Factors affecting erythropoietin production and correction of anemia in kidney transplant recipients.
Anemia does not correct in many kidney transplant recipients, probably due to iron deficiency or inadequate erythropoietin (Epo) production. We evaluated effects of iron (Fe) availability on correction of anemia in renal transplant recipients and sought to characterize patterns of early Epo production by transplanted kidneys as related to peritransplant factors. In a prospective randomized trial, 51 consecutive renal transplant patients were followed for 6 months. Epo was measured on days 0, 3, 14, 48 and 168 posttransplantation. Fe status was monitored on days 14, 48 and 168. Pts were randomized at day 14 based on Fe status. Iron-deficient (FeD) patients (n = 24) were randomized to receive daily Fe supplementation (FeDs, n = 12) or no supplementation (FeDns, n = 12). Those with normal Fe status (FeN, n = 27) were followed as controls. No differences were found between groups at day 0 for Hct, Cr, Epo, age, dialysis history, or type of donor. Day 3 Creatinine and Hct were similar among groups, while Epo was significantly higher in FeD groups vs FeN (p < 0.004), and continued higher at 6 months. Though each pt improved Hct, most FeDns and FeN were anemic and Fe deficient at 6 months while all FeDs patients had corrected their anemia (p < or = 0.009) and Fe status. Four FeDs patients developed polycythemia. Epo production correlated inversely to cold ischemia time in cadaver renal allografts (p < 0.008).(ABSTRACT TRUNCATED AT 250 WORDS)


(Minus) S-adenosyl-L-methionine-magnesium protoporphyrin methyltransferase, an enzyme in the biosynthetic pathway of chlorophyll in Zea mays.
The enzyme (-) S-adenosyl-L-methionine-magnesium protoporphyrin methyltransferase, which catalyzes the transfer of the methyl group from (-) S-adenosyl-L-methionine to magnesium protoporphyrin to form magnesium protoporphyrin monomethyl ester, has been detected in chloroplasts isolated from Zea mays. Zinc protoporphyrin and free protoporphyrin also act as substrates in the system, although neither one is as active as magnesium protoporphyrin. THE FOLLOWING SCHEME OF CHLOROPHYLL SYNTHESIS IN HIGHER PLANTS IS PROPOSED: delta-aminolevulinic acid --> --> --> protoporphyrin --> magnesium protoporphyrin --> magnesium protoporphyrin monomethyl ester --> --> --> chlorophyll a.


[Current objectives for the improvement of work conditions and prevention of occupational diseases among miners].
Workers engaged into deep mining are subjected to occupational factors intensity of which is significantly higher than the allowable. Changing the mining enterprises involves deterioration of the working environment, increase in occupational morbidity. Features of the working environment, parameters of main occupational entities, recent social instability at mining enterprises necessitate further investigations on the problem.


Occurrence and removal of endocrine-disrupting chemicals in wastewater treatment plants in the Three Gorges Reservoir area, Chongqing, China.
Concentrations of six endocrine-disrupting compounds (EDCs), bisphenol A (BPA), estrone (E(1)), 17β-estradiol (E(2)), estriol (E(3)), 17α-ethynylestradiol (EE(2)) and diethylstilbestrol (DES), were assessed in influents, effluents and excess sludge in ten municipal wastewater treatment plants (WWTPs) in the Three Gorges Reservoir (TGR) area, Chongqing, China. Three types of activated sludge treatment processes, oxidation ditch (OD), reversed anaerobic-anoxic-oxic (rA(2)/O) technology and sequential batch reactor (SBR), were used in the surveyed WWTPs. These WWTPs were all combined landfill leachate-sewage treatment plants. All analytes were extracted by solid-phase extraction (SPE) in the dissolved phase and by accelerated solvent-based extraction (ASE) in sludge. Gas chromatography-mass spectrometry (GC-MS) was employed for the analysis of EDCs. Among these EDCs, BPA was the most frequently detected and abundant compound (100.0-10566.7 ng L(-1), 15.5-1210.7 ng L(-1) and 85.0-2470.4 ng g(-1) with respect to the influents, effluents and excess sludge samples). The greatest levels of steroidal estrogens in municipal influents were observed in E(3) which were all >100 ng L(-1), followed by E(1) (42.2-110.7 ng L(-1)) and E(2) (7.4-32.7 ng L(-1)), and in the effluents and sludge were E(1) > E(3) > E(2) which were all <31 ng L(-1) and 105 ng g(-1), respectively. Regarding synthetic estrogens, EE(2) was frequently detected in the influents, occurring below 50 ng L(-1), while DES was not detected at all. A high correlation coefficient was observed between the leachate-sludge ratio and concentrations of influent EDCs, and it was statistically significant (i.e., R > 0.65, P < 0.05), but removal efficiency of the EDCs did not show significant differences with OD, rA(2)/O and SBR processes. Furthermore, modification of treatment technology as well as operational parameters, such as hydraulic retention time (HRT), sludge retention time (SRT) and disinfection process (DP), were recommended to further eliminate the residual EDCs.


