Genetic variation in estrogen and progesterone pathway genes and breast cancer risk: an exploration of tumor subtype-specific effects.
To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina. Cases (n = 1,972) were women 20-74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (n = 1,776) were frequency matched to cases by age and race. A total of 195 SNPs were genotyped, and linkage disequilibrium was evaluated using the r (2) statistic. Odds ratios (ORs) and 95 % confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided p values <3.3 × 10(-4) were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (n = 679) and basal-like (n = 200), were based on the Wald statistic. ESR1 rs6914211 (AA vs. AT+TT, OR 2.24, 95 % CI 1.51-3.33), ESR1 rs985191 (CC vs. AA, OR 2.11, 95 % CI 1.43-3.13), and PGR rs1824128 (TT+GT vs. GG, OR 1.33, 95 % CI 1.14-1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African-Americans r (2) = 0.70; whites r (2) = 0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER-, and unclassified subtypes. ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.


Maleic anhydride adsorption on silicon (001).
The adsorption of maleic anhydride on the Si(001) surface has been investigated using the first-principles pseudopotential formalism. Our total-energy calculations suggest that maleic anhydride (C2H2-C2O3) adsorbs preferentially through a [2+2] cycloaddition of the C=C bond ([2+2]) with an adsorption energy of around 42 kcal/mol. Besides the [2+2] configuration we have also considered other possible coverages and adsorption models, including the adsorption on inter-row and intrarow dimer sites. Based on the analysis of the relative stability of different adsorption models, we propose the formation of mixed domains, containing the [2+2] unit and an interdimer unit. The comparison of our calculated electronic band structure, vibrational modes, and scanning tunneling microscopy images for the [2+2] and the favored interdimer adsorbed structures corroborate our proposed mixed domain model.


Verrucous carcinoma of the larynx management by radiotherapy and surgery.
Verrucous carcinoma is an unusual and distinct variant of well differentiated squamous cell carcinoma, and accounts for approximately 1 to 2% of all primary squamous cell carcinomas of the larynx. There has been considerable controversy regarding the role of radiotherapy in the managment of these tumors as they are said to be radioresistant, and in a number of instances "anaplastic transformation" has apparently occurred following such therapy. We have reviewed 18 patients with verrucous carcinoma of the larynx in which eight received surgical therapy alone, eight received radiotherapy alone, and two received combined therapy. We conclude that radiotherapy and surgery are equally effective in eradicating the disease. "Anaplastic transformation" of these tumors represents a small but nevertheless real risk following radiotherapy. Accordingly, our current therapeutic policy is to treat by surgical excision those smaller tumors which can be removed by conservation laryngectomy procedures, reserving radiotherapy for those large tumors which would require total laryngectomy if treated surgically.


Hormone-substrate responses to total fasting in lean and obese mice.
The hormone-substrate milieu has been investigated in male fasted lean (C57BL/6-+/+) mice and mutant obese mice of the same strain (C57BL/6-obob). The lean mouse, in winter, mobilized insufficient fat (due to inadequate stores) to permit survival beyong 3 days and was unable to achieve any degree of conservation of vital protein stores. By contrast, in summer, the same animals survived 7 days and showed evidence of greater and more sustained fat mobilization and ketosis and the ability to conserve protein. The insulin, glucagon, and insulin/glucagon molar ratios changed in both groups in a direction consistent with conversion to a catabolic state, and hence were probably largely responsible for the mobilization of substrates and stimulation of gluconeogenesis and ketogenesis. The seasonal difference in response is unexplained. The obob mice, generally employed as a model for obesity, hyperglycemia, and hyperinsulinemia showed these features but also adapted to fasting in a fashion permitting prolonged survival during this state. In a fashion analogous to that known to occur in man, these animals developed fall in glycemia, rise in circulating fat-derived substrates, and marked protein conservation. Profound fall in insulinemia was associated with a fall in glucagonemia, the latter from normal levels. Thus the initial markedly "anabolic" insulin/glucagon molar ratio diminished, but nevertheless remained higher than at any time in the lean mice. Pancreatic contents of insulin showed markedly different changes with fasting in obob compared with lean mice. The ability of the obese mouse to adapt to prolonged fasting in a fashion largely analogous to that of man renders it a useful model for the study of metabolism in this state, with the potential of applicability of findings to man.


Exploring New Mechanism of Depression from the Effects of Virus on Nerve Cells.
Depression is a common neuropsychiatric disorder with long-term recurrent depressed mood, pain and despair, pessimism and anxiety, and even suicidal tendencies as the main symptoms. Depression usually induces or aggravates the development of other related diseases, such as sleep disorders and endocrine disorders. In today's society, the incidence of depression is increasing worldwide, and its pathogenesis is complex and generally believed to be related to genetic, psychological, environmental, and biological factors. Current studies have shown the key role of glial cells in the development of depression, and it is noteworthy that some recent evidence suggests that the development of depression may be closely related to viral infections, such as SARS-CoV-2, BoDV-1, ZIKV, HIV, and HHV6, which infect the organism and cause some degree of glial cells, such as astrocytes, oligodendrocytes, and microglia. This can affect the transmission of related proteins, neurotransmitters, and cytokines, which in turn leads to neuroinflammation and depression. Based on the close relationship between viruses and depression, this paper provides an in-depth analysis of the new mechanism of virus-induced depression, which is expected to provide a new perspective on the mechanism of depression and a new idea for the diagnosis of depression in the future.


Carotid artery injections in 40- to 99-g Fischer rats: technical note and evaluation of blood flow by various injection techniques.
Despite extensive clinical use of brain tumor chemotherapy via the internal carotid artery (ICA), demonstration of efficacy and toxicity screening of ICA chemotherapy in brain tumor models has been limited. A method for performing ICA injections in 40- to 99-g Fischer rats is described, with documentation of its effect upon cerebral blood flow. A 33 gauge cannula was secured into a PE-10 catheter and, after ligation of the external carotid (ECA) and the pterygopalatine arteries, injections were made into the common carotid artery (CCA). The reliability of this method compared to CCA injection with and without ligation of the ECA was evaluated utilizing 15-micrometers 103Ru microspheres. With this technique, 68.3 +/- 11.19% of the microspheres lodged in the brain, compared to 28.9 +/- 21.3% to 32.7 +/- 19.8% for the other techniques (P less than 0.01). With this technique, regional perfusion of brain tumors can be done in the avian sarcoma virus rat glioma model, the D-54 MG human glioma-immunosuppressed rat transplantation model, and any of the large rat brain tumor models. The relevance of this method of experimental regional perfusion for the preclinical assessment of the efficacy and of the toxicity of chemotherapy and immunotherapy via the ICA is discussed.


Flexion Instability After Total Knee Arthroplasty.
Flexion instability after total knee arthroplasty (TKA) is caused by an increased flexion gap compared with extension gap. Patients present with recurrent effusions, subjective instability (especially going downstairs), quadriceps weakness, and diffuse periretinacular pain. Manual testing for laxity in flexion is commonly done to confirm a diagnosis, although testing positions and laxity grades are inconsistent. Nonsurgical treatment includes quadriceps strengthening and bracing treatment. The mainstays to surgical management of femoral instability involve increasing the posterior condylar offset, decreasing the tibial slope, raising the joint line in combination with a thicker polyethylene insert, and ensuring appropriate rotation of implants. Patient outcomes after revision TKA for flexion instability show the least amount of improvement when compared with revisions for other TKA failure etiologies. Future work is needed to unify reproducible diagnostic criteria. Advancements in biomechanical analysis with motion detection, isokinetic quadriceps strength testing, and computational modeling are needed to advance the collective understanding of this underappreciated failure mechanism.


Transfer ribonucleic acid methylase deficiency found in UGA supressor strains.
Extracts of recessive UGA suppressor strains, designated supK, are deficient in transfer ribonucleic acid (tRNA)-methylating activity when compared to wild-type extracts. Moreover, the tRNA from suppressor strains is methyl deficient when compared to wild-type tRNA. This deficiency is due to the lack of a single tRNA methylase activity in suppressor strains. UGA suppressor activity may be caused by the miscoding of one or more methyl-deficient tRNA's in supK strains.


Sex differences in limb vasoconstriction responses to increases in transmural pressures.
Women compared with men are more likely to have orthostatic intolerance. The purpose of this study was to examine whether sex affects limb vasoconstrictor response to increases in transmural pressure. Brachial and femoral mean blood velocity (MBV) and diameter (Doppler Ultrasound) were measured in 10 women and 10 men as transmural pressure was altered by applying local suction (-25, -50, -75, and -100 mmHg) via pressurized-limb tanks for 1 min to a single arm and leg. With the abrupt application of forearm suction (-75 and -100 mmHg), women compared with men had a greater initial rise in MBV (peak), followed by a quicker dynamic rate of velocity reduction. In the leg, women had a tendency for higher peak MBV but had similar dynamic velocity reductions compared with men. After 60 s of suction, women compared with men had attenuated reductions in brachial flow and conductance (-8.05 +/- 1.71 vs. -16.25 +/- 1.71 ml/min; -0.12 +/- 0.03 vs. -0.20 +/- 0.03 ml x min(-1) x mmHg(-1); main effect, P < 0.05), as well as attenuated femoral flow and conductance to sustained leg negative pressure at -100 mmHg (P < 0.05). When the data were expressed as percent change, women compared with men continued to have attenuated brachial flow responses (-24 +/- 2 vs. -36 +/- 2%, main effect, P < 0.05), with a trend toward attenuation at the highest leg pressure (-25 +/- 11 vs. -46 +/- 4%; P = 0.08). These sex differences remained after normalizing the flow responses by limb volume (percent change). Our findings suggest that young women compared with men have attenuated brachial and femoral vasoconstrictor responses to increases in transmural pressure, which may have implications for the greater incidence of orthostatic intolerance in women.


Vaccine-preventable diseases and vaccination rates in South Dakota.
Vaccine-preventable diseases have historically caused much illness and death in South Dakota. Sixty-seven diphtheria deaths were reported in 1892 and 1,017 polio cases were reported at the peak of the polio epidemic in 1952. As vaccines have been developed, licensed and put into wide use, the rates of diphtheria, polio, measles, smallpox and other diseases have successfully decreased leading to control, statewide elimination or eradication. Other diseases, such as pertussis, have been more difficult to control by vaccination alone. Although current vaccination coverage rates for South Dakota's kindergarten children surpass the Healthy People 2020 targets of 95 percent, the coverage rates for 2-year-old children and teenagers are below the target rates. Until vaccine-preventable diseases are eradicated globally, we must vigilantly maintain high vaccination coverage rates and aggressively apply control measures to limit transmission when diseases do occur in South Dakota.


