Trans-fat supplementation over two generations of rats exacerbates behavioral and biochemical damages in a model of mania: Co-treatment with lithium.
We investigated whether trans-fat supplemented over two generations of rats could alter neuronal membranes and influence mania-like behaviors, as well as the effects of lithium (Li). Two generations of female rats were supplemented with soybean oil (SO-C, rich in n-6 fatty acids - FA) or hydrogenated vegetable fat (HVF, rich in trans-fatty acids - TFA). Male rats born from the 1st and 2nd generations were maintained in the same supplementation until adulthood, when they were exposed to an amphetamine (AMPH)-induced model of mania and co-treated with Li or not. AMPH increased locomotion of both generations and this influence was higher in the HVF than in the SO-C group. Conversely, AMPH increased long-term memory in SO-C group of the 2nd generation. HVF supplementation allowed hippocampal TFA incorporation in rats of both generations (0.1 and 0.2%, respectively). Oxidative parameters indicated higher levels of protein carbonyl (PC) in the HVF group with no changes in catalase (CAT) activity in the 1st generation. In the 2nd generation, AMPH increased PC levels of both experimental groups, whereas CAT activity was lower per se in the HVF group only. The co-treatment with Li leveled out all behavioral parameters, PC levels and CAT activity indicating a significant neuroprotective role. These findings suggest that chronic HVF consumption allows a rising incorporation of TFA in the brain, which may be reflected on the neuropsychiatric conditions related to mania, whereas the effects of Li are not modified in the course of this harmful dietary habit.


Insulin therapy induces antiatherogenic changes of serum lipoproteins in noninsulin-dependent diabetes.
To study the effects of rigorous insulin therapy on serum lipoproteins in patients with noninsulin-dependent diabetes not controlled with oral agents only, we measured serum lipoproteins, apoproteins, lipolytic enzymes, and glucose disposal using an insulin clamp technique before and after 4 weeks of insulin therapy. Lipoproteins were isolated by ultracentrifugation and high density lipoprotein (HDL) subfractions, by rate-zonal density gradient ultracentrifugation. The group included 11 women and eight men (age 58 +/- 1 years and RBW 125 +/- 4%). Body weight, glycosylated hemoglobin, mean diurnal glucose, plasma free insulin, and glucose uptake (M-value) were 75 vs. 76 kg; 11.9 vs. 8.9%; 234 vs. 124 mg/dl; 12 vs. 27 microU/ml; and 5.0 +/- 0.4 vs. 7.1 +/- 0.6 mg/kg/min before and after insulin therapy, respectively. After insulin therapy there was a decrease of very low density lipoprotein (VLDL) triglyceride (-60%, p less than 0.001) but an increase of HDL2 cholesterol (+21%, p less than 0.001); HDL2 phospholipids (+38%, p less than 0.001); HDL2 proteins (+23%, p less than 0.01); and HDL2 mass (127 +/- 11 vs. 158 +/- 12 mg/dl, p less than 0.001). There was a decrease of HDL3 cholesterol (-13%, p less than 0.05); HDL3 phospholipids (-16%, p less than 0.05); HDL3 proteins (-18%, p less than 0.001); and HDL3 mass (179 +/- 6 vs. 146 +/- 6, p less than 0.01). Zonal profiles showed a redistribution of particles from HDL3 to HDL2. Serum apo A-I increased (p less than 0.05), apo A-II remained constant, but apo B decreased (-29%, p less than 0.001). The most marked change during insulin therapy was a 2.3-fold increase in adipose tissue lipoprotein lipase (LPL) activity (p less than 0.001). The changes of VLDL and HDL subfractions were not explained by respective changes of the blood glucose, free insulin, or M-value. The data indicate that intensive insulin therapy induces antiatherogenic changes in serum lipids and lipoproteins and suggest that the induction of LPL by insulin is the major factor responsible for redistribution of HDL particles from HDL3 to HDL2.


MiRNAs that target amyloid precursor protein processing machinery in extracellular vesicles and particles derived from oral squamous cells carcinoma.
Considering that microRNAs (miRNAs), extracellular vesicles and particles (EVPs) and the amyloid precursor protein (APP) processing have been shown to be altered in oral squamous cells carcinoma (OSCC), it is possible that miRNAs that target APP processing pathways in EVPs are impacted in tumor cells. Our aim was to evaluate miRNAs that target APP itself or disintegrin and metalloproteinase domain 10 (ADAM10), which generate a trophic compound, sAPPα, in EVPs derived from OSCC cell lines, an aggressive and non-invasive, compared to normal keratinocytes. We used two OSCC cell lines, an aggressive human oral squamous cell carcinoma cell line (SCC09) and a less aggressive cell line (CAL27) compared with a keratinocyte lineage (HaCaT). Cells were maintained in cell media, from which we isolated EVPs. EVPs were evaluated regarding their size and concentration using Nanotracking Analysis. We measured the levels of miRNAs which had as potential downstream target APP or ADAM10, specifically miR-20a-5p, miR-103a-3p, miR-424-5p, miR-92b-3p, miR-31-5p, and miR-93-5. There were no differences on size distributions and concentration of isolated EVPs. OSCC cell lines-derived EVPs miR-20a-5p, miR-92b-3p, and miR-93-5p were upregulated in comparison to HaCaT-derived EVPs; while miR-31-5p was reduced in EVPs obtained from CAL27 cells. Our results indicate changes in miRNAs that target APP machinery processing in EVPs derived from OSCC cell lines of different aggressiveness, which may be involved with abnormal miRNA expression in OSCC tissue and/or releasing tumor suppressor miRNA.


Intraradicular bacteria and fungi in root-filled, asymptomatic human teeth with therapy-resistant periapical lesions: a long-term light and electron microscopic follow-up study.
Light and electron microscopy were used to analyze nine therapy-resistant and asymptomatic human periapical lesions, which were removed as block biopsies during surgical treatment of the affected teeth. The cases that required surgery represented about 10% of all of the cases which received endodontic treatment and root fillings during the period 1977 to 1984. These cases revealed periapical lesions when they were examined 4 to 10 yr after treatment. The biopsies were processed for correlated light and electron microscopy. Six of the nine biopsies revealed the presence of microorganisms in the apical root canal. Four contained one or more species of bacteria and two revealed yeasts. Of the four cases in which bacteria were found, only in one biopsy could they be found by light microscope. In the other three specimens, the bacterial presence could be confirmed only after repeated electron microscopic examination of the apical root canal by serial step-cutting technique. Among the three cases in which no microorganisms could be encountered, one showed histopathological features of a foreign body giant cell granuloma. These findings suggest that in the majority of root-filled human teeth with therapy-resistant periapical lesions, microorganisms may persist and may play a significant role in endodontic treatment failures. In certain instances such lesions may also be sustained by foreign body giant cell type of tissue responses at the periapex of root-filled teeth.


RNA degradation differentially affects quantitative mRNA measurements of endogenous reference genes in human placenta.
It has been highlighted that RNA quality and appropriate reference gene selection is crucial for the interpretation of RT-qPCR results in human placental samples. In this context we investigated the effect of RNA degradation on the mRNA abundance of seven frequently used reference genes in 119 human placental samples. Combining RNA integrity measurements, RT-qPCR analysis and mathematical modeling we found major differences regarding the effect of RNA degradation on the measured expression levels between the different reference genes. Furthermore, we demonstrated that a modified RNA extraction method significantly improved RNA quality and consequently increased transcript levels of all reference genes.


In vitro metabolism of triclosan and chemoprevention against its cytotoxicity.
Triclosan (TCS), a broad-spectrum antibacterial chemical, has been extensively used in personal daily care items, household commodities, and clinical medications; therefore, humans are at risk of being exposed to TCS in their daily lives. This chemical also accumulated in food chains, and potential risks were associated with its metabolism in vivo. The aim of this study was to investigate the difference in metabolic profile of TCS by hepatic P450 enzymes and extrahepatic P450s, and also identify chemical structures of its metabolites. The results showed that RLM mediated the hydroxylation and cleavage of the ether moiety of TCS, resulting in phenolic metabolites that are more polar than the parent compound, including 4-chlorocatechol, 2,4-dichlorophenol and monohydroxylated triclosan. The major metabolite of CYP1A1 and CYP1B1 mediated TCS metabolism is 4-chlorochol. We also performed molecular docking experiments to investigate possible binding modes of TCS in the active sites of human CYP1B1, CYP1A1, and CYP3A4. In addition to in vitro experiments, we further examined the cytotoxic effects of TCS on HepG2 cells expressing hepatic P450 and MCF-7/1B1 cells expressing CYP1B1. It exhibited significant cytotoxicity on HepG2, MCF-10A and MCF-7/1B1 cells, with IC50 values of 70 ± 10 μM, 20 ± 10 μM and 60 ± 20 μM, respectively. The co-incubation of TCS with glutathione (GSH) as a chemopreventive agent could reduce the cytotoxicity of TCS in vitro. The chemopreventive effects of GSH might be ascribed to the promotion of TCS efflux mediated by membrane transporter MRP1 and also its antioxidant property, which partially neutralized the oxidative stress of TCS on mammalian cells. This study contributed to our understanding of the relationship between the P450 metabolism and the toxicity of TCS. It also had implications for the use of specific chemopreventive agents against the toxicity of TCS.


Impact of diabetes education and self-management on the quality of care for people with type 1 diabetes mellitus in the Middle East (the International Diabetes Mellitus Practices Study, IDMPS).
Self-management (self-monitoring of blood glucose, plus self-adjustment of insulin dose) is important in diabetes care, but its complexity presents a barrier to wider implementation, which hinders attainment and maintenance of glycemic targets. More evidence on self-management is needed to increase its implementation and improve metabolic outcomes. Data from 1316 participants with type 1 diabetes mellitus who were enrolled from Middle East countries into the International Diabetes Management Practices Study (IDMPS), a multinational observational survey, were analyzed to assess the impact of education on disease management and outcomes. A majority (78%) of participants failed to achieve glycemic target (HbA1c < 7.0% [<53 mmol/mol]). Participants who had received diabetes education (59%) were more likely to practice self-management than those who had not (odds ratio [OR]: 2.51; 95% confidence interval [CI]: 1.7-3.69; p < 0.001), and those who practiced self-management were more likely to attain target HbA1c than those who did not (OR: 1.49; 95% CI: 1.06-2.09; p = 0.023). These relationships between diabetes education, self-management and glycemic control suggest that diabetes education provides knowledge and skills to optimize self-management, favoring HbA1c target attainment. Middle East health authorities should search for ways to facilitate access to diabetes education to optimize treatment outcomes.