A combined approach to the assessment of neurological dysphagia.
The dysphagia encountered by patients with neurological disorders can be both distressing and life threatening because of the associated problems of aspiration. Decisions regarding management are often difficult because the exact nature of the underlying disorder varies from patient to patient and is frequently complex. A new approach to the assessment and evaluation of acquired neurological dysphagia is presented. Management of the first 50 patients assessed by this method is described. The advantages of a joint dysphagia clinic comprising neurology, speech therapy, ENT and radiology departments are discussed.


Two-step chromatographic procedure for the purification of hen egg white ovomucin, lysozyme, ovotransferrin and ovalbumin and characterization of purified proteins.
An improved procedure is described involving gel permeation and anion-exchange chromatography for the purification of four major hen egg white proteins. The procedure involves a first-step purification of ovomucin and lysozyme by gel permeation on a Superose 6 Prep Grade column. In the second step, anion-exchange chromatography on Q Sepharose Fast Flow led to the isolation of ovotransferrin and ovalbumin from a gel permeation chromatographic peak. The purities were estimated as ca. 80, 100, 80 and 100% for ovomucin, lysozyme, ovotransferrin and ovalbumin, respectively. The purification yield was over 60% for each protein. Further characterization of purified lysozyme revealed that it was fully active and homogeneous in relation to the electrospray ionization mass spectrum. The electrospray ionization mass spectrum showed different ovotransferrin species. The amino acid composition of purified ovomucin was compared to those published previously.


Consumer demand for patient-oriented pharmacy services.
The purpose of this study was to investigate the extent of consumer demand for patient-oriented pharmacy services. Data, collected via a self-administered questionnaire distributed to 300 households, were analyzed using Kruskal's program for additive conjoint analysis. The results indicate substantial consumer demand for making advisory services available on request, moderate demand for provision of patient medication records, and little demand for voluntary provision of advisory services.


The neurobiological nature of syntactic hierarchies.
The review focuses on the neurobiological literature concerning the specific human ability to process linguistic hierarchies. First, we will discuss current ethological studies dedicated to the comparison between human and non-human animals for the processing of different grammar types. We will inspect the functional neuroanatomical structures of human and non-human primates more closely, including human developmental data, thereby suggesting interesting phylogenetic and ontogenetic differences. We then examine the neural reality of the Merge computation, being the most fundamental mechanism regulating natural language syntax, and offer new evidence for a possible localization of Merge in the most ventral anterior portion of BA 44. We conclude that BA 44, with its strong neural connection to the posterior temporal cortex, provides a recent evolutionary neurobiological basis for the unique human faculty of language.


Targeting the hypoxia pathway in malignant plasma cells by using 17-allylamino-17-demethoxygeldanamycin.
Multiple myeloma (MM) is characterized as a clonal expansion of malignant plasma cells in the bone marrow, which is often associated with pancytopenia and osteolytic bone disease. Interestingly, myeloma-infiltrated bone marrow is considered to be hypoxic, providing selection pressure for a developing tumour. Since HSP90 was shown to participate in stabilization of the subunit of the key transcription factor HIF-1, which controls the hypoxic response, the aim of this study was to investigate the influence of a HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG), on MM cells cultured under low oxygenation conditions. We confirmed that 17-AAG inhibits hypoxic induction of the HIF-1 target genes in malignant plasma cells and demonstrate the concentration range of severe hypoxia-specific cytotoxicity. Next, we selected the malignant plasma cells under severe hypoxia/re-oxygenation culture conditions in the presence or absence of 17-AAG and subsequently, the cells which survived were further expanded and analyzed. Interestingly, we have noticed significant changes in the survival and the response to anti-MM drugs between the parental cell lines and those selected in cyclic severe hypoxia in the presence and absence of 17-AAG. Importantly, we also observed that the lack of oxygen itself, irrespectively of HIF-1 inhibition, is the main/pivotal factor driving the selection process in the experiments presented here.