A randomized controlled trial of the effect of zinc as adjuvant therapy in children 2-35 mo of age with severe or nonsevere pneumonia in Bhaktapur, Nepal.
Pneumonia is a leading cause of illness and death in young children. Interventions to improve case management of pneumonia are needed. Our objective was to measure the effect of zinc supplementation in children with pneumonia in a population in which zinc deficiency is common. In a double-blind, placebo-controlled clinical trial, children aged 2-35 mo with severe (n = 149) or nonsevere (n = 2479) pneumonia defined according to criteria established by the World Health Organization were randomly assigned to receive zinc (10 mg for children aged 2-11 mo, 20 mg for children aged > or =12 mo) or placebo daily for 14 d as an adjuvant to antibiotics. The primary outcomes were treatment failure, defined as a need for change in antibiotics or hospitalization, and time to recovery from pneumonia. One of 5 children did not respond adequately to antibiotic treatment; the odds ratios between zinc and placebo groups for treatment failure were 0.95 (95% CI: 0.78, 1.2) for nonsevere pneumonia and 0.97 (95% CI: 0.42, 2.2) for severe pneumonia. There was no difference in time to recovery between zinc and placebo groups for nonsevere (median: 2 d; hazard ratio: 1.0; 95% CI: 0.96, 1.1) or severe (median: 4 d; hazard ratio: 1.1; 95% CI: 0.79, 1.5) pneumonia. Regurgitation or vomiting < or =15 min after supplementation was observed more frequently among children in the zinc group than among those in the placebo group during the supplementation period (37% compared with 13%; odds ratio: 0.25; 95% CI: 0.20, 0.30). Adjuvant treatment with zinc neither reduced the risk of treatment failure nor accelerated recovery in episodes of nonsevere or severe pneumonia. This trial was registered at clinicaltrials.gov as NCT00148733.


Identification and localization of procalcitonin-like immunoreactivity in the rat hypothalamus.
Procalcitonin (PCT) is a 116-amino acid polypeptide physiologically produced, as the precursor protein of calcitonin (CT), in the parafollicular cells of the thyroid gland, but physiological functions and other major sources of PCT remains unclear. The distribution of PCT-like immunoreactivity (PCT-LI) in the rat hypothalamus was examined by immunohistochemistry using a monoclonal antibody raised against the mid-region of human PCT (60-77-amino acid fragment). This antibody cross-reacts well with rat PCT and immature CT, but it cross-react poorly with free mature CT. Abundant expression of PCT-LI was found in zones at the interface between brain and cerebrospinal fluid (CSF) such as the ependymal layer and ventral glia limitans (VGL). Double labeling of PCT and glial fibrillary acidic protein (GFAP) identified this population of small cells as astrocytes, possibly tanycytes, a type of specialized glial cell that interacts in neuroendocrine functional dynamics. The fibers of these cells extend to circumventricular organs (CVOs) and to astrocytes located inside the parenchyma of key autonomic regulatory hypothalamic areas, with highest densities in the supraoptic nucleus (SO), arcuate nucleus (Arc), area postrema (AP), median eminence (ME), medial preoptic nucleus, tuber cinereum, and accessory neurosecretory nuclei. No strongly labeled cells were found in the paraventricular nucleus. The wide distribution of PCT-LI in the hypothalamus, in close correspondence with previous mapping of CT receptors in the rat brain, suggests that PCT may influence a multitude of biological activities associated with the hypothalamic-pituitary axis.


[The peripheral polyneuropathy in patients with chronic HCV infection treated peginterferon alfa with ribavirin].
IFN-alpha maybe stimulate to synthesis of autoantibodies which damaging of myelin sheath at peripheral neurons. We report the patient, man, with hepatitis C infection who was treated with peginterferon alfa-2a by one month and next with peginterferon alfa-2b by 3 months in combination with ribavirin. We observed paresis of hands and legs in fourth months of treatment. This patient's dust of difficulty with walking. In EMG investigation was detected demyelin damage of sensor motor nerves. These changes were on whole length or in distal part of neuron. It is qualified hard whether cause of peripheral polineuropathy: interferon's or pegylated part. The finished of antiviral treatments as well as use of steroids in therapy were reason of fast improvement of patients.


Cardiovascular Functions of Ena/VASP Proteins: Past, Present and Beyond.
Actin binding proteins are of crucial importance for the spatiotemporal regulation of actin cytoskeletal dynamics, thereby mediating a tremendous range of cellular processes. Since their initial discovery more than 30 years ago, the enabled/vasodilator-stimulated phosphoprotein (Ena/VASP) family has evolved as one of the most fascinating and versatile family of actin regulating proteins. The proteins directly enhance actin filament assembly, but they also organize higher order actin networks and link kinase signaling pathways to actin filament assembly. Thereby, Ena/VASP proteins regulate dynamic cellular processes ranging from membrane protrusions and trafficking, and cell-cell and cell-matrix adhesions, to the generation of mechanical tension and contractile force. Important insights have been gained into the physiological functions of Ena/VASP proteins in platelets, leukocytes, endothelial cells, smooth muscle cells and cardiomyocytes. In this review, we summarize the unique and redundant functions of Ena/VASP proteins in cardiovascular cells and discuss the underlying molecular mechanisms.


[Research progress on pesticide residues of Panax ginseng].
Panax ginseng, a perennial herb, is prone to diseases and insect pests in the growth process, which are primarily prevented and treated by pesticides. However, due to the lack of standardization in the types, frequencies, and doses of pesticides, pesticide residues have become the main exogenous pollutants of P. ginseng. To explore the risk of pesticide residues in P. ginseng, this paper summarized and analyzed the common pesticide residues in P. ginseng, detection techniques, and pesticide residue limit stan-dards based on the published literature in recent years. The results revealed that the main pesticide residues in P. ginseng were organochlorine pesticides, such as tetrachloronitrobenzene, pentachloronitrobenzene, and hexachlorobenzene, and the detection techniques were dominated by gas chromatography(GC), liquid chromatography(LC), or those combined with mass spectrometry(MS). Because of the long half-life and difficulty in degradation, organochlorine pesticides have become the main factor affecting the export of P. ginseng. It is worth mentioning that P. ginseng has been classified as food in Japan, South Korea, the European Union, and other countries, and the standards of pesticide residues and limits are stricter than those in China. The quality and safety of P. ginseng are prerequisites for the efficacy of Chinese medicine and the development of traditional Chinese medicine. The formulation of scientific and effective standards for pesticide application and limits would promote the high-quality development of the P. ginseng industry.


LincRNA-p21 knockdown enhances radiosensitivity of hypoxic tumor cells by reducing autophagy through HIF-1/Akt/mTOR/P70S6K pathway.
Hypoxic conditions are common in solid tumors and have a significant effect on tumor progression, therapeutic and prognosis. Long noncoding RNAs (lncRNAs) are longer than 200 nucleotides and cannot be translated into proteins, which play important roles in some diseases including cancer. Although previous analysis have showed that long intergenic non-coding RNA (lincRNA)-p21 is hypoxia-responsive and functions as a new regulator of cell cycle, apoptosis and warburg effect in cervical cancer, its biological roles in hypoxic hepatoma and glioma are unknown. In this work, we found that X-ray irradiation or hypoxia treatment elevated lincRNA-p21 expression in SMMC7721 hepatoma and U251MG glioma cells. Knockdown of lincRNA-p21 induced G2/M phase arrest, promoted apoptosis, decreased cell proliferation and motility, and reduced autophagy through HIF-1/Akt/mTOR/P70S6K pathway in hypoxic tumor cells. Our results delineated a novel mechanism of lincRNA-p21 in enhancing hypoxic tumor cell radiosensitivity, which might provide valuable targets for radiation therapy for solid tumors, such as hepatoma and glioma.


Laser-Assisted In Situ Keratomileusis Surgery on a Patient with Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease or Neuromyelitis Optica Spectrum Disorder.
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD) are rare central demyelinating diseases that may affect refractive surgery outcomes. Optic neuritis and brainstem syndromes affecting cranial nerves are particularly relevant to corneal refractive surgery (CRS), such as laser-assisted in situ keratomileusis (LASIK), photorefractive keratectomy, or small incision lenticule extraction. There is currently no existing literature concerning the outcomes of CRS in patients with MOGAD or NMOSD. This article reports the clinical outcome of a MOGAD patient who underwent LASIK.


The MEK/ERK pathway promotes NOTCH signalling in pancreatic cancer cells.
Activation of the NOTCH receptors relies on their intracellular proteolysis by the gamma-secretase complex. This cleavage liberates the NOTCH intracellular domain (NIC) thereby allowing the translocation of NIC towards the nucleus to assemble into a transcriptional platform. Little information is available regarding the regulatory steps operating on NIC following its release from the transmembrane receptor up to its association with transcriptional partners. Interfering with these regulatory steps might potentially influences the nuclear outcome of NOTCH signalling. Herein, we exploited a reliable model to study the molecular events occurring subsequent to NOTCH1 cleavage. In pancreatic cancer cells, pulse of NOTCH1 activation led to increased expression of NOTCH target genes namely HES1 and c-MYC. We uncovered that, upon its release, the NOTCH1 intracellular domain, NIC1, undergoes a series of post-translational modifications that include phosphorylation. Most interestingly, we found that activation of the MEK/ERK pathway promotes HES1 expression. Inhibition of the gamma-secretase complex prevented the MEK/ERK-induced HES1 expression suggesting a NOTCH-dependent mechanism. Finally, higher levels of NIC1 were found associated with its transcriptional partners [CBF1, Su(H) and LAG-1] (CSL) and MASTERMIND-LIKE 1 (MAML1) upon MEK/ERK activation providing a potential mechanism whereby the MEK/ERK pathway promotes expression of NOTCH target genes. For the first time, our data exposed a signalling pathway, namely the MEK/ERK pathway that positively impacts on NOTCH nuclear outcome.