Effects of anti-depressant treatments on FADD and p-FADD protein in rat brain cortex: enhanced anti-apoptotic p-FADD/FADD ratio after chronic desipramine and fluoxetine administration.
Fas-associated death domain (FADD) is an adaptor of death receptors that can also induce anti-apoptotic actions through its phosphorylated form (p-FADD). Activation of monoamine receptors, indirect targets of classic anti-depressant drugs (ADs), reduced FADD and increased p-FADD and p-FADD/FADD ratio in brain. To ascertain whether ADs, which indirectly regulate monoamine receptors, modulate FADD protein forms to promote anti-apoptotic actions. The effects of selected norepinephrine transporter (NET), serotonin transporter (SERT), monoamine oxidase (MAO) inhibitors, atypical ADs, and electroconvulsive shock (ECS) or behavioral procedures (forced swim test, FST) on FADD forms and pro-survival FADD-like interleukin-1β-converting enzyme-inhibitory protein (FLIP-L) and phosphoprotein enriched in astrocytes of 15 kDa (p-PEA-15) contents were assessed in rat brain cortex by western blot analysis. Acute NET (e.g., nisoxetine) but not SERT (e.g., fluoxetine) inhibitors decreased cortical FADD (up to 37 %) and increased p-FADD/FADD ratio (up to 1.9-fold). Nisoxetine effects were prevented by α2-antagonist RX-821002, suggesting the involvement of presynaptic α2-autoreceptors. Immobility time in the FST correlated with increases of pro-apoptotic FADD and decreases of anti-apoptotic p-FADD. The MAO-A/B inhibitor phenelzine decreased FADD (up to 33 %) and increased p-FADD (up to 65 %) and p-FADD/FADD (up to 2.4-fold). Other MAO inhibitors (clorgyline, Ro 41-1049, rasagiline), atypical ADs (ketamine and mirtazapine), or ECS did not modulate cortical FADD. Chronic (14 days) desipramine and fluoxetine, but not phenelzine, increased p-FADD (up to 59 %), p-FADD/FADD ratio (up to 1.8-fold), and pro-survival p-PEA-15 (up to 46 %) in rat brain cortex. Multifunctional FADD protein, through an increased p-FADD/FADD ratio, could participate in the mechanisms of anti-apoptotic actions induced by ADs.


Influence of route of administration on the plasma concentrations of ivermectin in reindeer.
The concentration of ivermectin in the plasma of reindeer was measured after it was administered either topically as a pour-on preparation at 500 micrograms kg-1 bodyweight at different seasons to animals of different ages, or after subcutaneous and oral doses of 200 micrograms kg-1 bodyweight. The plasma concentrations of ivermectin were highest and least variable after it was administered subcutaneously.


The effect on relapse rate and psychiatric symptomatology: Switching a combination of first- and second-generation antipsychotic polypharmacy to antipsychotic monotherapy in long-term inpatients with schizophrenia and related disorders. A pragmatic randomized open-label trial (SwAP trial).
There is little evidence to support the use of antipsychotic polypharmacy, and there are concerns about safety and side effects. Nonetheless, it is commonly used in the treatment of long-term inpatients with schizophrenia. This study investigated the effects of switching from a combination of first- and second-generation antipsychotics (FGA and SGA) to monotherapy (FGA or SGA) on relapse rates and psychiatric symptomatology. Institutionalized patients with chronic psychotic disorders using a combination of SGA and FGA (n = 136) participated in a randomized open-label trial. The SWITCH group discontinued either FGA or SGA, the STAY group continued combination treatment. Relapse and psychotic symptoms were measured at baseline and during follow-up at 3, 6, and 9 months. Psychiatric symptomatology was measured using the Brief Psychiatric Rating Scale (BPRS). Relapse was defined as (i) an increase in BPRS score of at least 2 points on any item, or (ii) an increase of at least 4 points in total BPRS score and an adjustment of antipsychotics. A logistic regression model, corrected for sex, showed that the probability of relapse was significantly lower in the SWITCH group: 0.29 (95% CI 0.13-0.62). The protective effect of switching to monotherapy was attributable to patients continuing clozapine as monotherapy. For patients who did not experience a relapse nor dropped out, BPRS total scores decreased significantly more in the SWITCH group (p = 0.0001). Switching from a combination of FGA and SGA to monotherapy in long-term inpatients does not increase the relapse rate and may even reduce it.


Identification of the novel HLA-A*30:162 allele in a Brazilian candidate donor for bone marrow donation.
Identification of the novel HLA-A*30:162 allele that differs from HLA-A*30:02:01:01 in exon 3.


Antilogic, a new supervised machine learning software for the automatic interpretation of antibiotic susceptibility testing in clinical microbiology: proof-of-concept on three frequently isolated bacterial species.
Antibiotic susceptibility testing (AST) is necessary in order to adjust empirical antibiotic treatment, but the interpretation of results requires experience and knowledge. We have developed a machine learning software that is capable of reading AST images without any human intervention and that automatically interprets the AST, based on a database of antibiograms that have been clinically validated with European Committee on Antimicrobial Susceptibility Testing rules. We built a database of antibiograms that were labelled by senior microbiologists for three species: Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus. We then developed Antilogic, a Python software based on an original image segmentation module and supervised learning models that we trained against the database. Finally, we blind tested Antilogic against a validation set of 5100 photos of antibiograms. We trained Antilogic against a database of 18072 pictures of antibiograms. Overall agreement against the validation set reached 97% (16 855/17 281) regarding phenotypes. The severity rate of errors was also evaluated: 1.66% (287/17 281) were major errors and 0.80% (136/17 281) were very major errors. After implementation of uncertainty quantifications, the rate of errors decreased to 0.80% (114/13 451) and 0.42% (51/13 451) for major and very major errors respectively. Antilogic is the first machine learning software that has been developed for AST interpretation. It is based on a novel approach that differs from the typical diameter measurement and expert system approach. Antilogic is a proof of concept that artificial intelligence can contribute to faster and easier diagnostic methods in the field of clinical microbiology.


Deletion of Brg1 causes abnormal hair cell planer polarity, hair cell anchorage, and scar formation in mouse cochlea.
Hair cells (HCs) are mechanosensors that play crucial roles in perceiving sound, acceleration, and fluid motion. The precise architecture of the auditory epithelium and its repair after HC loss is indispensable to the function of organ of Corti (OC). In this study, we showed that Brg1 was highly expressed in auditory HCs. Specific deletion of Brg1 in postnatal HCs resulted in rapid HC degeneration and profound deafness in mice. Further experiments showed that cell-intrinsic polarity of HCs was abolished, docking of outer hair cells (OHCs) by Deiter's cells (DCs) failed, and scar formation in the reticular lamina was deficient. We demonstrated that Brg1 ablation disrupted the Gαi/Insc/LGN and aPKC asymmetric distributions, without overt effects on the core planer cell polarity (PCP) pathway. We also demonstrated that Brg1-deficient HCs underwent apoptosis, and that leakage in the reticular lamina caused by deficient scar formation shifted the mode of OHC death from apoptosis to necrosis. Together, these data demonstrated a requirement for Brg1 activity in HC development and suggested a role for Brg1 in the proper cellular structure formation of HCs.


Study of fibrous plaques occurring in the coronary arteries of children.
The pathology of the coronary arteries of children, in relation to atherosclerotic involvement, appeared as a pathology of the main emergence areas and branching points of the left coronary artery and particularly of the anterior descending artery. The first atherosclerotic lesions occurred as non-raised fibrous plaques in 2% of children 6--10 years old and in 4% of children and juveniles 11--15 years old. In the latter age group fatty streaks and gelatinous plaques were also seen in 6% of the subjects; in their appearance they lag behind fibrous plaques by 5--8 years. Indirect evidence was obtained that some branch pads or cushions might be converted into fibrous plaques. The transitional aspects included edema, histolysis (elastolysis, collagenolysis, ground-substance depletion and degenerative cell changes), followed by reorganization and homogeneization of the pre-existing heterogeneous microarchitecture; in a final stage the prevalent processes seemed to be the nodular proliferation of smooth muscle cells and the abundant neoformation of collagen fibers. In essence the results show that in atherosclerosis the coronary arteries are involved in a different sequence and histogenetic pattern than the aorta.


Bromine in human tissue.
The normal levels of bromine in human tissue are given and their use in the interpretation of levels found when over-exposure is a possibility is described. Bromine is "normally" distributed in human tissue as are essential trace elements. This allows a bromine (microgram) to chlorine (mg) ratio to be established (3.2) above which bromine exposure must be considered. The bromine concentrations in sections of hair can be used to establish the time of administration even when small amounts are ingested, but owing to the long half-life (about 15 days) found in human tissue interpretation after multiple doses may be difficult.


Impact of albumin on drug delivery--new applications on the horizon.
Over the past decades, albumin has emerged as a versatile carrier for therapeutic and diagnostic agents, primarily for diagnosing and treating diabetes, cancer, rheumatoid arthritis and infectious diseases. Market approved products include fatty acid derivatives of human insulin or the glucagon-like-1 peptide (Levemir(®) and Victoza(®)) for treating diabetes, the taxol albumin nanoparticle Abraxane(®) for treating metastatic breast cancer which is also under clinical investigation in further tumor indications, and (99m)Tc-aggregated albumin (Nanocoll(®) and Albures(®)) for diagnosing cancer and rheumatoid arthritis as well as for lymphoscintigraphy. In addition, an increasing number of albumin-based or albumin-binding drugs are in clinical trials such as antibody fusion proteins (MM-111) for treating HER2/neu positive breast cancer (phase I), a camelid albumin-binding nanobody anti-HSA-anti-TNF-α (ATN-103) in phase II studies for treating rheumatoid arthritis, an antidiabetic Exendin-4 analog bound to recombinant human albumin (phase I/II), a fluorescein-labeled albumin conjugate (AFL)-human serum albumin for visualizing the malignant borders of brain tumors for improved surgical resection, and finally an albumin-binding prodrug of doxorubicin (INNO-206) entering phase II studies against sarcoma and gastric cancer. In the preclinical setting, novel approaches include attaching peptides with high-affinity for albumin to antibody fragments, the exploitation of albumin-binding gadolinium contrast agents for magnetic resonance imaging, and physical or covalent attachment of antiviral, antibacterial, and anticancer drugs to albumin that are permanently or transiently attached to human serum albumin (HSA) or act as albumin-binding prodrugs. This review gives an overview of the expanding field of preclinical and clinical drug applications and developments that use albumin as a protein carrier to improve the pharmacokinetic profile of the drug or to target the drug to the pathogenic site addressing diseases with unmet medical needs.