Adenoid Cystic Carcinoma Metastasized to Colon.
Adenoid cystic carcinoma (ACC) is an infrequent cause of malignancy that accounts for 1% of all tumors of the oral and maxillofacial region. We present a 59-year-old woman with a past medical history of adenoid cystic carcinoma of the left salivary gland treated with radiation and thoracotomy due to lung metastasis. Years after the onset of diagnosis, she presented with nonspecific gastrointestinal symptoms. For this reason, an abdominal computed tomography (CT) scan was done, revealing a liver mass in the right lobe, involving segments eight and five, concerning for malignancy. A colonoscopy was indicated for screening purposes, showing a large polyp that was biopsied. A histopathologic examination of the colon polyp and a liver biopsy was compatible with ACC metastatic carcinoma. We report this case to highlight an unusual location of metastatic ACC. Furthermore, there is no case report in the literature where colon metastasis has been described.


[Effect of intracellular administration of L-tyrosine and L-phenylalanine on voltage dependent calcium current in PC 12 pheochromocytoma cells].
Changes in the high-threshold calcium current (Ica) induced by intracellular administration of L-tyrosine and L-phenylalanine have been studied on internally perfused PC 12 pheochromocytoma cells using whole-cell voltage-clamp technique. L-tyrosine (20 microM/l) not only prevented a decay of Ica occurring during intracellular perfusion but induced also its transient recovery. In contrast, L-phenylalanine (20 microM/l) accelerated a decline of Ica. Replacement of ATP in the perfusing solution by an equivalent amount of ADP (2 mmol/l) did not alter the effect of amino acids. alpha-methyl-D, L-tyrosine (a specific blocker of tyrosine hydroxylase) caused the effect similar to that of L-tyrosine.


[Electropiezolithotripsy in anomalous kidneys].
The results of electropiezolithotripsy (EPL) are presented for 54 patients with anomalous kidneys. Nineteen of them had a shield kidney, 12 had double kidney, 9 showed different types of dystopia, L- and S-shaped kidneys were in 3 and 1 patient, respectively, 2 patients had a sponge kidney. Anomalies of the upper urinary tracts themselves are not a contraindication to extracorporeal EPL under satisfactory urine passage distally from the calculus. EPL to treat urolithiasis in a sponge kidney is recommended in the concrement location in the pelvis or calyces. The attempts of EPL in parenchymal stones resulted in massive macrohematuria and pyelonephritic attacks.


Imaging collective magnonic modes in 2D arrays of magnetic nanoelements.
We have used time resolved scanning Kerr microscopy to image collective spin wave modes within a 2D array of magnetic nanoelements. Long wavelength spin waves are confined within the array as if it was a continuous element of the same size but with effective material properties determined by the structure of the array and its constituent nanoelements. The array is an example of a magnonic metamaterial, the demonstration of which provides new opportunities within the emerging field of magnonics.


Clonidine as a preoperative sedative.
The purpose of this study was to -examine the use of oral clonidine as a preoperative sedative prior to parenteral moderate sedation. Initially, four patients were given 0.2 mg oral clonidine but reduced to 0.1 mg clonidine due to -significant drops in blood pressure. Oral clonidine doses of 0.1 mg were then given to 19 patients preoperatively. In all these patients, blood pressure measurements decreased, but there were no significant differences in amounts of sedative agents needed in the clonidine group and the control group (N = 80). The conclusions reached suggest that clonidine has an advantage over other preoperative sedation agents in anxious patients exhibiting hypertension and tachycardia. However, the preop ideal dose required to reduce the amount of sedative drugs used as well as provide anxiolysis remains unknown. In further studies, different doses should be explored to determine what dosage of clonidine may offer hemodynamic protection as well as decrease sedative drugs needed.