Functional and phenotypic effects of AhR activation in inflammatory dendritic cells.
Aryl hydrocarbon receptor (AhR) activation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induces immune suppression. Dendritic cells (DCs) are key antigen presenting cells governing T cell activation and differentiation. However, the consequences of AhR activation in DCs are not fully defined. We hypothesized that AhR activation alters DC differentiation and generates dysfunctional DCs. To test this hypothesis, inflammatory bone marrow-derived DCs (BMDCs) from C57Bl/6 mice were generated in the presence of vehicle or TCDD. TCDD decreased CD11c expression but increased MHC class II, CD86 and CD25 expression on the BMDCs. The effects of TCDD were strictly AhR-dependent but not exclusively DRE-mediated. Similar effects were observed with two natural AhR ligands, 6-formylindolo[3,2-b]carbazole (FICZ) and 2-(1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid (ITE). TCDD increased LPS- and CpG-induced IL-6 and TNF-alpha production by BMDCs but decreased their NO production. TCDD decreased CpG-induced IL-12p70 production by BMDCs but did not affect their secretion of IL-10. TCDD downregulated LPS- and CpG-induced NF-kB p65 levels and induced a trend towards upregulation of RelB levels in the BMDCs. AhR activation by TCDD modulated BMDC uptake of both soluble and particulate antigens. Induction of indoleamine-2,3-dioxygenase (IDO) and TGF-beta3 has been implicated in the generation of regulatory T cells following AhR activation. TCDD increased IDO1, IDO2 and TGF-beta3 mRNA levels in BMDCs as compared to vehicle. Despite the induction of regulatory mediators, TCDD-treated BMDCs failed to suppress antigen-specific T cell activation. Thus, AhR activation can directly alter the differentiation and innate functions of inflammatory DCs without affecting their ability to successfully interact with T cells.


Fecal diversion in the management of Crohn's disease of the colon.
The clinical course of 44 patients undergoing elective proximal fecal diversion for Crohn's disease of the colon is reported. Sustained disease remission was obtained in 31 patients (70 percent). Diversion was associated with a significant reduction in steroid requirements (P < 0.01) and a significant improvement in hemoglobin (P < 0.001), erythrocyte sedimentation rate (P < 0.001), and albumin (P < 0.05). Sixteen patients (36.4 percent) have required a proctocolectomy, 19 patients (43.2 percent) remain defunctioned, and four patients (9 percent) have died. Five patients have had intestinal continuity restored, which has remained intact in four patients for a mean follow-up of 99 (range 21-153) months. Fecal diversion for Crohn's disease of the colon produces a high incidence of sustained disease remission, but for the majority of patients the prospect of future restoration of intestinal continuity is limited.


Choroid plexus aquaporin 1 and intracranial pressure are increased in obese rats: towards an idiopathic intracranial hypertension model?
Idiopathic intracranial hypertension (IIH) is a condition of increased intracranial pressure (ICP) without identifiable cause. The majority of IIH patients are obese, which suggests a connection between ICP and obesity. The aim of the study was to compare ICP in lean and obese rats. We also aimed to clarify if any ICP difference could be attributed to changes in some well-known ICP modulators; retinol and arterial partial pressure of CO2 (pCO2). Another potential explanation could be differences in water transport across the choroid plexus (CP) epithelia, and thus we furthermore investigated expression profiles of aquaporin 1 (AQP1) and Na/K ATPase. ICP was measured in obese and lean Zucker rats over a period of 28 days. Arterial pCO2 and serum retinol were measured in serum samples. The CPs were isolated, and target messenger RNA (mRNA) and protein were analyzed by quantitative PCR and western blot, respectively. Obese rats had elevated ICP compared to lean controls on all recording days except day 0 (P<0.001). Serum retinol (P=0.35) and arterial pCO2 (P=0.16) did not differ between the two groups. Both AQP1 mRNA and protein levels were increased in the CP of the obese rats compared to lean rats (P=0.0422 and P=0.0281). There was no difference in Na/K ATPase mRNA or protein levels (P=0.2688 and P=0.1304). Obese Zucker rats display intracranial hypertension and increased AQP1 expression in CP compared to lean controls. The mechanisms behind these changes are still unknown, but appear to be unrelated to altered pCO2 levels or retinol metabolism. This indicates that the increase in ICP might be related to increased AQP1 levels in CP. Although further studies are warranted, obese Zucker rats could potentially model some aspects of the IIH pathophysiology.


Arousal, processing, and risk taking: consequences of intergroup anger.
Intergroup emotions theory (IET) posits that when social categorization is salient, individuals feel the same emotions as others who share their group membership. Extensive research supporting this proposition has relied heavily on self-reports of group-based emotions. In three experiments, the authors provide converging evidence that group-based anger has subtle and less explicitly controlled consequences for information processing, using measures that do not rely on self-reported emotional experience. Specifically, the authors show that intergroup anger involves arousal (Experiment 1), reduces systematic processing of persuasive messages (Experiment 2), is moderated by group identification (Experiment 2, posttest), and compared to intergroup fear, increases risk taking (Experiment 3). These findings provide converging evidence that consistent with IET, emotions triggered by social categorization have psychologically consequential effects and are not evident solely in self-reports.


Probing compartment-specific sphingolipids with targeted bacterial sphingomyelinases and ceramidases.
Sphingolipids contribute to the regulation of cell and tissue homeostasis, and disorders of sphingolipid metabolism lead to diseases such as inflammation, stroke, diabetes, and cancer. Sphingolipid metabolic pathways involve an array of enzymes that reside in specific subcellular organelles, resulting in the formation of many diverse sphingolipids with distinct molecular species based on the diversity of the ceramide (Cer) structure. In order to probe compartment-specific metabolism of sphingolipids in this study, we analyzed the Cer and SM species preferentially produced in the inner plasma membrane (PM), Golgi apparatus, ER, mitochondria, nucleus, and cytoplasm by using compartmentally targeted bacterial SMases and ceramidases. The results showed that the length of the acyl chain of Cer becomes longer according to the progress of Cer from synthesis in the ER to the Golgi apparatus, then to the PM. These findings suggest that each organelle shows different properties of SM-derived Cers consistent with its emerging distinct functions in vitro and in vivo.


Effect of antimicrobial compounds on Balamuthia mandrillaris encystment and human brain microvascular endothelial cell cytopathogenicity.
Cycloheximide, ketoconazole, or preexposure of organisms to cytochalasin D prevented Balamuthia mandrillaris-associated cytopathogenicity in human brain microvascular endothelial cells, which constitute the blood-brain barrier. In an assay for inhibition of cyst production, these three agents prevented the production of cysts, suggesting that the biosynthesis of proteins and ergosterol and the polymerization of actin are important in cytopathogenicity and encystment.


Biochemical evidence for a deficiency of vitamin B6 in the carpal tunnel syndrome based on a crossover clinical study.
In a patient with severe carpal tunnel syndrome and a significant deficiency of vitamin B(6), the evidence for the deficiency was an extraordinarily low basal specific activity of the glutamic-oxaloacetic transminase of the erythrocytes (EGOT). This enzyme was also deficient in pyridoxal phosphate. The patient was treated with the recommended dietary allowance of pyridoxine, 2 mg/day, for 11 weeks, then 100 mg/day for 12 weeks, a placebo for 9 weeks, and again pyridoxine at 100 mg/day for 11 weeks. Sixty-one monitorial assays of EGOT over 48 weeks supported the following interpretations. (i) His diet permitted the development of a debilitating carpal tunnel syndrome. (ii) Treatment with pyridoxine at 2 mg/day reduced the deficiency of EGOT activity from about 70% to 50%, maintained a deficiency of pyridoxal phosphate, and relieved but allowed a marginal syndrome. (iii) Treatment at 100 mg/day for 12 weeks nearly achieved a "ceiling" level of EGOT and eliminated the deficiency of pyridoxal phosphate. (iv) After placebo for 7 weeks, the deficiencies of EGOT activity and pyridoxal phosphate reappeared, and clinical symptoms become worse. (v) Retreatment at 100 mg/day reestablished a "ceiling" EGOT, with no deficiency of pyridoxal phosphate, and the patient was asymptomatic. These data also support the concept that a deficiency of vitamin B(6) is significant in the etiology of the carpal tunnel syndrome. Mechanistically, a state of deficiency of the coenzyme seems to lower the level of the apoenzyme; a state of no deficiency of the coenzyme regulates a ceiling level of the transaminase. The latter state is presumably desired for health.


Expression of rat hepatic 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase is affected by a high protein diet and by streptozotocin-induced diabetes.
In the tryptophan-niacin conversion, 2-amino-3-carboxymuconate-6-semiardehyde decarboxylase (ACMSD; formerly termed picolinic carboxylase) is an important enzyme regulating the generation of quinolinate. In a series of experiments, we investigated alterations of ACMSD expression in rats by feeding a high protein diet and by inducing diabetes with streptozotocin (STZ). Male Sprague-Dawley rats (5-wk-old) were fed a diet containing 40% casein for 11 d, and hepatic ACMSD activity and mRNA expression were determined at intervals. The enzyme activity had increased at d 2, and it continued to increase through d 11. ACMSD mRNA expression had increased at d 1 and the elevated levels were maintained through d 11. Shifting from the 40% casein diet to a 20% casein diet restored hepatic ACMSD activity and mRNA expression to normal levels within 5 d and 2 d, respectively. In another series of experiments, male Wistar rats were injected with STZ (50 mg/kg) and the time-course (d 0, 1, 2, 4, 8 and 14) of the change in hepatic ACMSD activity and mRNA expression were examined. The activity increased dramatically after d 4, while mRNA expression was significantly elevated at d 2, followed by slight increases through d 14. Insulin administration (2 U/12 h) reduced the elevated ACMSD activity and fully suppressed the elevated ACMSD mRNA expression due to STZ injection. These results indicated that the fluctuation of hepatic ACMSD mRNA expression was followed by that of ACMSD activity.


A Mixed-Methods Investigation of Medical Follow-Up in Long-Term Childhood Cancer Survivors: What Are the Reasons for Non-Attendance?
As long-term childhood cancer survivors (CCS) are at risk for late effects, ongoing medical care is crucial to detect and treat physical illnesses as early as possible. However, previous research from around the world has shown that many adult survivors did not participate in long-term medical follow-up. This study aimed to provide insight into German survivors' care situation, with a particular focus on barriers to follow-up care. We investigated a sample of adult CCS (N = 633) (age M = 34.92; SD = 5.70 years) drawn from the German Childhood Cancer Registry's oldest cohort (> 25 years after diagnosis). Our analyses included data from a standardized medical examination, a self-report questionnaire, and in-depth interviews with a subsample (n = 43). Half of the participants (n = 314, 49.6%) reported participating in some kind of medical follow-up. In a logistic regression analysis, attendance of medical follow-up care was associated with higher age. Reasons for non-attendance were assigned to four categories: lack of information about medical follow-up and/or its purpose (n = 178), termination by the health care provider (n = 53), structural barriers (n = 21), and emotional-motivational aspects (n = 17). The interviews contributed to a better understanding of how these reported barriers played out in the care of individual survivors. Further, they revealed that some survivors currently in medical follow-up had had periods without follow-up care in the past-which were also in many cases related to a lack of information, both on the part of health care providers and CCS themselves. The results indicated that a large proportion of long-term CCS do not receive the recommended follow-up care. Further, there is a great need for more information regarding the aims of long-term medical follow-up and available offers. This is an important prerequisite for CCS to make informed decisions.