Migration of BHT and Irganox 1010 from low-density polyethylene (LDPE) to foods and food-simulating liquids.
The most widely used food-wrapping material is low-density polyethylene (LDPE). Food-wrap grades contain antioxidants to minimize degradation during processing and, in the final films, such additives are normally present at levels of several hundred ppm. During use, the antioxidants may migrate into food stored in LDPE wraps. Two typical antioxidants, BHT and Irganox 1010, were radiolabelled to allow accurate analytical measurement of the extent of their migration into foods and food-simulating liquids (FSL). The results show that BHT, a much smaller and more volatile molecule than Irganox 1010, migrates more rapidly into foods, but the differences are less for FSL. In most instances, migration appears to be controlled by diffusion of the antioxidant in the polymer, and the quantity lost can be correlated in a linear fashion with the square root of time. With aqueous FSL, and, presumably aqueous-type foods, however, anomalies result; the migration is often erratic, but is more closely related to time than to the square root of time. A tentative model developed to explain these facts assumes that the antioxidants decompose in aqueous media and the net migration rate is controlled largely by the rate of chemical decomposition. It is also shown that dry foods can be surprisingly effective sinks for antioxidants under typical storage conditions.


Inhibition of crystallin expression and induction of apoptosis by lens-specific E1A expression in transgenic mice.
Previous studies have shown that the adenovirus E1A oncoprotein can bind to and inactivate the retinoblastoma tumor suppressor protein (pRb) and the transcriptional coactivators CBP/p300. In this study, wild-type E1A12S or two deletion mutants (delN, which binds pRb but not CBP/p300; delCR2, which binds to CBP/p300 but not pRb) were linked to the lens-specific alphaA-crystallin promoter, and used to generate transgenic mice. Lens fiber cells expressing E1A12S or delCR2, both of which bind to CBP/p300, failed to upregulate beta-crystallin and gamma-crystallin expression. In contrast, lens fiber cells expressing delN showed significant expression of beta- and gamma-crystallins. Lens fiber cells expressing delN showed cell cycle entry, marked apoptosis, and evidence for p53 activation, while cells expressing either 12S or delCR2 showed limited apoptosis and no evidence for upregulation of the p53-inducible gene p21. Our results suggest that the transcriptional coactivators CBP and/or p300 are required for the dramatic increases in crystallin expression that accompany terminal differentiation in the lens, and also for activation of p53 in response to inactivation of pRb in the lens.


Profiling of neuropeptides released at the stomatogastric ganglion of the crab, Cancer borealis with mass spectrometry.
Studies of release under physiological conditions provide more direct data about the identity of neuromodulatory signaling molecules than studies of tissue localization that cannot distinguish between processing precursors and biologically active neuropeptides. We have identified neuropeptides released by electrical stimulation of nerves that contain the axons of the modulatory projection neurons to the stomatogastric ganglion of the crab, Cancer borealis. Preparations were bathed in saline containing a cocktail of peptidase inhibitors to minimize peptide degradation. Both electrical stimulation of projection nerves and depolarization with high K+ saline were used to evoke release. Releasates were desalted and then identified by mass using MALDI-TOF (matrix-assisted laser desorption/ionization-time-of-flight) mass spectrometry. Both previously known and novel peptides were detected. Subsequent to electrical stimulation proctolin, Cancer borealis tachykinin-related peptide (CabTRP), FVNSRYa, carcinustatin-8, allatostatin-3 (AST-3), red pigment concentrating hormone, NRNFLRFa, AST-5, SGFYANRYa, TNRNFLRFa, AST-9, orcomyotropin-related peptide, corazonin, Ala13-orcokinin, and Ser9-Val13-orcokinin were detected. Some of these were also detected after high K+ depolarization. Release was calcium dependent. In summary, we have shown release of the neuropeptides thought to play an important neuromodulatory role in the stomatogastric ganglion, as well as numerous other candidate neuromodulators that remain to be identified.


Association of Endothelin-1 rs5370 G>T gene polymorphism with the risk of nephrotic syndrome in children.
Primary nephrotic syndrome (NS) is a common kidney disease in children. Objectives: The present study was aimed to investigate whether rs5370 G>T (lys198Asn) genetic variant of endothelin-1 (ET-1) is involved in the susceptibility to NS. This case-control study was performed on 138 patients with NS and 150 healthy children. Genomic DNA was extracted from whole blood using salting out method. Polymorphism of the ET-1 rs5370 G>T (lys198Asn) polymorphism detected by T-ARMS-PCR as well as PCR-RFLP method. The results showed that the genotype and allelic frequencies of the ET-1 rs5370 G>T variant were not significantly different between cases and controls. Furthermore, subgroup analysis showed that rs5370 G>T variant was not associated with gender of patients. In NS patients the genotype was not associated with cholesterol, triglyceride, total protein and albumin levels. In conclusion, our findings indicate that ET-1 rs5370 G>T is not associated with NS. Further studies with larger sample sizes and different ethnicities are required to validate our findings.


Comment on Pata et al. Sclerobanding (Combined Rubber Band Ligation with 3% Polidocanol Foam Sclerotherapy) for the Treatment of Second- and Third-Degree Hemorrhoidal Disease: Feasibility and Short-Term Outcomes. J. Clin. Med. 2022, 11, 218.
Dr. Pata kindly tweeted the publication of the above-mentioned paper [...].


Sex Differences and the Effects of Estradiol on Striatal Function.
The striatal brain regions, including the caudate-putamen, nucleus accumbens core, and nucleus accumbens shell, mediate critical behavioral functions. These functions include but are not limited to motivated behavior, reward, learning, and sensorimotor function in both pathological and normal contexts. The phenotype and/or incidence of all of these behaviors either differ by sex or are sensitive to the presence of gonadal hormones such as 17β-estradiol and testosterone. All three striatal brain regions express membrane-associated estrogen receptors. Here we present a brief review of the recent literature reporting on sex differences and effects of the estrogenic hormone 17β-estradiol on behavioral and neural function across all three striatal regions, focusing upon the most prominent striatal neuron type, the medium spiny neuron. We emphasize recent findings in three broad domains: (1) select striatal-relevant behaviors and disorders, (2) striatal medium spiny neuron dendritic spine density, and (3), striatal medium spiny neuron electrophysiological properties including excitatory synaptic input and intrinsic cellular excitability. These recent advances in behavior, neuroanatomy, and electrophysiology collectively offer insight into the effects of sex and estrogen on striatal function, especially at the level of individual neurons.


Microtubules, MAPs and plant directional cell expansion.
Plant microtubules (MTs) polymerize and depolymerize in a process termed dynamic instability. This allows the assembly, reorganization, and disassembly of at least four MT arrays throughout the cell cycle. The cortical MT array lines the plasma membrane during interphase and plays a central role in directional cell expansion. Microtubule-associated proteins (MAPs) decorate cortical MTs with distinct patterns, regulating MT dynamic instability, MT severing, and other array-ordering processes. The Arabidopsis root has emerged as a highly useful system for identifying and studying cell-expansion-related MAPs. Here, we review how cortical MTs are thought to behave and become ordered in expanding root cells, and we discuss the emerging picture of how MAPs fundamentally govern MT ordering and directional growth processes.


Establishment and characterization of two hamster macrophage cell lines.
Two hamster macrophage cell lines (HM-1 and HM-2) were established in vitro from lymphoid tumors produced in hamsters by direct implantation of normal human umbilical cord leukocytes. Despite long-term culture, both cell lines maintained the morphological, functional and surface characteristics of normal macrophages. It is considered that these cell lines were derived from host macrophages infiltrating the heterotransplants.


Analysis of structure-function relationships of neuropeptide Y using molecular dynamics simulations and pharmacological activity and binding measurements.
Studies on the structure-function relationship of neuropeptide Y (NPY) were undertaken using a combination of in vacuo molecular dynamics (MD) simulations and pharmacological receptor binding and biological activity measurements. Following a conformational search of NPY from which a theoretical structure was determined, a study of the structural and dynamic changes in the region of amino acids 25-36 was performed in a variety of NPY fragments and in the NPY free acid. Results revealed an increased structural change as the fragment size was decreased. Also, the mobility appears to be lowest in the full NPY vs the NPY fragments. Pharmacological measurements showed a decreased receptor binding and biological activity as fragment size decreased. Combination of the two approaches suggests a model where conformational maintenance and low configurational entropy of the 25-36 region of NPY favors both receptor binding and biological activity. Furthermore, the possibility of two receptor interaction modes is suggested. Analysis of the NPY structure suggests the direct importance of the amidated C-terminus, Gln34 and His26, an indirect importance of the Tyr1 sidechain as well as the potential importance of an apparent electric 'dipole' in NPY for receptor binding and biological activity.


Comparison of the effectiveness of two versions of the Rey memory test in discriminating between actual and simulated memory impairment, with and without the addition of a standard memory test.
The superiority of the modified 16-item Rey memory test over the original 15-item test has yet to be established in relation to the detection of feigned memory deficits. This study compares the effectiveness of these two versions of the test in combination with a standard memory test. Sixty-four participants, equally divided into "controls" and "simulators", and 32 "memory-impaired" volunteers completed the WAIS-III Digit Span test and either the 15-item or 16-item Rey test. The median scores of the simulators were worse than those of both the controls and the memory-impaired subjects on two types of score on the 16-item test compared to just one on the 15-item test. However, combining the total score from the 16-item test with the digits forward span accurately detected 63% of simulators (with only 6% of nonsimulators wrongly classified as simulators). This performance was better than that obtained from any of the test scores taken singly or from any other combination of a digit span score with a Rey score. It is concluded that the addition of a standard memory test to the Rey memory test improves the detection of individuals feigning memory impairment.


The apparent mechanical effect of isolated amyloid-β and α-synuclein aggregates revealed by multi-frequency MRE.
Several biological processes are involved in dementia, and fibrillar aggregation of misshaped endogenous proteins appears to be an early hallmark of neurodegenerative disease. A recently developed means of studying neurodegenerative diseases is magnetic resonance elastography (MRE), an imaging technique investigating the mechanical properties of tissues. Although mechanical changes associated with these diseases have been detected, the specific signal of fibrils has not yet been isolated in clinical or preclinical studies. The current study aims to exploit the fractal-like properties of fibrils to separate them from nonaggregated proteins using a multi-frequency MRE power law exponent in a phantom study. Two types of fibril, α-synuclein (α-Syn) and amyloid-β (Aβ), and a nonaggregated protein, bovine serum albumin, used as control, were incorporated in a dedicated nondispersive agarose phantom. Elastography was performed at multiple frequencies between 400 and 1200 Hz. After 3D-direct inversion, storage modulus (G'), phase angle (ϕ), wave speed and the power law exponent (y) were computed. No significant changes in G' and ϕ were detected. Both α-Syn and Aβ inclusions showed significantly higher y values than control inclusions (P = 0.005) but did not differ between each other. The current phantom study highlighted a specific biomechanical effect of α-Syn and Aβ aggregates, which was better captured with the power law exponent derived from multi-frequency MRE than with single frequency-derived parameters.