Improved emotion regulation following a trauma-informed CBT-based intervention associates with reduced risk for recidivism in justice-involved emerging adults.
Male youth who have been involved in the juvenile legal system have disproportionate rates of trauma and violence exposure. Many justice-involved youth have untreated mental illness, with an estimated 66% of young men who are incarcerated meeting criteria for at least one mental health disorder, including posttraumatic stress disorder (PTSD), depression, and substance abuse. While Cognitive Behavioral Therapy (CBT) approaches are considered among effective evidence-based treatments for addressing and treating behavioral and emotional difficulties, male youth with a history of incarceration and youth who are at risk for (re)incarceration, violence, emotion dysregulation, and trauma face significant barriers in accessing these services. Roca, Inc. (Roca), an internationally recognized organization moving the needle on urban violence by working relentlessly with young people at the center of violence in Massachusetts and Maryland, employs a trauma-informed CBT-based skills curriculum and approach in their intervention model, to improve youths' educational, employment, parenting, and life skills opportunities, while decreasing risk for recidivism, addressing trauma and increasing skills for emotion regulation. The aim of this analysis was to assess the effectiveness of Roca's trauma-informed CBT skills curriculum on youths' emotional and behavioral outcomes. We analyzed data from over 300 participating emerging adult men from four sites in Massachusetts and one site in Baltimore, Maryland who had at least three series of data collection across multiple skills-based sessions. We found improvements in outcomes in overall mean scores related to decreased distress about employment and education, as are expected with standard intervention approaches for justice-involved youth. Participants who show improvement in emotion regulation across engagement (approximately half the cohort), were found to have significant improvements in distress related to relationship and family functioning and self-care, and decreased substance use, along with other outcomes compared to those participants with less improvement in emotion regulation. Furthermore, improvement in different aspects of emotion regulation were associated with improved relationships, life distress, substance use, and improved prosocial thinking. Together, these data suggest that adding mental health support and skills training, such as with trauma-informed CBT models, to programs for justice-involved youth may lead to significant improvements in functioning, quality of life, and mental health outcomes.


Bioreductive activation of catechol estrogen-ortho-quinones: aromatization of the B ring in 4-hydroxyequilenin markedly alters quinoid formation and reactivity.
There is a clear association between excessive exposure to estrogens and the development of cancer in several tissues including breast and endometrium. The risk factors for women developing these cancers are all associated with longer estrogen exposure, as may be facilitated by early menses, late menopause and long-term estrogen replacement therapy. Equilenin (1,3,5(10),6,8-estrapentaen-3-ol-17-one) or its 17-hydroxylated analogs make up 15% of the most widely prescribed estrogen replacement formulation, Premarin, and yet there is very little information on the human metabolism of these estrogens. In this study, we synthesized the catechol metabolite of equilenin, 4-hydroxyequilenin, and examined how aromatization of the B ring affects the formation and reactivity of the o-quinone (3,5-cyclohexadien-1,2-dione). 4-Hydroxyequilenin-o-quinone is much more redox-active and longer-lived than the endogenous catechol estrone-o-quinones, which suggests that the mechanism(s) of toxicity of the former could be quite different. Interestingly, the rate of reduction of the 4-hydroxyequilenin-o-quinone is increased at least 13-fold in the presence of NAD(P)H:quinone oxidoreductase (DT-diaphorase). Once NADH is consumed however, the catechol auto-oxidized rapidly to the o-quinone. NADH consumption was accompanied by dicumarol-sensitive oxygen uptake both with the purified enzyme and with cytosol from human melanoma cells with high levels of DT-diaphorase activity. P450 reductase and rat liver microsomes also catalyzed NADPH consumption and oxygen uptake. 4-Hydroxyestrone-o-quinone was also rapidly reduced by NAD(P)H; however, this o-quinone does not auto-oxidize and once the o-quinone is reduced the reaction terminates. Including oxidative enzymes in the incubation completes the redox couple and 4-hydroxyestrone-o-quinone behaves like 4-hydroxyequilenin-o-quinone. These data suggest that reduction of estrogen-o-quinones may not result in detoxification. Instead this could represent a cytotoxic mechanism involving consumption of reducing equivalents (NADH/NADPH) as well as formation of superoxide and other reactive oxygen species leading to oxidative stress. Finally, we have compared the cytotoxicity of 4-hydroxyequilenin with that of the estrone catechols in human melanoma cells. 4-Hydroxyequilenin is 5-fold more toxic in these cells compared with 4-hydroxyestrone (ED50 = 7.8 versus 38 microM, respectively) suggesting that formation of the longer-lived redox-active 4-hydroxyequilenin-o-quinone was responsible for the cytotoxic differences. These results substantiate the conclusion that the involvement of quinoids in catechol estrogen toxicity depends on a combination of the rate of formation of the o-quinone, the lifetime of the o-quinone, and the electrophilic/redox reactivity of the quinoids.


