibition of the immune-checkpoint molecule CD47 has shown promising results in preclinical small-cell lung cancer (SCLC) models, whereas anti-programmed death-ligand 1 (PD-L1) inhibitors have been recently implemented in the standard of care of advanced-stage SCLC patients. Nevertheless, the expression pattern, clinical relevance and prognostic implication of both CD47 and PD-L1 are rather controversial in surgically treated SCLC patients. In total, 104 Caucasian SCLC patients from two Central European thoracic centers were included in this study. CD47 and PD-L1 expression as well as the expression of the four major SCLC molecular subtype markers (ASCL1, NEUROD1, YAP1 and POU2F3) were measured by immunohistochemistry. Expression levels were independently evaluated and statistically correlated with clinicopathological data and survival. Positive CD47 and PD-L1 expressions were seen in 84.6% and 9.6% of the samples, respectively. Meanwhile, the tumor-associated stroma was positive for PD-L1 in 59.6% of the cases. Stromal PD-L1 expression correlated with longer overall survival (OS) (versus PD-L1-negative stroma; median OS was 42 versus 14 months, respectively, P = 0.003) and was confirmed as an independent predictor of favorable outcome upon multivariate analysis (hazard ratio 0.530, 95% confidence interval 0.298-0.943, P = 0.031). Notably, neither CD47 nor PD-L1 presence was related to a distinct molecular SCLC subtype. CD47 shows a remarkably high expression while tumoral PD-L1 expression is generally low in surgically treated SCLC. Importantly, stromal PD-L1 expression may indicate a favorable clinical outcome and serve as a novel prognostic factor in these patients. Additional studies are warranted to further investigate the clinical impact of CD47 and PD-L1 expression in SCLC.


Astroglial trophic support and neuronal cell death: influence of cellular energy level on type of cell death induced by mitochondrial toxin in cultured rat cortical neurons.
Previous in vivo and in vitro analyses have shown that both necrosis and apoptosis are involved in neuronal cell death induced by energy impairment caused by mitochondrial dysfunction. However, little is known about the key factors that determine whether the cells undergo necrosis or apoptosis. In the present study, we analyzed neuronal cell death induced by 3-nitropropionic acid (3-NP), an irreversible inhibitor of mitochondrial complex II, in a primary culture system of rat cortical neurons. The neurons were maintained for a week in coculture with astroglial cells, and then they were treated with 3-NP in the presence or absence of astroglial cells. As judged from morphological (Hoechst 33258 staining) and biochemical (DNA fragmentation and caspase activation) analyses, the cortical neurons appeared to die through an apoptotic process after 3-NP treatment in the presence of astroglial cells. However, caspase inhibitors did not suppress the 3-NP-induced cell death, suggesting the involvement of a caspase-independent pathway of 3-NP-induced neuronal cell death in the presence of astroglial cells. On the other hand, 3-NP induced necrotic cell death within 1 day in the absence of astroglial cells, following a rapid decrease in intracellular ATP level. These changes were attenuated by the presence of astroglial cells or the addition of astroglial conditioned medium. These results suggest that astroglial trophic support influences the alteration of the intracellular energy state in 3-NP-treated neurons and consequently determines the type of neuronal cell death, apoptosis or necrosis.