Immunity to cartilage link protein in patients with juvenile rheumatoid arthritis.
To determine whether children with juvenile rheumatoid arthritis (JRA) express cellular immunity to cartilage link protein. Link protein was purified from human fetal epiphyseal and bovine adult nasal cartilage. It was used in proliferation assays with the peripheral blood lymphocytes isolated from 54 children with JRA and 22 nonarthritic controls. Patients with JRA expressed a significantly higher prevalence of cellular proliferation to human link protein compared with the control group, independent of whether they had pauciarticular, polyarticular, or systemic disease. In the case of bovine link protein, significant differences were only noted for the polyarticular group. There was significant correlation between the immunity to bovine and to human link proteins. Furthermore, immune responses to both molecules correlated with measures of joint disease activity. These results suggest that immunity to link protein may play a role in the pathogenesis of JRA.


The association of cholesterol absorption gene Numb polymorphism with Coronary Artery Disease among Han Chinese and Uighur Chinese in Xinjiang, China.
Hypercholesterolemia is a major risk factor for coronary artery disease (CAD). As Numb is an important regulating factor for intestinal cholesterol absorption and plasma cholesterol level, the aim of the present study is to assess the association between human Numb gene polymorphism and CAD among Han and Uighur Chinese. We have conducted two independent case-control studies in Han Chinese (384 CAD patients and 433 controls) and Uighur Chinese (506 CAD patients and 351 controls) subjects. All subjects were genotyped for four kinds of SNPs (rs12435797, rs2108552, rs1019075 and rs17781919) and SNP is used as a genetic marker for human Numb gene. Genotyping was undertaken using TaqMan SNP genotyping assay, and the subjects' ethnicity and gender were considered in the analysis. We found that rs2108552 was associated with CAD in the dominant model (CC vs CG + GG) for the total Han Chinese population (n = 200) and Han Chinese males (n = 115) (P = 0.004 and P = 0.001, respectively). The difference remained statistically significant after multivariate adjustment (total: OR = 1.687, P = 0.004; male: OR = 1.498, P = 0.006). Further, for the total (n = 817) and male (n = 490) Han Chinese, the frequency of the haplotype (T-C-T-C) was significantly higher in the CAD patients than in the controls (P = 0.004 and P = 0.002), and the frequency of the haplotype (G-G-T-C) was significantly lower in the CAD patients than in the control subjects (P = 0.013, P = 0.007). In addition, for the total (n = 857) and male (n = 582) Uighur Chinese, we observed that rs12435797 was associated with CAD in an additive and recessive model (P = 0.021 and P = 0.009; P = 0.048 and P = 0.034). However, the difference did not remain statistically significant after multivariate adjustment. The overall distribution of rs2108552, rs1019075 and rs17781919 genotypes, alleles and the frequency of the haplotype established by four SNPs showed no significant difference between CAD patients and control subjects in the total, male and female Uighur Chinese. The results of this study indicate that CC genotype of rs2108552 and T-C-T-C haplotypes in Numb gene is a possible risk genetic marker and G allele and G-G-T-C haplotypes is a possible protective genetic marker for CAD in male Han Chinese.


Patient and surgical factors associated with postoperative urinary retention after lumbar spine surgery.
Retrospective case series. The objectives of this study were to (1) determine the rate of postoperative urinary retention (POUR) in a series of patients undergoing lumbar spine surgery, (2) compare length of hospital stay between patients who developed POUR and patients who did not, and (3) identify the patient and surgical factors associated with the development of POUR. Although POUR is a common complication in many surgical subspecialties, sparse literature is present regarding development of POUR after posterior lumbar surgical procedures. A retrospective review was conducted of all posterior lumbar surgery cases performed at single institute from July 2008 to July 2012. Data collected included demographic variables (age, sex, body mass index), length of stay, comorbid medical conditions, and surgical data. The Wilcoxon rank sum test with continuity correction was used to compare length of hospital stay between patients who developed POUR and patients who did not. A multivariate logistic regression model was created using all patient and surgical factors and systematically pruned of variables not improving overall predictive power. A total of 647 patients (291 decompression, 356 decompression and fusion) were included in the study. Of 647 patients, 36 had urinary retention after lumbar spine surgery (5.6%). Patients who developed POUR had a longer length of stay than patients who did not develop POUR (3.94 d vs. 2.34 d; P=0.005). Male sex, benign prostatic hyperplasia, age, diabetes, and depression were significantly associated with development of POUR (odds ratio=3.05, 9.82, 1.04, 3.32, and 2.51, respectively). Smoking was inversely associated with the development of POUR (odds ratio=0.45). The risk of developing POUR after posterior lumbar spine surgery is approximately 5%. Male sex, benign prostatic hyperplasia, age, diabetes, and depression were significantly associated with the POUR group. Patients who developed POUR had a greater length of hospital stay. 4.


Localization and ontogeny of cells expressing preprodynorphin mRNA in the rat cerebral cortex.
The regional distribution of preprodynorphin (PPD) mRNA-containing cells (PPD cells) in the rat cerebral cortex was investigated by in situ hybridization histochemistry using a synthetic oligonucleotide probe. In the isocortex, PPD cells were small or medium-sized and were mainly located in layer V. While they were less numerous in the allocortex than in the isocortex. Only a few labeled cells were seen in the piriform and entorhinal cortices. In the hippocampal formation, labeled cells were observed in the granular layer of the dentate gyrus. An ontogenetic study revealed that PPD mRNA-containing cells appeared on postnatal day 7 in the isocortex and the allocortex and on day 14 in the dentate gyrus. Thereafter, they increased in number and signal intensity to reach a plateau on postnatal day 14 in both the isocortex and the allocortex and on day 35 in the dentate gyrus. The time-course of development of PPD mRNA-containing neurons in the cerebral cortex suggested that PPD-derived peptide has a neuromodulator and/or neurotransmitter role in these regions of the brain.


An aerodynamic model for insect flapping wings in forward flight.
This paper proposes a semi-empirical quasi-steady aerodynamic model of a flapping wing in forward flight. A total of 147 individual cases, which consisted of advance ratios J of 0 (hovering), 0.125, 0.25, 0.5, 0.75, 1 and ∞, and angles of attack α of -5 to 95° at intervals of 5°, were examined to extract the aerodynamic coefficients. The Polhamus leading-edge suction analogy and power functions were then employed to establish the aerodynamic model. In order to preserve the existing level of simplicity, K P and K V, the correction factors of the potential and vortex force models, were rebuilt as functions of J and α. The estimations were nearly identical to direct force/moment measurements which were obtained from both artificial and practical wingbeat motions of a hawkmoth. The model effectively compensated for the influences of J, particularly showing outstanding moment estimation capabilities. With this model, we found that using a lower value of α during the downstroke would be an effective strategy for generating adequate lift in forward flight. The rotational force and moment components had noticeable portions generating both thrust and counteract pitching moment during pronation. In the upstroke phase, the added mass component played a major role in generating thrust in forward flight. The proposed model would be useful for a better understanding of flight stability, control, and the dynamic characteristics of flapping wing flyers, and for designing flapping-wing micro air vehicles.


[Value of E-selectin and L-selectin determination in children and youth with inflammatory bowel disease].
Chronic inflammation is the common feature of inflammatory bowel disease. Infiltration of leucocytes is mediated by definite adhesion molecules expressed on the surface of activated leucocytes, platelets and endothelial cells. to investigate the clinical value of determining concentrations of sE-selectin and sL-selectin in children and youth with Crohn's disease and ulcerative colitis. soluble adhesion molecules were studied in the serum of 31 patients with Crohn's disease (CD) and 27 with ulcerative colitis (UC) and 20 healthy controls aged 6-18. Crohn's disease and ulcerative colitis patients were divided according to Hyams and Truelove-Witts' indeces of disease activity. Serum levels of sE-selectin and sL-selectin were measured using an enzyme-linked immunosorbent assay kit of Bender MedSystem. sE-selectin levels of the inflammatory bowel disease patients were higher then those of controls and sL-selectin levels of the IBD patients were lower than those of controls but without statistical significant differences. The sE-selectin levels of Crohn's disease patients with active disease were statistically significant higher then those with remission of the disease (29,17 + 25,65 ng/ml vs 50,74 + 20,00 ng/ml). There was no statistically significant difference in the levels of L-selectin between patients with active disease and those with remission. There were no statistically significant differences in the levels of sE-selectin and sL-selectin between patients with active ulcerative colitis disease and patients with remission. determination of sE-selectin in children with Crohn's disease is of significance in estimation of inflammation activity.


Beneficial effects on employment and preventive health care: the concept and results of counselling processes from a German project.
Since December 1998 a project of working time counselling named "Design of Modern Working Times" is supported by the federal state of North Rhine-Westphalia in Germany and the European Union; AWiS-consult is entrusted to carry out this project. The service offered to all companies, institutions, work committees, and employees interested covers information, assessment of existing working time schedules, development of alternative or new working time schedules, and accompanying implementation processes. Up to June 2001 nearly 300 inquiries were worked on, most of them from industry, service companies, and from the field of care and hospitals. Working time design in this project aims not only at work safety and health care but also at beneficial effects on employment. In a special campaign from May 2000 to May 2001, 61 companies were supported by AWiS-consult, with the result of more than 400 new employees and 16 companies with employment secured, so the combination of preventive health care and beneficial effects on employment by working time design can be assessed as successful.


Association of iron therapy with incidence of chronic kidney disease.
We investigated the association of oral iron replacement with the incidence of chronic kidney disease (CKD) in a population with normal kidney function to study the effects of iron replacement on the development of new onset CKD. In a national cohort of US Veterans with no pre-existing CKD, we identified 33 894 incident new users of oral iron replacement and a comparable group of 112 780 patients who did not receive any iron replacement during 2004-2018. We examined the association of oral iron replacement versus no iron replacement with the incidence of eGFR <60 mL/min/1.73 m2 and the incidence of urine albumin creatinine ratio (UACR) ≥30 mg/g in competing risk regressions and in Cox models. We used propensity score weighing to account for differences in key baseline characteristics associated with the use of oral iron replacement. In the cohort of 146 674 patients, a total of 18 547 (13%) patients experienced incident eGFR <60 mL/min/1.73 m2 , and 16 117 patients (11%) experienced new onset UACR ≥30 mg/g. Oral iron replacement was associated with significantly higher risk of incident eGFR <60 mL/min/1.73 m2 (subhazard ratio, 95% confidence interval [CI]: 1.3 [1.22-1.38], p < .001) and incident albuminuria (subhazard ratio, 95% CI: 1.14 [1.07-1.22], p < .001). Oral iron replacement is associated with higher risk of new onset CKD. The long-term kidney safety of oral iron replacement should be tested in clinical trials.