Hepatic adenoma mimicking a metastatic lesion on computed tomography-positron emission tomography scan.
Positron emission tomography (PET) using ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) is an imaging modality which reflects cellular glucose metabolism. Most malignant cells accumulate and trap ¹⁸F-FDG, allowing the visualisation of increased uptake. It is hence widely used to differentiate malignant from benign lesions. "False positive" findings of hepatic lesions have been described in certain instances such as hepatic abscesses, but are rare in cases involving hepatocellular adenomas. To our knowledge, there have been only 7 reports in the English literature documenting PET-avid hepatocellular adenomas; 6 of the 7 reports were published in the last 3 years with the first report by Patel et al. We report the case of a 44-year-old Chinese female patient with a history of cervical adenocarcinoma, referred for a hepatic lesion noted on a surveillance computed tomography (CT) scan. A subsequent CT-PET performed showed a hypermetabolic lesion (standardized uptake value 7.9) in segment IVb of the liver. After discussion at a multi-disciplinary hepato-pancreato-biliary conference, the consensus was that of a metastatic lesion from her previous cervical adenocarcinoma, and a resection of the hepatic lesion was performed. Histology revealed features consistent with a hepatocyte nuclear factor-1 α inactivated steatotic hepatocellular adenoma.


Emerging therapies for multiple sclerosis.
This review examines the mode of action, safety profile and clinical efficacy of some of the most promising new therapeutic strategies for multiple sclerosis. Autologous hematopoietic stem cell transplantation can regenerate a new and tolerant immune system and is a potentially effective rescue therapy in a subset of patients with aggressive forms of MS refractory to approved immunomodulatory and immunosuppressive agents. High-dose cyclophosphamide without stem cell support is suggested to induce prolonged remissions through similar immunological mechanisms with less toxicity. Fingolimod (FTY720) is a novel oral immunomodulating agent that acts through preventing lymphocyte recirculation from lymphoid organs. Monoclonal antibody therapy has provided scientists and clinicians the opportunity to rationally direct the therapeutic intervention against specific molecules. Targeting molecules of the immune system such as CD52 (alemtuzumab), CD25 (daclizumab), VLA-4 (natalizumab) and CD20 (rituximab) have resulted in potent immunomodulatory effects through sometimes unpredicted mechanisms. The potential of immunoglobulins to induce remyelination in the CNS is being investigated in an attempt to develop therapies promoting tissue repair and functional recovery. The evidence supporting the potential of these emerging immunotherapies suggests that strong progress is being made in the development of effective cures for multiple sclerosis.


Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection.
Recent studies linked cytokine gene polymorphisms to H pylori related gastric cancer development. The current study evaluated the role of cytokine gene polymorphisms for mucosal cytokine expression, the gastric inflammatory response, and bacterial colonisation during H pylori infection. In 207 H pylori infected patients with chronic gastritis, polymorphisms at different loci of the interleukin (IL)-10, IL-1B, IL-1 receptor antagonist (IL-1RN), tumour necrosis factor (TNF)-A, and interferon (IFN)-G genes were genotyped by polymerase chain reaction (PCR), restriction fragment length polymorphism (RFLP) analysis, and allelic discriminating TaqMan PCR. Mucosal cytokine mRNA copy numbers were determined by real time quantitative PCR. Presence of bacterial virulence factors was investigated by cagA, vacAs1/2, and babA2 PCR. Biopsies were assessed with regard to the degrees of granulocytic/lymphocytic infiltration and the presence of intestinal metaplasia (IM) and atrophic gastritis (AG). Proinflammatory IL-1 polymorphisms (IL-1RN*2(+)/IL-1B-511T/-31C(+)) were associated with increased IL-1beta expression, more severe degrees of inflammation, and an increased prevalence of IM and AG. Carriers of the IL-10-1082G/-819C/-592C alleles (GCC haplotype) had higher mucosal IL-10 mRNA levels than ATA haplotype carriers and were associated with colonisation by more virulent cagA(+), vacAs1(+), and babA2(+) H pylori strains. The TNF-A-307(G/A) and IFN-G+874(A/T) polymorphisms did not influence mucosal cytokine expression or the inflammatory response to H pylori. Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and the long term development of precancerous lesions in H pylori infection. Host polymorphisms are associated with certain bacterial strain types, suggesting host specific colonisation or adaptation. These findings contribute to the understanding of the complex interplay between host and bacterial factors involved in the development of gastric pathology.