Barriers to recruiting urban African American women into research studies in community settings.
This qualitative study identified barriers to African American women's participation in a community-based behavioral intervention trial to increase mammography screening. Four themes emerged from focus group discussions with community agency providers and research team members. These themes were (1) going to the gatekeepers; (2) knowing the culture; (3) location is everything; and (4) protocols, policies, and possibilities. A checklist of actions that nurse researchers could consider to increase African American women's participation in community trials is provided.


Design and testing the validity of an inexpensive and accessible sham dry needling protocol.
To use a simple method of needle blunting to produce a placebo dry needling protocol which is indistinguishable from the sensations felt during therapeutic dry needling. A randomised cross-over design was used to compare the perception of needle skin penetration, pain experienced and types of sensations experienced following a single placebo dry needling and a single therapeutic dry needling application. There were no significant differences in the proportions of patients reported ability to perceive needle penetration (p = 0.646), description of needling sensations (p = 0.3) or pain rating (p = 0.405) when comparing placebo needling to therapeutic dry needling. Needle tip bending creates a simple, cost-effective and effective placebo needle for use in comparisons with therapeutic dry needling. This offers researchers a viable alternative to expensive and inappropriate acupuncture sham devices when conducting dry needling trials.


Hepcidin, an antimicrobial peptide is downregulated in ceruloplasmin-deficient mice.
Hepcidin, a principle regulator of iron metabolism, is synthesized by the liver. Contradictory results have been reported on the regulation of hepcidin expression in response to serum transferrin saturation and liver iron content. In the present study, we explore the expression of murine hepcidin mRNA and further analyze the relationship between liver hepcidin mRNA expression, liver iron stores, and serum iron level utilizing ceruloplasmin gene knockout mice. We find that hepcidin expression correlates significantly with serum transferrin saturation, whereas there is a negative correlation of hepcidin expression with liver tissue iron level.


Enhanced Mn-SOD immunoreactivity in the dopaminergic neurons of long-evans cinnamon rats.
The abundance of cellular superoxide dismutase (Mn-SOD) was examined immunocytochemically in different regions of the brain of Long-Evans Cinnamon (LEC) rats at 4 and 50 weeks of age. When all animals develop chronic hepatitis, the substantia nigra and striatum showed a marked increase in Mn-SOD immunoreactivity versus Long-Evans agouti (LEA) rats of the same age. Mn-SOD was localized predominantly in dopaminergic neurons. The elevation of Mn-SOD level in the dopaminergic neurons of LEC rats may reflect the oxidative stress caused by copper accumulation in this brain area. Our data suggest that LEC rats may contribute to the mechanistic study of neurological manifestations in nigro-striatal dopaminergic system of Wilson's disease.


[Contribution of monocyte chemoattractant protein-1 and c-fms/macrophage colony-stimulating factor receptor to coronary artery disease: analysis of human coronary atherectomy specimens].
Primary coronary atherosclerotic lesions(de novo lesions) are a type of inflammatory vascular disease. Restenotic lesions after percutaneous coronary intervention mainly consist of proliferative vascular smooth muscle cells. Recent studies have demonstrated that locally synthesized cytokines, including chemokines, are important in both these coronary lesions. Monocyte chemoattractant protein(MCP)-1 and macrophage colony-stimulating factor(M-CSF) are two of the associated chemokines, but their role in coronary artery disease has not been sufficiently clarified. This study investigated the expression of MCP-1 and c-fms/M-CSF receptor in human coronary tissues. Histological and immunohistochemical studies used samples obtained from patients who underwent directional coronary atherectomy(28 de novo lesions and 16 restenotic lesions). The following primary antibodies were used: anti-MCP-1, anti-c-fms, anti-macrophages and anti-alpha-smooth muscle actin. Focal accumulation of macrophage-derived foam cells, thrombus, cholesterol clefts and calcification tended to be more frequent in de novo lesions than in restenotic lesions. On the other hand, restenotic lesions mainly consisted of stellate vascular smooth muscle cells and extracellular matrix. The expression of MCP-1-positive cells almost coincided with the macrophages. In contrast, staining for MCP-1 was little seen in the stellate vascular smooth muscle cells. Expression of c-fms was found in both macrophages and stellate vascular smooth muscle cells. Expression patterns of MCP-1 and c-fms exhibited no difference between the two lesion types. Both MCP-1 and the M-CSF/c-fms system are involved in the atherogenesis of de novo lesions. However, the M-CSF/c-fms system, rather than MCP-1, is more important in the late stage of restenosis.


The coordination of copper(II) to 1-hydroxy-4-(glycyl-histidyl-lysine)-anthraquinone; a synthetic model of anthraquinone anti-cancer drugs.
Results are reported of a pH-metric and spectroscopic (CD and ESR) study of the complexes formed between the pseudo-peptide 1-hydroxy-4-(Gly-His-Lys)-anthraquinone (Q-GHK) since, when complexed to copper ions, Q-GHK has been shown to be very effective in promoting the formation of free radicals and inducing DNA cleavage. Q-GHK forms very stable complexes with copper, the major species being bonded to three nitrogen donors in the coordination plane: an imidazole-N of the His residue and the peptide nitrogens of the Gly and His residues. This species is probably stabilized through bonding of the fourth planar coordination site of Cu(II) to the 9-anthraquinone oxygen. At high Q-GHK:copper ratios a second Q-GHK molecule is coordinated through its imidazole-N donor.


Mathematical and experimental validation of an approach for simultaneously determining the binding parameters of two drugs to a receptor.
Quantifying drug-protein interactions has a pivotal role in both early phase drug development and clinical processes. Diverse affinity chromatographic methods like nonlinear chromatography can realize such quantification, however, their throughputs are challenged due to the loading of a single ligand during each run. This work derivatized a new equation for simultaneously determining the bindings of two ligands to a protein relying on assumption that the retention factors of the ligands are dependent on their injection amounts. Experimental validation of the derivatization was performed on an immobilized endothelin A receptor (ETAR) column taking ambrisentan, bosentan, and macitentan as injecting solutes. All three ligands presented a decrease in retention times along with increasing moles of injection when they were singly injected into the column. Likewise, negative relationships between the retentions and the injection amounts were observed when co-injection of ambrisentan/bosentan or bosentan/macitentan was performed, thus confirming the assumption of the derivatization. The association constants of ambrisentan, bosentan, and macitentan binding to ETAR were (1.42 ± 0.78)×104, (1.81 ± 0.22)×104, and (1.71 ± 0.41)×104 L/mol when each of them was singly loaded on the column. Such data displayed insignificant changes in four weeks thereby providing a proof of good stability of the column during the period. Co-injections of the two ligand pairs resulted in the association constants of (2.97 ± 0.13)×104 for ambrisentan, (2.51 ± 0.87)×104 for bosentan, and (2.88 ± 0.34)×104 L/mol for macitentan. These results were in good agreement with the calculation when each of the ligands was injected alone into the column and demonstrated little differences from the data by nonlinear chromatography. Owning to the simultaneous analysis of two ligands, the throughput of the proposed method was twofold higher than the typical assays including frontal analysis, zonal elution, and nonlinear chromatography. It is possible to become an alternative for rapid analysis of drug-protein interaction.


Estimation Of The Quality Of Life Benefits Associated With Treatment For Spinal Muscular Atrophy.
Spinal muscular atrophy (SMA) is a rare, genetic, progressive neuromuscular disorder characterized by severe muscle atrophy and weakness and is a leading genetic cause of death in infants and children. Nusinersen was the first treatment targeting the underlying cause of disease approved by the FDA, EMA and other countries for patients with SMA. There are currently very limited data available on the health-related quality of life (HRQoL) burden of SMA suitable for use in a cost-effectiveness analysis. This study was designed to estimate quality of life weights or utilities for different SMA states. SMA case studies were developed describing Type I (infantile onset) and Type II (later-onset) patients and different outcomes from treatment. These were developed so that quality of life weights or utilities (where the value of health ranges from 1 - full health to 0 - dead) could be estimated for cost-effectiveness analysis. Clinical experts (n=5) rated each of the case studies using standardized HRQoL instruments - the EQ-5D-Y and PedsQL-NMM (baseline states only). The SMA Type I utilities ranged from -0.33 (requires ventilation) to 0.71 (Type I patient reclassified as Type III following treatment), with quite substantial differences between some states. Most Type I states had a utility score below zero indicating the severity of the states. The SMA Type II utilities ranged from -0.13 (worsened) to 0.72 (stands/walks unaided). In general, the results showed HRQoL improved in line with better health states. The utility scores obtained in this study highlight the very substantial burden experienced by SMA patients. Despite the limitations in the methods used, this study produced data with face validity and is a useful starting point for understanding the burden of SMA Types I and II in cost-effectiveness analysis.


Globotriosyl ceramide is specifically recognized by the Escherichia coli verocytotoxin 2.
Two Escherichia coli cytotoxins (verotoxins 1 and 2) have been previously implicated in the cytopathology of the Hemolytic Uremic Syndrome. We have examined the glycolipid binding specificity of verotoxin (VT)2. This toxin specifically binds to globotriosyl ceramide (galactose alpha 1-4 galactose beta 1-4 glucosyl ceramide). Removal, or substitution of the terminal a galactose residue with N-acetyl galactosamine in beta 1-3 linkage, deletes binding activity. The toxin does not recognize similar terminal a galactose residues on a glycoglycerolipid. Thus the binding specificity of VT2 is the same as previously reported for VT1. Liposomes containing globotriosyl ceramide are able to specifically remove VT1 and VT2 cytotoxicity and cell lines selected in vitro for resistance to VT1 are cross resistant to VT2.


Autoradiology: patient heal thyself.
All in all, our program has been a great success, endorsed by everyone from patients to health care providers and hospital administrators. The PPP will revolutionize diagnostic and interventional radiologic procedures and will free the radiologist to perform more critical maneuvers--the out-of-department lunch, the extended afternoon off, and perfection of the golf swing.