Nanosecond laser-induced photochemical oxidation method for protein surface mapping with mass spectrometry.
We have developed an ultrafast pulse method for protein surface footprinting by laser-induced protein surface oxidations. This method makes use of a pulse UV laser that produces, in nanoseconds, a high concentration of hydroxyl (OH) free radicals by photodissociation of a hydrogen peroxide (H2O2) solution. The OH radicals oxidize amino acid residues located on the protein surface to produce stable covalent modifications. The oxidized protein is then analyzed by mass spectrometry to map the oxidized amino acid residues. Ubiquitin and apomyoglobin were used as model proteins in this study. Our results show that a single laser pulse can produce extensive protein surface oxidations. We found that monooxidized ubiquitins were more susceptible to further oxidations by subsequent laser irradiation, as compared to nonoxidized ones. This is due to the conformational changes of proteins by oxidation that increases the solvent-accessible surface area. Therefore, it is crucial to perform this experiment with a single pulse of laser so as to avoid oxidation of proteins after conformation of the protein changes. Subsequently, to obtain a high frequency and coverage of the oxidation sites while keeping the number of laser shots to one, we further optimized the laser power and concentration of hydrogen peroxide as well as the concentration of protein. This ultrafast OH radical generation method allows for rapid and accurate detection of surface residues, enabling mapping of the solvent-accessible regions of a protein in its native state.


[Structure and ecological environmental efficiency of urban forestation].
It is proposed that a new pattern of forestation, arbor-shrub-lawn composite construction, based on analyzing the form and the actual state of the urban forestation. The arbor-shrub-lawn is superior by comparing with the urban lawn as for ecological environmental function including landscape. It is suggested that forestation's ecological saving efficiency and management, maintaining and reducing cost should be thought over simultaneously.


Plant growth-promoting rhizobacteria associated with avocado display antagonistic activity against Phytophthora cinnamomi through volatile emissions.
Rhizobacteria associated with crops constitute an important source of potentially beneficial microorganisms with plant growth promoting activity or antagonistic effects against phytopathogens. In this study, we evaluated the plant growth promoting activity of 11 bacterial isolates that were obtained from the rhizosphere of healthy avocado trees and from that of avocado trees having survived root rot infestations. Seven bacterial isolates, belonging to the genera Bacillus, Pseudomonas and Arthrobacter, promoted in vitro growth of Arabidopsis thaliana. These isolates were then tested for antagonistic activity against Phytophthora cinnamomi, in direct dual culture assays. Two of those rhizobacterial isolates, obtained from symptomatic-declining trees, displayed antagonistic activity. Isolate A8a, which is closely related to Bacillus acidiceler, was also able to inhibit P. cinnamomi growth in vitro by 76% through the production of volatile compounds. Solid phase microextraction (SPME) and analysis by gas chromatography coupled with mass spectrometry (GC-MS) allowed to tentatively identify the main volatiles emitted by isolate A8a as 2,3,5-trimethylpyrazine, 6,10-dimethyl-5,9-undecadien-2-one and 3-amino-1,3-oxazolidin-2-one. These volatile compounds have been reported to show antifungal activity when produced by other bacterial isolates. These results confirm the significance of rhizobacteria and suggest that these bacteria could be used for biocontrol of soil borne oomycetes through their volatiles emissions.


Experimental renal candidiasis in mice and guinea pigs.
As a part of an experimental study of the spread of urogenital infections, male guinea pigs and mice were intravenously injected with a sublethal dose of Candida albicans in a long-time experiment. The kidney was the organ of maximum infection. Spread in the kidney was observed from the cortical and glomerular capillaries, where the injected yeast cells first lodged, but after pseudomycelial transformation penetrated into the Bowman's space and into the lumen of the tubuli. Guinea pigs recovered from the infection. In mice the renal candidiasis progressed and two types of the disease could be distinguished: an acute type with cortical abscesses and a chronic type with partly necrotic tips of the pyramids and adhering fungal masses in the pelves. A similar picture has been observed in man. The pathogenesis of renal candidiasis seems to resemble that of renal tuberculosis.


Impact of maternal diabetes mellitus on the thermoregulation of the offspring.
Maternal diabetes mellitus (DM) can induce metabolic alterations in both newborn and adult offspring. It is believed that inadequate intrauterine conditions can impair thermogenic capacity of the offspring. The objective of the present study was to evaluate the effects of maternal DM on the offspring thermoregulation. DM was induced by streptozotocin injection (60 mg/g) in Wistar EPM-1 female rats. Control animals were injected with an equal volume of citrate buffer solution (pH 4.5). Fifteen days after confirmation of diabetes by glycaemia higher than 250 mg/dl, the rats were mated and the intercourse was confirmed by vaginal smear. Diabetic animals received daily 1 UI of insulin and control animals, an equivalent volume of saline. After delivery, 6 newborn females were randomly assigned to each mother in order to assure equivalent nutritional status during lactation during which body weight of the offspring was recorded daily. At weaning (28th day) the animals were transferred to individual metallic cages kept inside a chamber under a room temperature of 25 degrees C. In the 60th day, half of the offspring was moved to a chamber at 5 degrees C, remaining there until the 90th day. Four experimental groups were thus formed that were the offspring of control or diabetic dams acclimated at 25 degrees C or 5 degrees C. During the whole experimental period body weight and food intake were recorded and during the acclimation period energy balance was determined. When rats were 90 days-old, they were blood sampled and the carcasses prepared for calorimetric determination. At birth, weaning and 90 days of age, animals were killed for quantification of body fat, protein and water. Blood samples were collected and used to determine blood glucose and insulin. Offspring from diabetic dams showed lower body weight than controls throughout the whole experiment. No effect of maternal DM on energy balance of offspring acclimated at 25 degrees C or at 5 degrees C was observed. Nevertheless, as expected, cold induced an increase in energy intake and energy expenditure as well as a reduction in food efficiency, which was characterized by lower body weight and fat gain without change in body protein. Body composition was altered only at birth, when animals from diabetic mothers showed decreased body fat content and increased percentage of water in the carcass. Only at 90 days the rats from diabetic mothers showed higher glycaemia and lower blood insulin levels than controls suggesting delayed effects of maternal DM on the offspring. After weaning, rectal temperature of the animals was measured at 25 degrees C and 5 degrees C during 2 hours at time 0, 30, 60, 90, and 120 minutes. This parameter was determined at weaning and at 45, 60, 75, and 90 days of age. The results showed that the offspring from diabetic mothers not only had a delayed thermogenic capacity as shown by their inability to keep body temperature at 5 degrees C until 90 days. It is, thus, suggested that maternal diabetes mellitus delayed thermoregulation of the offspring.


Differentially expressed mRNAs, lncRNAs, and miRNAs with associated co-expression and ceRNA networks in ankylosing spondylitis.
Ankylosing spondylitis (AS) is a chronic autoimmune disease characterized by systemic inflammation and pathological osteogenesis. However, the genetic etiology of AS remains largely unknown. This study aimed to explore the potential role of coding and noncoding genes in the genetic mechanism of AS. Using microarray analyses, this study comprehensively compared lncRNA, microRNA, and mRNA profiles in hip joint ligament tissues from patients with AS and controls. A total of 661 lncRNAs, 574 mRNAs, and 22 microRNAs were differentially expressed in patients with AS compared with controls. Twenty-two of these genes were then validated using real-time polymerase chain reaction. Gene ontology and pathway analyses were performed to explore the principal functions of differentially expressed genes. The pathways were involved mainly in immune regulation, intercellular signaling, osteogenic differentiation, protein synthesis, and degradation. Gene signal transduction network, coding-noncoding co-expression network, and competing endogenous RNA expression network were constructed using bioinformatics methods. Then, two miRNAs, miR-17-5p and miR-27b-3p, that could increase the osteogenic differentiation potentials of ligament fibroblasts were identified. Finally, differentially expressed, five lncRNAs, four miRNAs, and five mRNAs were validated using quantitative real-time polymerase chain reaction. These results suggested that mRNAs, lncRNAs, and microRNAs were involved in AS pathogenesis. The findings might help characterize the pathogenesis of AS and provide novel therapeutic targets for patients with AS in the future.


An Exploratory Study of Sevoflurane as an Alternative for Difficult Sedation in Critically Ill Children.
To analyze the effectiveness of inhaled sevoflurane in critically ill children with challenging sedation. Prospective case series. Two PICUs of university hospitals in Spain. Prospective observational study and exploratory investigation conducted in two PICUs in Madrid, Spain, over a 6-year period. Children treated with inhaled sevoflurane due to difficult sedation were included. Sevoflurane was administered via the anesthetic conserving device (AnaConDa) connected to a Servo-I ventilator (Maquet, Solna, Sweden). A morphine infusion was added to sevoflurane for analgesia. Demographic and clinical data, oral and IV sedatives, Sedation and Analgesic Clinical scores, and Bispectral Index Score monitoring were registered. Twenty-three patients with a median age of 6 months old were included. Fifty percentage of the patients had critical heart diseases. Sedative and analgesic drugs used before starting sevoflurane were mainly midazolam (63%) and fentanyl (53%). Six patients (32%) also received muscle relaxants. Sevoflurane was administered for a median of 5 days (interquartile range, 5.5-8.5 d). Median end-tidal sevoflurane concentration was 0.8% (interquartile range, 0.7-0.85%), achieved with an infusion rate of 7.5 mL/hr (5.7-8.6 mL/hr). After 48 hours of treatment, some sedative drugs could be removed in 18 patients (78%). Median Bispectral Index Score value prior to sevoflurane administration was 61 (interquartile range, 49-62), falling to 42 (interquartile range, 41-47; p < 0.05) after 6 hours of treatment. Six patients (26%) presented withdrawal syndrome after sevoflurane suspension, and all of them had received sevoflurane at least for 6 days. The main side effect was moderate hypotension in seven patients (30%). Inhaled sevoflurane appeared to be an effective sedative agent in critically ill children and can be useful in those patients on mechanical ventilation difficult to sedate with conventional drugs. It can be administered easily in the PICU with conventional ventilators using the AnaConDa system. Withdrawal syndrome may occur with prolonged treatment.