[About standardization of specialized medical care].
The article presents materials of studying of such important problem of health care as standardization of specialized medical care provided in conditions of hospital and modernization of regional health care. The issues of standardization of specialized medical care are considered in medical, economic and social aspects. The implementation of medical standards was determined as one of main tasks of the regional program of modernization of health care. The program was developed with direct involvement of the authors of article. The comparative analysis of classes of diseases and nosologic forms on main indices of hospitalized morbidity and lethality was used for substantiation of priority of implementing medical standards in the region. The questionnaire survey was carried out on sampling of 510 patients of hospitals. The sociological questionnaire survey was applied to sampling of 8732 patients comprised by system of mandatory medical insurance. Such an approach determined reliability of derived results. The expertise of medical standards was implemented by 124 experienced and competent physicians participating in implementation of medical standards. The results of expertise confirmed expediency of implementation of medical standards. Kepy following shortcomings were established: inadequate financing; lacking of modern equipment and analysis techniques in hospitals, etc. The article presents evidences of effectiveness of process of standardization of specialized of medical care provided in hospital conditions. The basis of such an assumption was reliable increasing of level of satisfaction of quality of its organization and achievement of planned indices of "road map" in the section of increasing of salary of medical workers and decreasing of mortality of population because of controllable causes.


Association with phagocytic inhibition of anti-Pseudomonas aeruginosa immunoglobulin G antibody subclass levels in serum from patients with cystic fibrosis.
Serum from cystic fibrosis patients colonized with Pseudomonas aeruginosa specifically inhibits phagocytosis of P. aeruginosa by alveolar macrophages. Serum was examined for P. aeruginosa lipopolysaccharide-specific immunoglobulin G (IgG) subclass levels (by enzyme-linked immunosorbent assay) and for the effect on macrophage phagocytosis (by radiolabeled P. aeruginosa uptake). Sera from cystic fibrosis patients with no known P. aeruginosa colonization history had negligible amounts of lipopolysaccharide-specific IgG and a mean phagocytic enhancement of 5%. The sera of normal volunteers also had negligible amounts of lipopolysaccharide-specific IgG. Serum from cystic fibrosis patients with P. aeruginosa respiratory tract infections had substantial titers (range, 1:20 to 1:1,280) of lipopolysaccharide-specific IgG2, IgG3, and IgG4 and a mean phagocytic inhibition of 56%. However, these patients had low or absent titers of lipopolysaccharide-specific IgG1. No consistent variation in the level of individual IgG subclasses in the sera of colonized patients was observed, as determined by radial immunodiffusion. The results suggest that during P. aeruginosa infection phagocytosis-inhibitory activity develops coincident with production of lipopolysaccharide-specific IgG subclasses.


Application on Timm sulphide silver method for electron microscope localization of lead ions in blood cells.
The application of the Timm sulphide silver method for the demonstration of lead ions in peripheral blood cells is investigated, using male white adult Wistar rats treated with a single dose of lead acetate, range 150 mg/kg b.w. To improve the Timm reaction for electron microscopy, fixation of whole cells with glutaraldehyde fixative solution saturated with H2S, an agarose embedding and physical development of thick sections without prior cryostat sectioning are presented. At 6.0 hours after injection both erythrocytes as well as white cells reveal the positive Timm reaction. All types of blood cells contain numerous cytoplasmic precipitates illustrating the intracellular lead accumulation. It is shown that the invaginations of white cell nuclear membrane possess a storing function as areas of lead depots. As a rule, the neutrophils display a highest amount of cytoplasmic precipitates and exclusively a low amount of reaction products in basophils is observed. At 14 days after injection, precipitates are present only in erythrocytes and monocytes. A suggestion of a possible functional significance of changes in the Timm staining pattern in blood cell types is discussed in this paper.


Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme.
Nitric oxide mediates vascular relaxing effects of endothelial cells, cytotoxic actions of macrophages and neutrophils, and influences of excitatory amino acids on cerebellar cyclic GMP. Its enzymatic formation from arginine by a soluble enzyme associated with stoichiometric production of citrulline requires NADPH and Ca2+. We show that nitric oxide synthetase activity requires calmodulin. Utilizing a 2',5'-ADP affinity column eluted with NADPH, we have purified nitric oxide synthetase 6000-fold to homogeneity from rat cerebellum. The purified enzyme migrates as a single 150-kDa band on SDS/PAGE, and the native enzyme appears to be a monomer.


Type I cystinuria and its genetic basis in a population of Turkish school children.
Cystinuria is a common inherited disorder characterized by an abnormal urinary excretion of cystine and dibasic amino acids resulting in nephrolithiasis. The SLC3A1 gene, which encodes a dibasic amino acid transporter protein, is involved in the pathogenesis of cystinuria. In the present study we aimed to investigate the prevalence of cystinuria among children in Sivas province (Central Anatolia, Turkey) and to study M467T and M467K mutations and 231T/A polymorphism in patients with cystinuria. A total of 8500 children were screened for cystinuria. The cyanide-nitroprusside test was applied to urine samples of all children. Children having a positive cyanide-nitroprusside test were further analyzed. M467T and M467K mutations (exon 8) and 231T/A polymorphism (exon 1) in the SCL3A1 gene were studied using a restriction fragment length polymorphism (RFLP) assay. We have found that the prevalence of cystinuria (11 cystinuric patients) is 1/772 in our population. Results of mutation analysis in the patients with cystinuria showed that M467T was the only mutation that was found in six cystinuric patients. One patient was homozygous and five were heterozygous for this mutation. The frequency of cystinuria in Sivas Province is the highest among the other populations studied to date. The frequency of M467T mutation is relatively higher than those reported for most populations. High frequency of cystinuria in this region could be due to consanguineous marriages.


Evidence for an essential role of megalin in transepithelial transport of retinol.
Transepithelial transport of retinol is linked to retinol-binding protein (RBP), which is taken up and also synthesized in a number of epithelia. By immunocytochemistry of human, rat, and mouse renal proximal tubules, a strong staining in apical endocytic vacuoles, lysosomes, endoplasmic reticulum, Golgi, and basal vesicles was observed, in accordance with luminal endocytic uptake as well as a constitutive synthesis and basal secretion of RBP. Analysis of mice with target disruption of the gene for the major endocytic receptor of proximal tubules, megalin, revealed no RBP in proximal tubules of these mice. Western blotting and HPLC of the urine of the megalin-deficient mice instead revealed a highly increased urinary excretion of RBP and retinol, demonstrating that glomerular filtered RBP-retinol of megalin-deficient mice escapes uptake by proximal tubules. A direct megalin-mediated uptake of purified RBP-retinol was indicated by surface plasmon resonance analysis and uptake in immortalized rat yolk sac cells. Uptake was partially inhibited by a polyclonal megalin antibody and the receptor-associated protein. The present data show that the absence of RBP-binding megalin causes a significantly increased loss of RBP and retinol in the urine, demonstrating a crucial role of megalin in vitamin A homeostasis.