Separation surgery followed by stereotactic ablative radiotherapy for metastatic epidural spinal cord compression: A systematic review and meta-analysis for local progression rate.
Spinal metastasis is the most common metastatic skeletal disease in cancer patients. Metastatic epidural spinal cord compression (MESCC), which occurs in 5-14% of cancer patients, is an oncological emergency because it may cause a permanent neurological deficit. Separation surgery followed by stereotactic ablative radiotherapy (SABR), so-called "hybrid therapy," has shown effectiveness in local control of spinal metastasis and has become an integral treatment option for patients with MESCC. Therefore, we performed a meta-analysis and meta-regression analysis to clarify the local progression rate of hybrid therapy and the risk factors for local progression. We searched PubMed, EMBASE, Scopus, Cochrane Library, and Web of Science databases from inception to December 2021. Meta-analyses of proportions were used to analyze the data using a random-effects model to calculate the pooled 1-year local progression rate and confidence interval. Subgroup analyses were performed using meta-analyses of odds ratio (OR) for comparisons between groups. We also conducted a meta-regression analysis to identify the factors that caused heterogeneity. A total of 661 patients from 13 studies (10 retrospective and 3 prospective) were included in the final meta-analysis. The quality of the included studies assessed using the Newcastle - Ottawa scale ranged from poor to fair (range, 4-6). The pooled local progression rate was 10.2 % (95 % confidence interval [CI], 7.8-12.8 %; I2 = 30 %) and 13.7 % (95 % CI, 9.3-18.8 %; I2 = 55 %) at postoperative 1 and 2 years, respectively. The subgroup analysis indicated that patients with a history of prior radiotherapy (OR, 5.14; 95 % CI, 1.71-15.51) and lower radiation dose per fraction (OR, 4.57; 95 % CI, 1.88-11.13) showed significantly higher pooled 1-year local progression rates. In the moderator analysis, the 1-year local progression rate was significantly associated with the proportion of patients with a history of prior radiotherapy (p = 0.036) and those with colorectal cancer as primary origin (p < 0.001). The pooled 1-year local progression rate of hybrid therapy for MESCC was 10.2%. In subgroup and moderator analyses, a lower radiation dose per fraction, history of prior radiotherapy, and colorectal cancer showed a significant association with the 1-year local progression rate.


New approach to preoperative vascular exclusion for carotid body tumor.
We report a new approach to preoperative vascular exclusion of a carotid body tumor. Before surgery, covered stents were placed in the external carotid artery, resulting in vascular exclusion of the tumor. Subsequent surgical excision was uneventful, with operative blood loss less than 200 mL and no neurologic complications postoperatively. This technique deserves further consideration as a reasonable alternative to conventional embolization.


Abnormal segmental relaxation patterns in hypertensive disease and symptomatic diastolic dysfunction detected by strain echocardiography.
An abnormal segmental relaxation pattern exists as an early sign of diastolic dysfunction (DD), detectable by strain (S) echocardiography. The objective of this study was to investigate the relation of segmental relaxation patterns with longitudinal systolic function and symptomatic DD in patients with hypertension (HTN). We evaluated 30 healthy volunteers and 78 volunteers with HTN, divided as follows: (1) patients without DD (n: 28); (2) patients with asymptomatic DD (n: 25); and (3) patients with symptomatic DD (n: 25). All groups had normal ejection fraction greater than or equal to 55%. The symptomatic group had mild exertional dyspnea. All participants underwent 2-dimensional and color Doppler myocardial imaging, and the mean longitudinal strain (S) and S rate (SR) were estimated. Early and late diastolic SR parameters (SR(E) and SR(A)) were also recorded from the basal, mid, and apical segments for each wall. Altered segmental relaxation (SR(E)/SR(A) < 1.1) was regarded as an index of segmental DD. Patients who were symptomatic with DD were found to have more segments with an abnormal relaxation pattern (segmental DD) and more deteriorated longitudinal systolic function based on S and SR, compared with patients with asymptomatic HTN and control subjects. Segmental DD was correlated with structural changes of left ventricular (LV) remodeling such as wall thickness (r: 0.64), relative wall thickness (r: 0.58), and LV mass index (r: 0.59), as well as mean S (r: -0.61), SR (r: -0.62), systolic blood pressure (r: 0.44), age (r: 0.49), and filling pressures (r: 0.50), all P less than .01. In multiple regression analysis, segmental DD and systolic blood pressure were independently related to symptomatic status (segmental DD: beta = 0.33, P = .003; systolic blood pressure: beta = 0.24, P = .009, R(2): 0.33). Compared with conventional indices of DD (deceleration time of the E wave, isovolumic relaxation time, E, A, and E/A), segmental DD was the only parameter that predicted symptomatic status (coefficient: 0.3817, SE: 0.1101, P = .0005, odds ratio: 1.4648, 95% confidence interval: 1.1761-1.7485). LV segmental relaxation demonstrates progressive deterioration in HTN disease, which is more pronounced in patients with symptomatic DD. Altered segmental relaxation is related to structural changes of LV remodeling and constitutes an independent predictor for the presence of a symptomatic status.


Parkinson's disease and sex-related differences in electromyography during daily life.
Daily bilateral electromyography (EMG) recordings reveal muscle activation patterns implicated in asymmetric Parkinson's disease (PD)-related functional decline. Also, daily EMG recordings reveal sex-differences in muscle activity that give rise to unique PD presentation in males and females. Quantify handgrip strength and daily muscle quiescence through analysis of gaps in the EMG signal in males and females with PD. Bilateral daily EMG was recorded and normalized to maximal voluntary exertions (MVE). EMG gap was defined as <1% amplitude of MVE for >0.1s and characterized as number, duration and time occupied by gaps. A dynamometer evaluated maximal grip-strength. Three-way repeated measures ANOVA examined differences in gap characteristics and strength. Gap duration was shorter (p=0.04) and occupied less time (p=0.02) in PD than controls. Females had fewer gaps with shorter duration (p=0.004), occupying less time (p=0.004) compared with males. Gaps were fewer (p=0.04) and occupied less time (p=0.01) on more-affected than less-affected side. PD was weaker than controls (p=0.04), females were weaker than males (p=0.00), and the more-affected PD side was weaker than less-affected (p=0.04). Quantification of muscle quiescence through gaps in the EMG signal recorded during daily life provides insight into mechanisms underlying differential change in functional performance in males and females with PD.


A prospective assessment of cardiac biomarkers for hemodynamic stress and necrosis and the risk of falls among older people: the ActiFE study.
Falls are related to a complex interaction of risk factors. We examined if cardiac biomarkers for hemodynamic stress (N-terminal pro Brain Natriuretic Peptide-NT-proBNP), and for necrosis [high sensitive (hs) cardiac troponins T (cTnT) and I (cTnI)] are associated with falls in older people. Biomarkers were measured at baseline in a cohort of 1506 community-dwelling adults ≥65 years. Falls were assessed prospectively in a falls calendar (median 370 days). Cox-proportional hazards models evaluated the association of each biomarker with the incidence of the first fall accounting for established confounders. We observed 430 incident falls among 1327 participants and an effect modification by sex for all biomarkers. In multivariable analyses among men a one unit increment of log-transformed hs-cTnI was associated with a hazard ratio (HR) of 1.26 (95 % CI 1.04, 1.53). Men with hs-cTnT ≥ 14 ng/L had a HR of 1.74 (95 % CI 1.15, 2.61) compared to those with undetectable hs-cTnT levels. In women cTn were not associated with falls. We did not detect an association between NT-proBNP and the risk of fall. Our results suggest that cardiac troponins may not only identify subjects at risk for cardiovascular diseases, but also help to understand the underlying complex pathophysiology of falls.


The state of Veterans Affairs sleep medicine programs: 2012 inventory results.
The Veterans Health Administration (VHA) represents one of the largest integrated health-care systems in the country. In 2012, the Veterans Affairs Sleep Network (VASN) sought to identify available sleep resources at VA medical centers (VAMCs) across the country through a national sleep inventory. The sleep inventory was administered at the annual 2012 VA Sleep Practitioners meeting and by email to sleep contacts at each VAMC. National prosthetics contacts were used to identify personnel at VAMCs without established sleep programs. Follow-up emails and telephone calls were made through March 2013. One hundred eleven VA medical centers were included for analysis. Thirty-nine programs did not respond, and 10 were considered "satellites," referring all sleep services to a larger neighboring VAMC. Sleep programs were stratified based on extent of services offered (i.e., in-lab and home testing, sleep specialty clinics, cognitive behavioral therapy for insomnia (CBT-i)): 28 % were complex sleep programs (CSPs), 46 % were intermediate (ISPs), 9 % were standard (SSPs), and 17 % offered no formal sleep services. Overall, 138,175 clinic visits and 90,904 sleep testing encounters were provided in fiscal year 2011 by 112.1 physicians and clinical psychologists, 100.4 sleep technologists, and 115.3 respiratory therapists. More than half of all programs had home testing and CBT-i programs, and 26 % utilized sleep telehealth. The 2012 VA sleep inventory suggests considerable variability in sleep services within the VA. Demand for sleep services is high, with programs using home testing, sleep telehealth, and a growing number of mid-level providers to improve access to care.


Transcriptome sequencing analysis of maize embryonic callus during early redifferentiation.
Maize is one of the primary crops of genetic manipulation, which provides an excellent means of promoting stress resistance and increasing yield. However, the differences in induction and regeneration capacity of embryonic callus (EC) among various genotypes result in genotypic dependence in genetic transformation. In this study, embryonic calli of two maize inbred lines with strong redifferentiation capacity and two lines with weak redifferentiation capability were separately subjected to transcriptome sequencing analysis during the early redifferentiation stages (stage I, 1-3 d; stage II, 4-6 d; stage III, 7-9 d) along with their corresponding controls. A total of ~ 654.72 million cDNA clean reads were yielded, and 62.64%~ 69.21% clean reads were mapped to the reference genome for each library. In comparison with the control, the numbers of differentially expressed genes (DEGs) for the four inbred lines identified in the three stages ranged from 1694 to 7193. By analyzing the common and specific DEGs of the four materials, we found that there were 321 upregulated genes and 386 downregulated genes identified in the high-regeneration lines (141 and DH40), whereas 611 upregulated genes and 500 downregulated genes were specifically expressed in the low-regeneration lines (ZYDH381-1 and DH3732). Analysis of the DEG expression patterns indicated a sharp change at stage I in both the high- and low-regeneration lines, which suggested that stage I constitutes a crucial period for EC regeneration. Notably, the specific common DEGs of 141 and DH40 were mainly associated with photosynthesis, porphyrin and chlorophyll metabolism, ribosomes, and plant hormone signal transduction. In contrast, the DEGs in ZYDH381-1 and DH3732 were mainly related to taurine and hypotaurine metabolism, nitrogen metabolism, fatty acid elongation, starch and sucrose metabolism, phenylpropanoid biosynthesis, and plant circadian rhythm. More importantly, WOX genes, which have an ancestral role in embryo development in seed plants and promote the regeneration of transformed calli, were specifically upregulated in the two high-regeneration lines. Our research contributes to the elucidation of molecular regulation during early redifferentiation in the maize embryonic callus.


RSV-induced tumors in chickens: resistance to pulsed current in terminal and non-terminal types.
Terminal Rous sarcoma virus-induced tumors in chickens had lower resistance to a pulsed current than non-terminal tumors or healthy tissues. This finding suggests the existence of some basic physiological difference between terminal and non-terminal tumors. The terminal tumors may have a higher concentration of mobile ions than either non-terminal types or healthy tissue.