Utility of Contrast Echocardiography in the Diagnosis of a Primary Nonfunctioning Cardiac Paraganglioma with a Coronary Aneurysm.
Cardiac paragangliomas (PGLs) are rare neuroendocrine tumors, and data regarding the features of nonfunctioning PGLs are limited. These tumors are extensively vascularized and have high risk of hemorrhage for surgery and even biopsy. Differential diagnosis including biochemical analysis of these PGLs is important for further management. In this case report, we present the clinical, laboratory, imaging, and radionuclide presentations of a rare primary nonfunctioning cardiac PGL with a coronary aneurysm. Echocardiography initially showed a large echogenic mass in the left atrioventricular groove. The mass presented a diffuse hyperenhancement pattern with a central perfusion defect on contrast echocardiography. The tumor enclosed the left coronary artery from the coronary orifice, and an aneurysm was found in the left circumflex artery, with significantly increased flow velocity. These echocardiographic features and its susceptible location are indicative of the presence of a cardiac PGL. Although all biochemical evaluations of catecholamines from blood and urine samples were negative, positron emission tomography and scintigraphy finally confirmed the diagnosis of a primary cardiac PGL. Therefore, when imaging features are indicative of the presence of PGLs, the implementation of radionuclide imaging for final diagnosis is required even if the biochemical results are negative. Recognizing these uncommon Doppler and contrast echocardiographic characteristics is important for early diagnosing these nonfunctioning PGLs.


Broadband infrared luminescence in γ-ray irradiated bismuth borosilicate glasses.
The influence of γ-ray irradiation on the optical properties of Bi(2)O(3)-B(2)O(3)-SiO(2) glass has been investigated. Broadband infrared (IR) emission at 1310 nm with a FWHM over 200 nm is observed in the γ-ray irradiated glass. The IR luminescence depends on the γ-ray irradiation dose and the concentration of Bi(2)O(3). The thermal stability of the γ-ray irradiated IR luminescence center is studied, and the origin of the IR luminescence center has been suggested.


A peculiarly characterised case of isoniazid-induced pellagra- 2 Ds and a C: a case report.
Niacin or tryptophan deficiency causes pellagra. Isoniazid interferes with the absorption of niacin and individuals on Isoniazid (INH) are at risk of pellagra. Isoniazid preventive therapy (IPT) is the administration of isoniazid to immunosuppressed individuals to prevent active tuberculosis (TB). IPT, in sub-Saharan Africa, the region worst hit by HIV and with a high TB prevalence, is recommended. A 40-year-old, HIV+ Zambian woman on Antiretroviral therapy for five years and IPT for three months presented with a four-day history of constipation, generalised body weakness and irrelevant talk. She complained of a generalised rash, sloughing off, and darkening of the skin on the face, neck, forearms, and dorsum of both feet. A physical examination revealed features of pellagra, and rapid response to oral niacin reaffirmed the diagnosis of pellagra. Unlike typical cases of pellagra presenting with the classic 3 Ds of Diarrhoea, Dementia and Dermatitis, our patient presented with constipation instead of diarrhoea. A consideration of Pellagra in HIV+ patients on IPT whose diet is mostly maize-based will be beneficial, even if the classic 3 Ds of diarrhoea, dementia, and dermatitis are not wholly present. A timely diagnosis and prompt treatment of pellagra can be lifesaving.


Defining a T-cell epitope within HSP 65 in recurrent aphthous stomatitis.
The 65 kD heat shock protein (HSP) has been implicated in the aetiology of recurrent aphthous stomatitis (RAS). We have previously demonstrated that peptide 91-105 derived from the sequence of mycobacterial 65 kD HSP stimulates specifically lymphocytes from patients with RAS. In this investigation, we show that both CD4+ and CD8+ T cells were significantly stimulated with mycobacterial peptide 91-105. In contrast, the human homologous peptide 116-130 stimulated only CD4+ T cells. Inhibition studies showed that CD4+ T cells were class II restricted, whereas CD8+ T cells were class I restricted. We then used truncated or substituted peptides, and demonstrated that residues 95-105 appear to be important, and residue 104(Arg) critical, in stimulating the T cells. Thus, peptide 95- 105 may constitute a T-cell proliferative epitope in RAS. We postulate that the high load of micro-organisms that colonize the oral mucosa may initiate an immune response by the microbial HSP 65-derived peptide 95-105, stimulating the numerous Langerhans cells in the oral mucosa to activate a cross-reacting immune response to the homologous peptide 116-130 within the epithelial HSP 60, initiating the immunopathological changes that lead to RAS.


Integrated Metabolomics and Network Pharmacology Approach to Explain Possible Action Mechanisms of Xin-Sheng-Hua Granule for Treating Anemia.
As a well-known traditional Chinese medicine (TCM) prescription, Xin-Sheng-Hua Granule (XSHG) has been applied in China for more than 30 years to treat postpartum diseases, especially anemia. However, underlying therapeutic mechanisms of XSHG for anemia were still unclear. In this study, plasma metabolomics profiling with UHPLC-QTOF/MS and multivariate data method was firstly analyzed to discover the potential regulation mechanisms of XSHG on anemia rats induced by bleeding from the orbit. Afterward, the compound-target-pathway network of XSHG was constructed by the use of network pharmacology, thus anemia-relevant signaling pathways were dissected. Finally, the crucial targets in the shared pathways of metabolomics and network pharmacology were experimentally validated by ELISA and Western Blot analysis. The results showed that XSHG could exert excellent effects on anemia probably through regulating coenzyme A biosynthesis, sphingolipids metabolism and HIF-1α pathways, which was reflected by the increased levels of EPOR, F2, COASY, as well as the reduced protein expression of HIF-1α, SPHK1, and S1PR1. Our work successfully explained the polypharmcological mechanisms underlying the efficiency of XSHG on treating anemia, and meanwhile, it probed into the potential treatment strategies for anemia from TCM prescription.


Escherichia coli K1 polysialic acid O-acetyltransferase gene, neuO, and the mechanism of capsule form variation involving a mobile contingency locus.
Potential O-acetylation of the sialic acid residues of Escherichia coli K1, groups W-135, Y, and C meningococci, and group B Streptococcus capsular polysaccharides modifies their immunogenicity and susceptibility to glycosidases. Despite the biological importance of O-acetylation, no sialic or polysialic acid O-acetyltransferase has been identified in any system. Here we show that the E. coli K1 O-acetyltransferase encoded by neuO is genetically linked to the endo-neuraminidase tail protein gene of a chromosomal accretion element, designated CUS-3, with homology to lambdoid bacteriophage. Molecular epidemiological analysis established concordance between O-acetyltransferase and CUS-3 in a set of E. coli K1 strains. Deleting neuO eliminated enzymatic activity, which was restored by complementation in trans, and confirmed by (13)C-NMR analysis of the acetylated product. Analysis of mutants that accumulate intracellular polysialic acid because of export defects (kpsM and kpsS) or an inability to synthesize the sialic acid precursor, N-acetylmannosamine (neuC), indicated that NeuO does not require constant association with its substrate for activity. DNA sequencing and PCR analysis of neuO from strains that had undergone random capsule form variation showed that slip strand DNA mispairing or unequal recombination resulted in gain or loss of (5'-AAGACTC-3')(n) heptanucleotide repeats (where n approximately equals 14-39) located in the neuO 5' region. These repeats code for a previously undescribed structure designated the poly(Psi) motif. The unexpected discovery of the neuO contingency locus (hypervariable gene controlling expression of a surface epitope) in E. coli, and of a potential phage for redistributing variant neuO alleles, provides a robust system for investigating the functions of localized hypermutability in pathogen evolution.


Mechanisms of irregular vibration in a physical model of the vocal folds.
Previous investigations have shown that one mechanism of irregular vocal fold vibration may be a desynchronization of two or more vibratory modes of the vocal fold tissues. In the current investigation, mechanisms of irregular vibration were further examined using a self-oscillating, physical model of vocal fold vibration, a hemi-model methodology, and high-speed, stereoscopic, digital imaging. Using the method of empirical eigen-functions, a spatiotemporal analysis revealed mechanisms of irregular vibration in subharmonic phonation and biphonation, which were not disclosed in a standard acoustic spectrum.


[Filiform keratosis].
A 53-year-old female patient developed disseminated, filiform keratoses up to 4 mm long on the back, arms and neck and upper thorax for the first time 10 years ago. There were no associated diseases or symptoms. Treatment with etretinate was successful. After discontinuing this therapy the patient had a relapse. With this observation we bring new arguments into the discussion on filiform keratoses.


The Role of Adverse Childhood Experiences on People in Opiate Agonist Treatment: The Importance of Feeling Unloved.
Adults in opiate agonist treatment (OAT) often have a background of adverse childhood experiences (ACEs) and are more likely to be exposed to a variety of risks that may trigger post-traumatic stress disorder (PTSD). Summative ACE scores are often used to identify individuals at risk of PTSD and continued substance use. What has not been addressed is whether specific ACE factors are exerting a greater influence on the individual. This study investigated whether specific ACEs predicted PTSD, and current continued substance use among adults in long-term OAT. An analysis of data that were collected at the follow-up stage of a study among 131 adults who attended OAT was conducted. Participants attended one of six OAT settings, covering 45% (n = 890) of clients in a defined area of Dublin, Ireland in 2017. Interviews were conducted with 104 participants, 66 males (63%) and 38 females (37%), with an average age of 43 years (SD = 7.4). The Adverse Childhood Questionnaire (ACQ); PTSD checklist (PCL-5); heroin; tranquilliser; cannabis; alcohol; and cocaine used in the previous 28 days were measured using the quantity used score within the Opiate Treatment Index. Socio-demographics and age of first use of these four substances were also collected. The analysis has focussed on relating ACEs to PTSD, age of first drugs use, and current drug use of the participants. Bivariate analysis showed that the summative ACQ score was significantly correlated with age of first opiate use (p = 0.004). Multiple regression analysis showed that the summative ACQ score and tranquilliser use predicted higher levels of PTSD (R2 = 0.50). Four specific ACEs predicted 54% of the variance in PTSD, these were feeling unloved (β = 0.328) living with a household member who had a problem with alcohol or used illicit street drugs (β = 0.280); verbal abuse (β = 0.219); and living with a person who had a mental illness (β = 0.197). While a summation of all ten ACEs predicted higher levels of PTSD, the factor "feeling unloved" as a child provided the single strongest predictor and may represent an overarching risk of PTSD and continued substance use in later life among adults in treatment for an opiate use disorder.