Degradation of alachlor in aqueous solution by using hydrodynamic cavitation.
The degradation of alachlor aqueous solution by using hydrodynamic cavitation was systematically investigated. It was found that alachlor in aqueous solution can be deomposed with swirling jet-induced cavitation. The degradation can be described by a pseudo-first-order kinetics and the degradation rate was found to be 4.90x10(-2)min(-1). The effects of operating parameters such as fluid pressure, solution temperature, initial concentration of alachlor and medium pH on the degradation rates of alachlor were also discussed. The results showed that the degradation rates of alachlor increased with increasing pressure and decreased with increasing initial concentration. An optimum temperature of 40 degrees C existed for the degradation rate of alachlor and the degradation rate was also found to be slightly depend on medium pH. Many degradation products formed during the process, and some of them were qualitatively identified by GC-MS.


Amygdaloid kindling is anxiogenic but fails to alter object recognition or spatial working memory in rats.
Kindling in rats produces enduring behavioral changes that parallel the psychobehavioral disturbances frequently accompanying temporal lobe epilepsy. Some evidence suggests that the site of kindling is an important determinant of the type of behavioral changes observed following kindling, although this variable has not been systematically investigated. In the present experiments, the effects of amygdaloid kindling were assessed on a battery of behavioral tests we used previously to assess the effects of kindling in dorsal hippocampus or perirhinal cortex. Three generalized seizures were kindled with stimulation in or near the basolateral amygdala. One week later, rats were tested successively on measures of anxiety, activity, object recognition memory, and spatial working memory over a period of 3 weeks. Amygdaloid kindling produced increased anxiety, but spared all other behaviors assessed. This pattern of results is partially distinct from the previously described effects of perirhinal cortical kindling, which increases anxiety but also impairs object recognition memory, and is completely distinct from dorsal hippocampal kindling, which selectively increases activity and impairs spatial working memory. The observations suggest that kindling of distinct highly interconnected temporal lobe sites produces distinct patterns of behavioral comorbidity. The underlying mechanisms are thus most likely localized to intrinsic circuits at the site of seizure origination.


The adenosine deaminase acting on RNA 1 p150 isoform is involved in the pathogenesis of dyschromatosis symmetrica hereditaria.
Dyschromatosis symmetrica hereditaria (DSH) is characterized by the presence of hyperpigmented and hypopigmented macules mostly on the dorsal aspects of the extremities. Mutations in the adenosine deaminase acting on RNA1 (ADAR1) gene have been revealed as the cause of DSH. ADAR1 is known to give rise to two protein isoforms (p150 and p110) that differ by the 295 N-terminal amino acids, but the specific roles of its two isoforms in the pathogenesis of DSH are poorly understood. A Chinese family with typical DSH was screened for mutation of ADAR1, and we aimed to investigate the functional significance of the identified mutation. All exons and adjacent exon-intron sequences were amplified and sequenced. The possible influence of the identified mutation on the functionality of p150 and p110 was analysed using the minigene strategy and dual-luciferase reporter assay, respectively. We identified a novel two-base-pair deletion of AG (c.271_272delAG) in exon 2 of ADAR1. The AG deletion caused a frameshift mutation in the p150 isoform, and the mutant p150 transcripts were subjected to nonsense-mediated mRNA decay. However, the deletion mutation did not alter the encoded amino acid sequence of the p110 protein due its position in the 5'-untranslated region of the p110 isoform, and had no significant influence on the expression of p110. The results represent the first evidence that the ADAR1 p150 isoform is the determinant of DSH and may give insight into the currently unknown mechanisms involved in the development of DSH.


Peptide separation selectivity in proteomics LC-MS experiments: Comparison of formic and mixed formic/heptafluorobutyric acids ion-pairing modifiers.
Separation selectivity and detection sensitivity of reversed-phase high-performance liquid chromatography with tandem mass spectrometry analyses were compared for formic (0.1%) and formic/heptafluorobutyric (0.1%/0.005%) acid based eluents using a proteomic data set of ∼12 000 paired peptides. The addition of a small amount of hydrophobic heptafluorobutyric acid ion-pairing modifier increased peptide retention by up to 10% acetonitrile depending on peptide charge, size, and hydrophobicity. Retention increase was greatest for peptides that were short, highly charged, and hydrophilic. There was an ∼3.75-fold reduction in MS signal observed across the whole population of peptides following the addition of heptafluorobutyric acid. This resulted in ∼36% and ∼21% reduction of detected proteins and unique peptides for the whole cell lysate digests, respectively. We also confirmed that the separation selectivity of the formic/heptafluorobutyric acid system was very similar to the commonly used conditions of 0.1% trifluoroacetic acid, and developed a new version of the Sequence-Specific Retention calculator model for the formic/heptafluorobutyric acid system showing the same ∼0.98 R2 -value accuracy as the Sequence-Specific Retention calculator formic acid model. In silico simulation of peptide distribution in separation space showed that the addition of 0.005% heptafluorobutyric acid to the 0.1% formic acid system increased potential proteome coverage by ∼11% of detectable species (tryptic peptides ≥ four amino acids).


Tuning social modulations of gaze cueing via contextual factors.
Gaze cueing reflects the tendency to shift attention toward a location cued by the averted gaze of others. This effect does not fulfill criteria for strong automaticity because its magnitude is sensitive to the manipulation of different social features. Recent theoretical perspectives suggest that social modulations of gaze cueing could further critically depend on contextual factors. In this study, we tested this idea, relying on previous evidence showing that Chinese participants are more sensitive to gazes on White than on Asian faces, likely as a consequence of differences in perceived social status. We replicated this effect when we made group membership salient by presenting faces belonging to the different ethnicities in the same block. In contrast, when faces belonging to different ethnicities were presented in separate blocks, a similar gaze-cueing effect was noted, likely because no social comparison processes were activated. These findings are consistent with the idea that social modulations are not rigid but are tuned by contextual factors.


Rapid and sustained improvements in patient-reported signs and symptoms with ixekizumab in biologic-naive and TNF-inadequate responder patients with psoriatic arthritis.
To analyse the onset and sustainability of patient-reported improvements in symptoms of psoriatic arthritis (PsA) following treatment with ixekizumab (IXE) up to Week 108. In patients with active PsA, either naive to biological DMARDs (SPIRIT-P1) or having inadequate response or intolerance to 1 or 2 prior TNF-inhibitors (TNFi‑experienced; SPIRIT-P2), we analysed the change from baseline in joint pain visual analogue scale (VAS; 0-100 scale), patient global assessment (PatGA VAS; 0-100 scale), fatigue numerical rating scale (NRS; 0 [no fatigue] to 10 [worst imaginable]), and Health Assessment Questionnaire-Disability Index (HAQ-DI; 0-3), up to Week 108. IXE-treated patients compared to placebo reported rapid and statistically significant improvement in pain VAS, PatGA, and HAQ-DI as early as Week 1 and this benefit was sustained or increased through Week 108. Fatigue scores improved in IXE-treated patients compared to placebo in both studies; results were statistically significant at Week 24 only in SPIRIT-P2. Improvements in fatigue with IXE were sustained over 2 years. The improvements observed in these patient-reported outcomes (PROs) were consistent in biologic-naive or TNFi-experienced patients. Patients treated with IXE versus PBO achieved significantly greater improvements and showed faster onset of improvements in patient-reported outcomes measuring symptoms and impact of PsA. Responses were sustained over 2 years and were generally consistent regardless of prior TNFi experience.


Absence of povidone-iodine-induced mutagenicity in mice and hamsters.
Povidone-iodine USP was tested for mutagenicity in mice by the dominant lethal assay or micronucleus test and in Chinese hamsters by the bone marrow test. None of the three tests revealed any evidence of mutagenic effect.


Evaluation of progenitor cell cultures from human embryos for neurotransplantation.
Human neural stem cells (HNSCs) are used in studies of neural development and differentiation, and are regarded as an alternative source of tissue for neural transplantation in degenerative diseases. Selection and standardization of HNSC samples is an important task in research and clinical approaches. We evaluated embryonal brain matter obtained from human 8-12-week-old fetuses by means of flow cytometry on a panel including: nestin; vimentin; NeuN; GFAP; beta-tubulin III; CD56; N-Cad; OB-Cad; HLA-ABC; HLA-DR; CD34, and annexin. Samples from embryos of even the same gestation differ dramatically regarding neural cell development, their phenotype and viability. The samples containing the highest proportion of stem cells and multipotent progenitors of neural types, and the least of definitive cells and antigens of histocompatibility, were selected for further expansion in serum-free medium. Secondary phenotyping 14 days later revealed again a marked heterogeneity of the cultures. For the final culturing for 24 h in a serum-containing medium we selected only samples having following phenotype: nestin+, and vimentin+ no less than 25%; HLA-DR+ and CD34+ no more than 5%; GFAP+ no more than 10%; beta-tubulin+ no more than 20%; CD56+, N-Cad+, OB-Cad+, HLA-A,B,C+, and annexin+ no more than 15%; cell viability no less than 60%. Immunocytochemical study of selected samples proved that numerous neural stem cells, and neuro- and glioblasts necessary for transplantation were present. Our results demonstrate that the flow cytometry phenotyping allows the screening and standardization of HNSC samples for further expansion and transplantation.


[Comparison of macular electroretinography and psychophysical tests in diabetic retinopathy with intraretinal edema].
Short comparison between psychophysic and electrodiagnostic tests in 20 eyes with macular edema from diabetic retinopathy. De Lange's curve, the critical flicker frequency in central fixation and the macular ERG are compared with the classical EOG and global ERG data. The methodology is briefly described. It allows a new approach of the macula and the macular ERG responses confirms the clinical tests.


Deciphering the decline of metabolic elasticity in aging and obesity.
Organisms must adapt to fluctuating nutrient availability to maintain energy homeostasis. Here, we term the capacity for such adaptation and restoration "metabolic elasticity" and model it through ad libitum-fasting-refeeding cycles. Metabolic elasticity is achieved by coordinate versatility in gene expression, which we call "gene elasticity." We have developed the gene elasticity score as a systematic method to quantify the elasticity of the transcriptome across metabolically active tissues in mice and non-human primates. Genes involved in lipid and carbohydrate metabolism show high gene elasticity, and their elasticity declines with age, particularly with PPARγ dysregulation in adipose tissue. Synchronizing PPARγ activity with nutrient conditions through feeding-timed agonism optimizes their metabolic benefits and safety. We further broaden the conceptual scope of metabolic and gene elasticity to dietary challenges, revealing declines in diet-induced obesity similar to those in aging. Altogether, our findings provide a dynamic perspective on the dysmetabolic consequences of aging and obesity.