The low-lying electronic excited states of NiCO.
Highly correlated coupled cluster methods with single and double excitations (CSSD) and CCSD with perturbative triple excitations were used to predict molecular structures and harmonic vibrational frequencies for the electronic ground state X 1Sigma+, and for the 3Delta, 3Sigma+, 3Phi, 1 3Pi, 2 3Pi, 1Sigma+, 1Delta, and 1Pi excited states of NiCO. The X 1Sigma+ ground state's geometry is for the first time compared with the recently determined experimental structure. The adiabatic excitation energies, vertical excitation energies, and dissociation energies of these excited states are predicted. The importance of pi and sigma bonding for the Ni-C bond is discussed based on the structures of excited states.


Evaluation of colistin nephrotoxicity administered at different doses in the rat model.
This study evaluated the usefulness of plasma Cystatin C (pCysC) along with urinary neutrophil gelatinase-associated lipocalin (NGAL), γ-glutamyltransferase (GGT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), aspartate (AST) and alanine (ALT) aminotransferase to monitor colistin nephrotoxicity. Male rats were given intramuscular (i.m.) injections of colistin in doses of 150,000 (G1), 300,000 (G2) and 450,000 IU/kg/day (G3) or normal saline (Control), every 12 h for 7 days. After the 14th injection, animals were placed in metabolic cages and urine samples were collected in the next 12 h. Thereafter, animals were euthanized, blood samples were collected and kidneys were removed for histological assessment. Nephrotoxicity was completely dose-dependent according to pathologic findings. The major insults were acute tubular necrosis in the tubules of G3. No significant change in pCr was observed in all treated groups, but pCysC increased in the G3 compared to the control. In urinary markers, uNGAL level showed a dose dependant increase with significant change in the G2 and G3 groups compared to the control. However, there was no significant change in the AST, ALT, LDH or ALP activities but only GGT increased in the G3 compared to the control. Based on colistin doses used in our experimental study on rat model, histopathologic assessment remains the most accurate way to diagnose colistin nephrotoxicity. pCysC appears to be more reliable than pCr, and uNGAL seems to be the most sensitive factor of colistin nephrotoxicity.


Testicular Fibrous Hypoplasia in Cynomolgus Monkeys ( Macaca fascicularis): An Incidental, Congenital Lesion.
Testicular fibrous hypoplasia is an incidental lesion characterized by replacement of the testicular parenchyma by mature collagen. A retrospective survey of hematoxylin and eosin-stained testicular sections from 722 purpose-bred Asian and 90 Mauritian cynomolgus monkeys from 56 safety assessment studies conducted between 1999 and 2011 was performed. The incidence of the lesion increased markedly over time. No cases occurred between 1999 and 2004. Between 2005 and 2009, the incidence ranged between 8.1% and 11.0% of the monkeys examined and then rose to 26.1% in 2010 and 30.9% in 2011. Overall, the lesion was identified in 10.94% of Asian monkeys with the highest incidence in animals originating from China and Vietnam; severity ranged from minimal to severe and it occurred unilaterally (38.5%) and bilaterally (61.5%). In Mauritian monkeys, the lesion was predominantly minimal in severity, bilateral in distribution, and affected 6.6% of the animals examined. The lesion occurred regardless of sexual maturation status but when present in mature monkeys was often associated with cystic tubular atrophy of the seminiferous epithelium. Based on the morphological characteristics of the lesion and the unilateral/bilateral distribution, the lesion is considered to be a congenital or developmental abnormality.


Food and feeding of Amphiesma stolatum (Linnaeus 1758).
The food and feeding behaviour of Amphiesma stolatum was studied. A total of 117 snakes were examined to analyse the diet composition. Ten live snakes were maintained in enclosure for evaluating the feeding habit, choice of food and rate of assimilation. The anurans constituted the major diet of the food spectrum. In captivity, fishes (fry), amphibians and reptiles were consumed by the snakes. A. stolatum exihibited Elaphe type of hunting behaviour. In most cases the snake struck the prey at its head. The assimilation rate with frog was highest.


Aptamer-Based Electrochemical Biosensor for Mercury Ions Detection Using AuNPs-Modified Glass Carbon Electrode.
A mercury ion aptamer electrochemical biosensor based on a Thymine-Hg2+-Thymine (T-Hg2+-T) structure has been constructed and successfully used to detect mercury ions in tap water samples. The aptamer electrochemical biosensor was assembled using a mercury ion aptamer-functionalized AuNPs-modified glass carbon electrode (aptamer/(AuNPs/CS)₂/GCE) capable of specifically detecting mercury ions through a T-Hg2+-T structure. The experimental results indicated the optimum electrochemical performance of the prepared aptamer biosensor when the (AuNPs/CS)₂/GCE surface was modified with 1.0 μM aptamer and incubated with Hg2+ for 60 min. Moreover, the aptamer biosensor exhibits a good linear relationship between the logarithm of the Hg2+ concentration and the DPV peak current in the range from 0.01 to 500 nM following the linearization equation Ip (μA) = 2.59902 + 0.2097logC (R² = 0.9994) with a limit of detection as low as 0.005 nM. Therefore, the constructed aptamer biosensor provides a simple and sensitive approach for Hg2+ detection in aqueous solution with promising application for trace Hg2+ detection in real samples.


[Breast feeding as "alternative" nutrition? An orientation aid in the field spanning ideology and current status].
Recommending breast feeding supports a trend "back to nature". However, there are believers in the unbiased goodness of nature, who claim effects of mothers milk, e.g. protection from the evils of civilization, that are not confirmed by current scientific knowledge. As nature is not uniquely good (it feeds the donkey and the lion), and as biology is not perfect, breast feeding does not guarantee an uneventful infancy and childhood. There is even a pathology of breast feeding that the pediatrician should be familiar with.- The proven benefits, claimed effects, and some risks of breast feeding are reviewed on the basis of research results, and conclusions are drawn to make breast feeding as uneventful an experience as possible. Potential fields of research are being identified.


A series of alpha-heterocyclic carboxaldehyde thiosemicarbazones inhibit topoisomerase IIalpha catalytic activity.
A series of novel thiosemicarbazone derivatives bearing condensed heterocyclic carboxaldehyde moieties were designed and synthesized. Among them, TSC24 exhibited broad antiproliferative activity in a panel of human tumor cells and suppressed tumor growth in mice. The mechanism research revealed that TSC24 was not only an iron chelator but also a topoisomerase IIalpha catalytic inhibitor. Its inhibition on topoisomerase IIalpha was due to direct interaction with the ATPase domain of topoisomerase IIalpha which led to the block of ATP hydrolysis. Molecular docking predicted that TSC24 might bind at the ATP binding site, which was confirmed by the competitive inhibition assay. These results about the mechanisms involved in the anticancer activities of thiosemicarbazones will aid in the rational design of novel topoisomerase II-targeted drugs and will provide insights into the discovery and development of novel cancer therapeutics based on the dual activity to chelate iron and to inhibit the catalytic activity of topoisomerase IIalpha.


[Ability of carbon dioxide to inhibit generation of superoxide anion radical in cells and its biomedical role].
The study was carried out on blood phagocytes and alveolar macrophages of 96 persons, cells of inner organs and tissue phagocytes (liver, brain, myocardium, lungs, kidneys, stomach, skeletal muscles), as well as on mitochondria of the liver of 186 non-linear white mice. Generation of active oxygen forms (AOF) was evaluated by various methods with CO2 directly affecting the cells and bioptates and indirectly the whole organism. The results show that CO2 with tension close to that of the blood (37.0 mm Hg) and at higher tensions (60 and 146 mm Hg) is a powerful inhibitor of AOF generation by human and animal cells, as well as by liver mitochondria of mice. The data obtained allow to explain, in terms of AOF role, a number of physiological and pathophysiological (medical) CO2 effects.


A formalism for traceable dosimetry in superficial electronic brachytherapy (eBT).
Objective. Despite the number of treatments performed with electronic brachytherapy (eBT) there is no uniform methodology for reference dosimetry for international traceability to primary dosimetry standards in different eBT systems. The objective of this study is to propose a formalism for traceability reference dosimetry in superficial eBT, that is easy to apply in the clinic. This method was investigated for an Elekta Esteya with one applicator.Approach. The calibration x-ray spectrum at the primary standards dosimetry laboratory was matched to the measured eBT photon spectrum. Subsequently, two ionization chambers of different types were calibrated at the primary standard dosimetry laboratory (PSDL) in terms of air kerma against a primary standard. The chambers were used to measure ionization chamber reading ratios in-air at different distances from the applicator. Monte Carlo based air kerma ratios were calculated at different positions from the eBT applicator as well as backscatter factors in water and average mass energy absorption ratios in water and in air. Relative measurements with radiochromic films were performed in a water phantom to determine the ratio of absorbed dose to water,Dw, at the surface toDwat 1 cm depth in water. These were compared with Monte Carlo calculations.Main results. Calculations and measurements were combined to estimate theDwat the surface and at 1 cm depth in water. Ionization chamber agreement of the surface dose was 1.7%, within an uncertainty of 6.8% (k= 2). They agreed with the manufacturer dosimetry within 1.8%, with an uncertainty of 5.0% (k= 2). The feasibility of the formalism and methodology for the Esteya system was demonstrated.Significance. This study proposes a method for harmonization of traceable reference dosimetry for eBT contact treatments which does not involve a detailed simulation of the ionization chamber. The method demonstrated feasibility for one eBT system using one surface applicator. In the future the method could be applied for different eBT systems.


LPCAT1 overexpression promotes the progression of hepatocellular carcinoma.
Hepatocellular carcinoma (HCC) remains one of the most common malignant neoplasms. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) plays a key role in the lipid remodelling and is correlated with various neoplasms. Nonetheless, the biological functions and molecular mechanisms of LPCAT1 underlying HCC remain obscure. In the present study, we investigated the role of LPCAT1 in the progression of HCC. In-house RT-qPCR, tissue microarrays, and immunohistochemistry were performed to detect the expression levels and the clinical value of LPCAT1 in HCC. External datasets were downloaded to confirm the results. Proliferation, migration, invasiveness, cell cycle, and apoptosis assays were conducted to reveal the biological effects LPCAT1 has on SMMC-7721 and Huh7 cells. HCC differentially expressed genes and LPCAT1 co-expressed genes were identified to explore the molecular mechanisms underlying HCC progression. LPCAT1 showed upregulated expression in 3715 HCC specimens as opposed to 3105 non-tumour specimens. Additionally, LPCAT1 might be an independent prognostic factor for HCC. LPCAT1-knockout hampered cellular proliferation, migration, and metastasis in SMMC-7721 and Huh7 cells. More importantly, the cell cycle and chemical carcinogenesis were the two most enriched signalling pathways. The present study demonstrated that increased LPCAT1 correlated with poor prognosis in HCC patients and fuelled HCC progression by promoting cellular growth, migration, and metastasis.