Experimental Research on the Influence of Microwave Radiation on Coal Permeability and Microstructure.
At present, there is limited information available about the effects of microwave radiation on desorption characteristics, microstructures, and functional groups of coal. This research focuses on the influence of microwave radiation on coal sample desorption and examines the changes in pore structures and oxygenic groups of different coal samples using liquid nitrogen adsorption, nuclear magnetic resonance, and X-ray photoelectron spectroscopy. Results prove that the methane desorption capacity and desorption rate are proportional to the increase in microwave energy; the initial dynamic diffusion coefficient is also proportional to microwave energy but negatively proportional to the attenuation coefficient. As a result of microwave radiation, the Brunauer-Emmett-Teller (BET) surface area, pore size, and Barret-Joyner-Halenda (BJH) pore volume decreased. The specific surface area of BET decreased and then increased as microwave energy increased, while the average pore size increased and then decreased. However, the change in the BJH cumulative adsorption pore volume was complicated. The microwave radiation decreases the volume and number of micropores while increasing the volume and number of medium pores. With the increase in microwave energy, the number and volume of micropores continue to decrease, while the number and volume of medium pores continue to increase. An increase in microwave energy increased the surface area of oxygenic groups with the increasing relative content of COO-, C-O, and C=O bonds; however, the relative content of C-C/C-H bonds decreased. These findings deepen the understanding of the antireflection effects of microwaves on coal.


[Chronic eosinophilic meningitis caused by cysticercosis cerebri].
The authors describe a case of encephalomeningitis chronica eosinophilia in a 60-year-old woman. The etiology was not investigated clinically. The autoptic diagnosis was cerebral cysticercosis.


Paclitaxel, bevacizumab, and everolimus/placebo as first-line treatment for patients with metastatic HER2-negative breast cancer: a randomized placebo-controlled phase II trial of the Sarah Cannon Research Institute.
Amplified PI3K/Akt/mTOR signaling is common in metastatic breast cancer (MBC). The mTOR inhibitor everolimus improves progression-free survival (PFS) when added to steroidal aromatase inhibitor therapy. This randomized phase II trial compares the efficacy of paclitaxel/bevacizumab/everolimus and paclitaxel/bevacizumab/placebo as first-line treatment for MBC. Patients with untreated HER2-negative MBC were randomized (1:1) to receive 28-day cycles of paclitaxel 90 mg/m(2) IV (days 1, 8, and 15) and bevacizumab 10 mg/kg IV (days 1, 15) with either everolimus 10 mg (Arm 1) or placebo (Arm 2) daily. Treatment continued (evaluation every 8 weeks) until progression or unacceptable toxicity. Treatment of 110 patients allowed detection of an improvement in median PFS from 11 to 16 months (70 % power, α = 0.10). Between August 2009 and June 2011, 113 patients (median age 58 years; 88 % ER or PR positive) were randomized (Arm 1, 56; Arm 2, 57). Patients in both arms received a median of six treatment cycles. Median PFS (95 % CI) was 9.1 months (6.8-18.8) for Arm 1, and 7.1 months (5.6-10.8) for Arm 2 (p = 0.89). Comparisons of other efficacy endpoints were also similar in the two treatment arms. Patients receiving everolimus had more anemia, stomatitis, diarrhea, rash, and arthralgia/myalgia, although the overall incidence of severe (grade 3/4) toxicity was similar. The addition of everolimus did not improve the efficacy of weekly paclitaxel/bevacizumab as first-line treatment for patients with HER2-negative MBC. These results contrast with the demonstrated efficacy of adding everolimus to either hormonal or HER2-targeted therapy in previously treated patients.


Air pollution-associated changes in lung function among asthmatic children in Detroit.
In a longitudinal cohort study of primary-school-age children with asthma in Detroit, Michigan, we examined relationships between lung function and ambient levels of particulate matter < or = 10 microm and < or = 2.5 microm in diameter (PM10 and PM2.5) and ozone at varying lag intervals using generalized estimating equations. Models considered effect modification by maintenance corticosteroid (CS) use and by the presence of an upper respiratory infection (URI) as recorded in a daily diary among 86 children who participated in six 2-week seasonal assessments from winter 2001 through spring 2002. Participants were predominantly African American from families with low income, and > 75% were categorized as having persistent asthma. In both single-pollutant and two-pollutant models, many regressions demonstrated associations between higher exposure to ambient pollutants and poorer lung function (increased diurnal variability and decreased lowest daily values for forced expiratory volume in 1 sec) among children using CSs but not among those not using CSs, and among children reporting URI symptoms but not among those who did not report URIs. Our findings suggest that levels of air pollutants in Detroit, which are above the current National Ambient Air Quality Standards, adversely affect lung function of susceptible asthmatic children.


High genetic burden of type 2 diabetes can promote the high prevalence of disease: a longitudinal cohort study in Iran.
Type 2 diabetes (T2D) is emerging as one of the serious public health issues in both developed and developing counties. Here, we surveyed the worldwide population differentiation in T2D-associated variants and assessed the genetic burden of the disease in an ongoing Tehran Cardio-Metabolic Genetic Study (TCGS) cohort represented the Iranian population. We found multiple SNPs that were significantly depleted or enriched in at least one of the five populations of 1,000 Genome Project (African, American, East Asian, European, and South Asian) as well as the Iranian population. Interestingly, TCF7L2, a well-known associated gene with T2D, harbors the highest number of enriched risk alleles almost in all populations except for East Asian, where this gene embraces the largest number of significantly depleted risk alleles. The polygenic risk score (PRS) of the enriched risk alleles was calculated for 1,867 diabetic and 2,855 non-diabetic participants in the TCGS cohort, interestingly demonstrating that the risk of developing T2D was almost two times higher in top PRS quintile compared with the lowest quintile after adjusting for other known risk factors.


Association of monocyte-lymphocyte ratio and proliferative diabetic retinopathy in the U.S. population with type 2 diabetes.
Diabetic retinopathy (DR), especially proliferative diabetic retinopathy (PDR) is a common cause of blindness and visual impairment. Early prediction of its occurrence and progression is important to improved patient outcomes. Inflammation-related markers may play important roles, and the monocyte-lymphocyte ratio (MLR) can act as a novel inflammatory marker. However, the association between MLR and PDR remains unclear. The aim of the present study was to investigate the association between MLR and PDR in the U.S. population with type 2 diabetes (T2D) based on DR data from NHANES in 2005-2008. This cross-sectional study was conducted in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008. DR was defined by the criteria of the Early Treatment for Diabetic Retinopathy Study based on nonmydriatic fundus photography. The MLR is the monocyte count/lymphocyte count. The lymphocyte count and monocyte count can be obtained directly from laboratory data files. Logistic regression was used to explore the association between MLR and PDR. Stratified analyses were also conducted according to age, sex, hemoglobin, and glycated hemoglobin categories. We applied the duration of diabetes with multiple imputations of missing data. A total of 367 participants were included, among whom the PDR prevalence was 7% (27/367). Multivariate regression models revealed that PDR was significantly associated with 0.1 unit increase in MLR (adjusted OR = 1.46, 95% CI: 1.08-1.96) after all covariates were adjusted. In the subgroup analysis, effect size of MLR on the presence of PDR in subgroups were stable (all P values > 0.05). MLR was significantly associated with PDR in participants with T2D. Assessing the MLR might be a valuable part of follow-up visits for patients with T2D.


Chemical analysis and NIR spectroscopy in the determination of the origin, variety and roast time of Mexican coffee.
Coffee is a product whose quality and price are associated with its geographical, genetic and processing origin; therefore, the development of analytical techniques to authenticate the above mentioned is important to avoid adulteration. The objective of this study was to compare conventional analytical methods with NIR technology for the authentication of roasted and ground coffee samples from different producing regions in Mexico (origins) and different varieties. A second objective was to determine, under the same processing conditions, if roasting times can be differentiated by using this technology. A total of 120 samples of roasted and ground commercial coffee were obtained from the states of Chiapas, Oaxaca, Tabasco and Veracruz in Mexico, 30 locally available samples per state. Samples from Veracruz included three different varieties, grown on the same farm and processed under the same conditions. One of these varieties was selected to evaluate the chemical composition of samples roasted at 185 °C using four different roasting times (15, 17, 19 and 21 min). Samples from different producing regions showed significant differences (P < 0.05) in fat content (from 7.45 ± 0.42% in Tabasco to 18.40 ± 2.95% in Chiapas), which was associated with the altitude of coffee plantations (Pearson's r = 0.96). The results indicate that NIR technology generates sufficient useful information to authenticate roasted and ground coffee from different geographical origins in Mexico and different varieties from the same coffee plantation, with similar results to those obtained by conventional analytical methods.


Corrigendum: Subjective and Oxytocinergic Responses to Mindfulness Are Associated With Subjective and Oxytocinergic Responses to Sexual Arousal.
[This corrects the article DOI: 10.3389/fpsyg.2019.01101.].


Inhibition by the mushroom toxins alpha-amanitin and phalloidin of hepatopoietin-induced 3H-thymidine incorporation into rat liver DNA and of plasma protein production in hepatocyte cultures.
In primary cultures of rat hepatocytes the induction of 3H-thymidine uptake into DNA of liver cells by the liver cell proliferation factor hepatopoietin demonstrates that this factor is active not only in vivo but also in vitro. Addition of the mushroom toxins alpha-amanitin or phalloidin to liver cell culture decreased the uptake of 3H-thymidine into hepatocytes (in the absence or presence of hepatopoietin) as well as the attachment of the hepatocyte cultures. Mushroom toxins also inhibited the production of plasma proteins in hepatocyte cultures. The inhibition, observed at toxin concentrations from 10(-5) to 10(-7) M, was dose-dependent. At low concentrations of phalloidin the inhibition appears to be selective for certain proteins.


Lifetime management of severely calcified coronary lesions: the treatment algorithm focused on the shape of calcification.
The concept of lifetime management has not been discussed in the field of percutaneous coronary intervention (PCI), because the durability of drug-eluting stent (DES) is considered to be long enough for most patients. Furthermore, even if in-stent restenosis occurs, the treatment for in-stent restenosis is simple in most cases. On the other hand, the long-term clinical outcomes after DES implantation are worse in severely calcified coronary lesions than in non-calcified lesions. Moreover, the treatment for in-stent calcified restenosis or restenosis due to stent underexpansion is not simple. The concept of lifetime management of severely calcified lesions may be necessary like that of aortic stenosis. Recently, several algorithms have been published in PCI to severely calcified lesions, partly because of the emergence of IVL. These algorithms focus on the selection of cracking and debulking devices for the preparation of stenting. However, the optimal stent expansion does not guarantee the long-term patency, when the target lesion includes calcified nodules. Stent restenosis due to calcified nodules is difficult to manage. In this review article, we propose the algorithm for severely calcified lesions focused on the shape of calcification. We do not need to hesitate stenting when multiple cracks on circumferential calcification are observed by intravascular imaging devices. However, DCB may be an option as final device in some situations, when lifetime management of severely calcified lesions is considered.