Inhibition of interleukin 1-induced matrix metalloproteinase 13 expression in human chondrocytes by interferon gamma.
Despite well-documented immunomodulation by interferon gamma (IFNgamma), its role and mechanism of regulation of matrix metalloproteinase 13 (MMP13) gene expression in human chondrocytes is unknown. To investigate the ability and mechanism of IFNgamma to suppress interleukin 1 (IL1)-induced MMP13 expression in articular chondrocytes. Human chondrocytes were treated with IFNgamma or IL1beta alone or in combination. MMP13 mRNA was analysed by semiquantitative reverse transcriptase-PCR. MMP13 protein, phospho-signal transducer and activator of transcription 1 (STAT1) and p44/42 mitogen-activated protein kinase levels were measured by western blotting. MMP13 promoter luciferase, cytomegalovirus cyclic AMP response element-binding protein (CBP)/p300 plasmids and STAT1 small interfering RNA (siRNA) were transfected by the calcium phosphate method. IFNgamma receptor was also neutralised. Activator protein (AP) 1 activity was monitored by the TransAM transcription factor kit. STAT1-CBP/p300 interaction was studied by immunoprecipitation. IFNgamma potently suppressed IL1-induced expression of MMP13 and promoter activity. Blockade with neutralising IFNgamma R1 antibody revealed that MMP13 inhibition by IFNgamma is mediated by the IFN receptor. IFNgamma-stimulated activation of STAT1 was directly correlated with MMP13 suppression. Knockdown of the STAT1 gene by specific siRNA or its inhibition with fludarabine partially restored the IL1beta induction of MMP13 expression and promoter activity. IFNgamma did not alter AP1 binding ability but promoted physical interaction of STAT1 and CBP/p300 coactivator. p300 overexpression reversed IFNgamma inhibition of endogenous MMP13 mRNA expression and exogenous MMP13 promoter activity. IFNgamma, through its receptor, activates STAT1, which binds with CBP/p300 coactivator, sequesters it from the cell system, and thus inhibits transcriptional induction of the MMP13 gene in chondrocytes. IFNgamma and its signalling pathways could be targeted therapeutically for diminishing IL1-induced cartilage degradation by MMP13 in patients with arthritis.


Reference genes for the developing mouse lung under consideration of biological, technical and experimental confounders.
For gene expression analysis, the raw data obtained from RT-qPCR are preferably normalized to reference genes, which should be constantly expressed regardless of experimental conditions. Selection of reference genes is particularly challenging for the developing lung because of the complex transcriptional and epigenetic regulation of genes during organ maturation and injury repair. To date, there are only limited experimental data addressing reliable reference genes for this biological circumstance. In this study, we evaluated reference genes for the lung in neonatal C57BL/6 mice under consideration of biological, technical and experimental conditions. For that, we thoroughly selected candidates from commonly used reference genes side-by-side with novel ones by analyzing publicly available microarray datasets. We performed RT-qPCR of the selected candidate genes and analyzed their expression variability using GeNorm and Normfinder. Cell-specific expression of the candidate genes was analyzed using our own single-cell RNA-sequencing data from the developing mouse lung. Depending on the investigated conditions, i.e., developmental stages, sex, RNA quality, experimental condition (hyperoxia) and cell types, distinct candidate genes demonstrated stable expression confirming their eligibility as reliable reference genes. Our results provide valuable information for the selection of proper reference genes in studies investigating the neonatal mouse lung.


Patient perspectives on the doctor of the future.
Health care reform has been the subject of considerable debate, particularly among those in politics, insurance, and business. Patients, however, have largely been ignored in this discussion. As the role of the health care consumer receives increased attention, it is important to consider patient values and preferences for a future system of care. This study describes what patients want and value in a future doctor This study was conducted in 1999-2000, using focus group methodology involving 78 members of communities in seven regions of Colorado. Participants were selected to ensure a distribution of rural/urban, racial/ethnic groups and different regions of the state. All participants had visited a health care provider in the previous 10 years. Data were analyzed with a team-based editing approach. Participants identified several primary domains and subthemes that describe what they want in a doctor of the future. The primary themes related to future doctors' medical and contextual knowledge of the patient, their personal characteristics and philosophical approach to health and health care, and desired qualities of the doctor-patient relationship. Patients wanted their future doctors to improve their experience of care and to be patient-centered, family-oriented, and community-oriented doctors. Patient perspectives of the doctor of the future should be considered in decisions about health care policy.


Chimeric Antigen Receptor-Engineered NK-92 Cells: An Off-the-Shelf Cellular Therapeutic for Targeted Elimination of Cancer Cells and Induction of Protective Antitumor Immunity.
Significant progress has been made in recent years toward realizing the potential of natural killer (NK) cells for cancer immunotherapy. NK cells can respond rapidly to transformed and stressed cells and have the intrinsic potential to extravasate and reach their targets in almost all body tissues. In addition to donor-derived primary NK cells, also the established NK cell line NK-92 is being developed for adoptive immunotherapy, and general safety of infusion of irradiated NK-92 cells has been established in phase I clinical trials with clinical responses observed in some of the cancer patients treated. To enhance their therapeutic utility, NK-92 cells have been modified to express chimeric antigen receptors (CARs) composed of a tumor-specific single chain fragment variable antibody fragment fused via hinge and transmembrane regions to intracellular signaling moieties such as CD3ζ or composite signaling domains containing a costimulatory protein together with CD3ζ. CAR-mediated activation of NK cells then bypasses inhibitory signals and overcomes NK resistance of tumor cells. In contrast to primary NK cells, CAR-engineered NK-92 cell lines suitable for clinical development can be established from molecularly and functionally well-characterized single cell clones following good manufacturing practice-compliant procedures. In preclinical in vitro and in vivo models, potent antitumor activity of NK-92 variants targeted to differentiation antigens expressed by hematologic malignancies, and overexpressed or mutated self-antigens associated with solid tumors has been found, encouraging further development of CAR-engineered NK-92 cells. Importantly, in syngeneic mouse tumor models, induction of endogenous antitumor immunity after treatment with CAR-expressing NK-92 cells has been demonstrated, resulting in cures and long-lasting immunological memory protecting against tumor rechallenge at distant sites. Here, we summarize the current status and future prospects of CAR-engineered NK-92 cells as off-the-shelf cellular therapeutics, with special emphasis on ErbB2 (HER2)-specific NK-92 cells that are approaching clinical application.


Effect of exposure to a boar on circulating concentrations of LH, FSH, cortisol and oestradiol in prepubertal gilts.
Serum concentrations of LH, FSH, oestradiol and cortisol were measured in control gilts not exposed to a boar and in gilts with fence-line exposure to a boar that allowed full muzzle contact. All gilts were between 134 and 200 days of age. Control gilts showed first oestrus at 193 +/- 7 days of age (n = 5). Twelve of the gilts exposed to the boar showed first oestrus at 169 +/- 5 days of age and five had not shown oestrus by 200 days of age. Introduction of a boar produced a transient increase in LH pulse frequency lasting no longer than 20 days (P < 0.001) in gilts responding to the boar with oestrus. Basal and mean serum LH concentrations were also increased (P < 0.05) in the gilts that responded to a boar with oestrus, but only in the 6 h after introducing the boar. Mean serum concentrations of FSH were lower in gilts exposed to a boar compared with the controls at 10 days after introduction of the boar, but by 20 days only gilts responding to the boar with oestrus had lower FSH concentrations (P < 0.05). Serum concentrations of cortisol decreased over the day the boar was introduced in all groups of gilts (P < 0.05) and were always highest in gilts exposed to a boar but not showing oestrus by 200 days of age (P < 0.05). There were no significant trends in serum concentrations of oestradiol but oestradiol concentrations varied over a wide range in gilts that did not respond to the boar with oestrus.(ABSTRACT TRUNCATED AT 250 WORDS)


Evaluate the Effect of Valproate Monotherapy on the Serum Homocysteine, Folate and Vitamin B12 Levels in Epileptic Children.
The data regarding Valproate and its influence on serum folate and homocysteine levels are conflicting. The aim of this study was to evaluate whether differences exist in homocysteine, folate, and vitamin B12 levels in children receiving Valproate. A total of 55 newly diagnosed epileptic children with ages ranging from 2 to 15 years were enrolled at the start of study but after 3 months follow up, the total sample size finally was only 50 epileptic children. 5 children dropped out of study due to poor follow up. 50 age and gender matched healthy control subjects were also studied on enrollment at the start of study. Serum homocysteine levels were analyzed by enzyme immunoassay method using the kits provided by Axis-Shield Diagnostics Ltd (Dundee DD2 1XA, United Kingdom). Serum folate and serum vitamin B12 were estimated by Competitive Chemiluminescent Enzyme Immunoassay method. The serum homocysteine level in epileptic children was found to be significantly increased after Valproate monotherapy as compared to before therapy. Moreover, a highly significant decrease was observed in the levels of serum folate in epileptic children after Valproate monotherapy as compared to before therapy. But a non significant difference was observed in serum vitamin B12 levels in epileptic children before and after Valproate monotherapy. Thus, we conclude that there is a significant increase in the levels of homocysteine and a significant decrease in the concentration of serum folate while vitamin B12 decreases non-significantly after Valproate monotherapy. The atherogenic effect of increased serum homocysteine level is well established; the patients under Valproate monotherapy should be monitored for possible atherogenic effects. Considering the above observation and results of children undergoing Valproate monotherapy, these children should be screened for levels of serum homocysteine, folate, and vitamin B12 and treated when their levels are found to be disturbed.


Moving average quality control: principles, practical application and future perspectives.
Moving average quality control (MA QC) was described decades ago as an analytical quality control instrument. Although a potentially valuable tool, it is struggling to meet expectations due to its complexity and need for evidence-based guidance. For this review, relevant literature and the world wide web were examined in order to (i) explain the basic concepts and current understanding of MA QC, (ii) discuss moving average (MA) optimization methods, (iii) gain insight into practical aspects related to applying MA in daily practice and (iv) describe future prospects to enable more widespread acceptance and application of MA QC. Each of the MA QC optimization methods currently available has their own advantages and disadvantages. Recently developed simulation methods provide realistic error detecting properties for MA QC and are available for laboratories. Operational MA management issues have been identified that allow developers of MA software to upgrade their packages to support optimal MA QC application and guide laboratories on MA management issues, such as MA alarm workup. The new insights into MA QC characteristics and operational issues, together with supporting online tools, may promote more widespread acceptance and application of MA QC.