Severe diabetic fetopathy despite strict metabolic control.
In pregnant women, diabetes mellitus (DM) can cause severe complications for both mother and child during pregnancy and delivery; for example, hypertension, pre-eclampsia, macrosomia or intrauterine fetal death. It is therefore essential to achieve good metabolic control in the mother from before conception to the postpartum period. A 35-year-old primipara with type 2 DM presented herself at our outpatient department at 21 weeks of gestation. Until this time her DM had been treated with oral antidiabetic drugs; these were withdrawn and conventional insulin therapy was initiated. Except for the first two weeks after insulin adjustment, blood glucose values were within the required range. Biometric tests performed until week 30 of gestation showed discreet fetal growth. In the week 31, fetal abdominal girth near the 95% limit was observed for the first time; this was soon followed by an explosion-like enlargement of the abdomen along with glycemic values at the lower limit. A cesarean section was performed in week 35 of gestation because of the excessive macrosomia. The female newborn had a birth weight of 4920 g and, one hour after delivery, a blood glucose of 10 mg/dl requiring an intravenous glucose bolus. In addition, the child needed oxygen and also needed both an enteral and a parenteral supply of glucose until day 7 after delivery. Mother and child were discharged from the clinic 19 days postpartum in good general condition. This case illustrates the complexity of treatment of glucose-tolerance disturbances during pregnancy and underlines the importance of fetal monitoring by ultrasound, given that measurement of maternal blood glucose does not always provide sufficient information on the metabolic situation of the fetus.


Genetic influences on eight psychiatric disorders based on family data of 4 408 646 full and half-siblings, and genetic data of 333 748 cases and controls.
Most studies underline the contribution of heritable factors for psychiatric disorders. However, heritability estimates depend on the population under study, diagnostic instruments, and study designs that each has its inherent assumptions, strengths, and biases. We aim to test the homogeneity in heritability estimates between two powerful, and state of the art study designs for eight psychiatric disorders. We assessed heritability based on data of Swedish siblings (N = 4 408 646 full and maternal half-siblings), and based on summary data of eight samples with measured genotypes (N = 125 533 cases and 208 215 controls). All data were based on standard diagnostic criteria. Eight psychiatric disorders were studied: (1) alcohol dependence (AD), (2) anorexia nervosa, (3) attention deficit/hyperactivity disorder (ADHD), (4) autism spectrum disorder, (5) bipolar disorder, (6) major depressive disorder, (7) obsessive-compulsive disorder (OCD), and (8) schizophrenia. Heritability estimates from sibling data varied from 0.30 for Major Depression to 0.80 for ADHD. The estimates based on the measured genotypes were lower, ranging from 0.10 for AD to 0.28 for OCD, but were significant, and correlated positively (0.19) with national sibling-based estimates. When removing OCD from the data the correlation increased to 0.50. Given the unique character of each study design, the convergent findings for these eight psychiatric conditions suggest that heritability estimates are robust across different methods. The findings also highlight large differences in genetic and environmental influences between psychiatric disorders, providing future directions for etiological psychiatric research.


Interaction of calcium and magnesium on gastric acid secretion and serum gastrin concentration in man.
The effect of magnesium on calcium- and pentagastrin-induced gastric acid secretion and on calcium-induced gastrin secretion were studied in healthy volunteers. Intravenous infusion of calcium gluconate increased serum gastrin concentration as well as gastric volume secretion, acidity, and acid output. Addition of magnesium sulfate to the infusion caused a slight but insignificant increase in serum gastrin concentration, whereas volume secretion, acidity, and acid output were significantly depressed. Intravenous infusion of magnesium sulfate had no effect on gastric acid secretion induced by a submaximal pentagastrin infusion. The results indicate that magnesium antagonizes the activation of gastric acid secretion by calcium without suppressing gastrin release and may suggest that magnesium does not change the sensitivity of the parietal cell to gastrin.


[Lipid peroxidation in persons with chronic odontogenic foci of infection].
In 86 patients with chronic granulomatous and granulating periodontitis in the absence of other pathology the lipid peroxidation products levels were increased as indicated by accumulation of malonic dialdehyde and diene conjugates in the whole blood. The relative content of disulphide groups in the red blood cells was increased and that of sulfhydryl groups decreased. The findings correlate with those detected in granulomas.


What the cerveau isolé preparation tells us nowadays about sleep-wake mechanisms?
The intercollicular transected preparation opened a rich field for investigations of sleep-wake mechanisms. Initial results showed that brain stem ascending influences are essential for maintaining an activated cortex. It was subsequently shown that the forebrain also develops activating influences, since EEG desynchronization of the cortex reappears in the chronic cerveau isolé preparation, and continuous or almost continuous theta rhythm is able to occur in the acute cerveau isolé preparation. A brief "intermediate stage" of sleep occurs during natural sleep just prior to and after paradoxical sleep. It is characterized by cortical spindle bursts, hippocampal low frequency theta activity (two patterns of the acute cerveau isolé preparation) and is accompanied by a very low thalamic transmission level, suggesting a cerveau isolé-like state. The chronic cerveau isolé preparation also demonstrates that the executive processes of paradoxical sleep are located in the lower brain stem, while the occurrence of this sleep stage seems to be modulated by forebrain structures.


Analysis of percussion response of dental implants: an in vitro study.
The Periometer® quantitative percussion system was used to interrogate the interfacial stability of implants in vitro for comparison with X-ray computer tomography (CT) data. Selected implants were placed as per standard practice in bone stimulant polyurethane blocks. The dimensions of the surgical sites surrounding the implants were analyzed using X-ray computer tomography (CT) to determine the quality of support at the implant-bone interface. In particular, the misfit between the size of the surgical site and the corresponding implant was determined for each sample. The resulting average surgical site error from the CT scans was found to exhibit good agreement with the presence of irregularities found in the percussion data.


A morphological and immunohistochemical study of lymphoid germinal centers in synovial and lymph node tissues from rheumatoid arthritis patients with special reference to complement components and their receptors.
Rheumatoid arthritis (RA) is one of the immune complex (IC) diseases in which lymphoid germinal centers (GCs) are found in the synovial tissue. Simultaneously, patients with RA often show swelling of lymph nodes. The morphology and function of the lymph-node GCs in patients with RA is not clear. The aim of this study was to evaluate the differences in morphology and immunoreactions to complement (C) components, their receptors, and IgM-rheumatoid factor (RF) between synovial GCs and lymph-node GCs in RA. Furthermore, the relationship between these immunoreactive substances and follicular dendritic cells (FDCs) in GCs was investigated. The tissues examined were 41 RA synovial specimens, seven RA lymph nodes with massive lymphadenopathy, and 10 non-RA lymph nodes. The number of synovial GCs was relatively decreased in comparison with lymph-node GCs in RA, and the diameter of each synovial GC was smaller than that of each lymph-node GC. The synovial GCs were edematous and less cellular, and moreover, those from RF-seronegative cases were smaller than those from RF-seropositive cases. On the other hand, the lymph-node GCs in RA were larger, more cellular and hyperplastic, but contained more tingible-body macrophages (TBMs) and neutrophils. In the GCs of both synovial tissues and lymph nodes in RA, early C components (C1q, C4, C3c, C3d), IgM-RF, and C3b receptor (C3bR) and C3d receptor (C3dR) were expressed as a lacy network by light microscopy, and were demonstrated on the surfaces of FDCs and lymphocytes, and in the intercellular spaces by electron microscopy.(ABSTRACT TRUNCATED AT 250 WORDS)


Detection of the human erythrocyte surface antigen gerbich by flow cytometry using human antibodies and phycoerythrin for extreme immunofluorescence sensitivity.
We used indirect immunofluorescence and flow cytometry to detect the human erythrocyte surface antigen Gerbich. The procedure consisted of sequential erythrocyte-labeling with human antibody to Gerbich, biotinylated goat anti-human IgG and finally phycoerythrin-conjugated streptavidin. With maximal excitation of phycoerythrin at 546 nm, an increase in the fluorescence sensitivity was achieved. All erythrocytes from normal controls had detectable Gerbich antigen with little variation in antigen density between individuals. Six Gerbich-negative patients had no detectable antigen. By diluting the erythrocytes, as few as 0.1% antigen-positive cells in an antigen-negative population could be detected. These studies indicate that flow cytometry is a useful technique for the detection of erythrocyte surface antigens.


Gadoxetic acid-enhanced MRI of macrotrabecular-massive hepatocellular carcinoma and its prognostic implications.
Despite the clinical and genetic significance of macrotrabecular-massive hepatocellular carcinoma (MTM-HCC), its characteristics on imaging have not been described. This study aimed to characterise MTM-HCC on gadoxetic acid-enhanced MRI and to evaluate the diagnostic accuracy and prognostic value of these imaging characteristics. We enrolled 3 independent cohorts from 2 tertiary care centres. The 3 cohorts consisted of a total of 476 patients who underwent gadoxetic acid-enhanced MRI and surgical resection for treatment-naïve single HCCs. Independent review of histopathology and MRI by 2 reviewers was performed for each cohort, and inter-reader agreement was evaluated. Based on the result of MRI review in the training cohort (cohort 1), we developed 2 diagnostic criteria for MTM-HCC and evaluated their prognostic significance. The diagnostic performance and prognostic significance were validated in 2 validation cohorts (cohorts 2 and 3). We developed 2 diagnostic MRI criteria (MRIC) for MTM-HCC: MRIC-1, ≥20% arterial phase hypovascular component; MRIC-2, ≥50% hypovascular component and 2 or more ancillary findings (intratumoural artery, arterial phase peritumoural enhancement, and non-smooth tumour margin). MRIC-1 showed high sensitivity and negative predictive value (88% and 95% in the training cohort, and 88% and 97% in the pooled validation cohorts, respectively), whereas MRIC-2 demonstrated moderate sensitivity and high specificity (47% and 94% in the training cohort, and 46% and 96% in the pooled validation cohorts, respectively). MRIC-2 was an independent poor prognostic factor for overall survival in both training and pooled validation cohorts. Using gadoxetic acid-enhanced MRI findings, including an arterial phase hypovascular component, we could stratify the probability of MTM-HCC and non-invasively obtain prognostic information. Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a histopathologic subtype of HCC characterised by aggressive biological behaviour and poor prognosis. We developed imaging criteria based on liver MRI that could be used for the non-invasive diagnosis of MTM-HCC. HCCs showing imaging findings of MTM-HCC were associated with poor outcomes after hepatic resection.