Psychosocial interventions for conversion disorder.
Conversion disorder is an alteration or loss of physical functioning suggestive of a physical disorder that is thought to be due to a psychological stressor or conflict. The fact that many theories about the cause of conversion disorder focus on psychological and social factors would suggest that a psychosocial intervention might be of most benefit. To investigate the efficacy of psychosocial interventions on people diagnosed with conversion disorder compared with standard care, a biological intervention or another psychosocial intervention. We searched the Cochrane Depression, Anxiety and Neurosis Group Trials Register (May 2004), various databases on OVID (February 2004), handsearched reference lists and textbooks on conversion disorder and contacted relevant authors. We included all randomised controlled trials that compared psychosocial interventions for conversion disorder with standard care or other interventions (biological or psychosocial). We reliably selected, quality assessed and extracted data from the studies. For dichotomous outcomes we calculated a relative risk with its associated 95% confidence interval and a number needed to treat. For continuous data we calculated a weighted mean difference. The search identified 260 references, 217 were clearly not relevant to this review and excluded on the basis of their titles and abstracts, 40 more were excluded after reading the full papers (the reasons are given in the excluded studies tables) and only three studies (total n =119) met the inclusion criteria. One study was concerned with paradoxical injunction therapy and the other two studied the value of hypnosis. The three studies had different interventions and control groups so the results could not be combined. All of the studies were of poor methodological quality and it is therefore difficult to place much value on the results of the studies. We were unable to include some data because of poor reporting. Randomised studies are possible in this field. The use of psychosocial interventions for conversion disorder requires more research and it is not possible to draw any conclusions about their potential benefits or harms from the included studies.


Trend in the annual risk of tuberculous infection in Egypt, 1950-1996.
To determine the trend in the risk of tuberculous infection in non-BCG vaccinated children in Egypt in the period 1950-1996. In 1949-1952, a tuberculin survey was carried out in Egypt by the World Health Organization (WHO) covering 103 districts. In 1995-1997 a tuberculin survey was carried in 73 620 primary school children in grade one in the same districts, using international guidelines. The trend in tuberculous infection was determined by comparing the prevalence of Mantoux reactions of > or =6 mm in the two surveys in subjects without apparent BCG scar aged 6-7 years. For an estimate of current risk of infection the 17 mm cut-off point (number with 17 mm plus twice the number with greater than 17 mm) was used. In 1995-1997, 76% of children had a BCG scar. Infection prevalence estimates in 14 766 non-BCG-vaccinated children with a mean age of 6.7 years were 11.9%, 4.1%, and 2.1% for the cut-off points 6 mm, 10 mm, and 17 mm, respectively. Decline in the risk of infection was estimated to be in the order of 50% over 45 years, or 1.5% per year. The geometric mean annual risk of infection in the 6.7 years before the survey was estimated at 0.32% (95% confidence interval 0.27-0.40%). For Egypt, the incidence of smear-positive tuberculosis was estimated at 16 per 100000 population, giving a case detection rate of 85% (range 56-100%). This survey has shown that the size of the tuberculosis problem in Egypt is considerably smaller now than it was 45 years ago.


Local Search and the Evolution of World Models.
An open question regarding how people develop their models of the world is how new candidates are generated for consideration out of infinitely many possibilities. We discuss the role that evolutionary mechanisms play in this process. Specifically, we argue that when it comes to developing a global world model, innovation is necessarily incremental, involving the generation and selection among random local mutations and recombinations of (parts of) one's current model. We argue that, by narrowing and guiding exploration, this feature of cognitive search is what allows human learners to discover better theories, without ever grappling directly with the problem of finding a "global optimum," or best possible world model. We suggest this aspect of cognitive processing works analogously to how blind variation and selection mechanisms drive biological evolution. We propose algorithms developed for program synthesis provide candidate mechanisms for how human minds might achieve this. We discuss objections and implications of this perspective, finally suggesting that a better process-level understanding of how humans incrementally explore compositional theory spaces can shed light on how we think, and provide explanatory traction on fundamental cognitive biases, including anchoring, probability matching, and confirmation bias.


Regulation of the host range of human papovavirus JCV.
Human papovavirus JCV is associated with the human demyelinating disorder progressive multifocal leukoencephalopathy. In tissue culture, the virus is largely restricted to growth in primary human fetal glial cell. In this study, we demonstrate two levels of regulation of the viral host range. Expression of the early JCV mRNA, which encodes the essential viral protein, large tumor antigen (T antigen), depends on recognition of the early enhancer/promoter elements by tissue-specific factors found in both human and rodent glial cells. In the presence of JCV T antigen, viral DNA replication requires a species-specific factor, presumably a component of DNA polymerase, which is found in a wide range of primate cells. We further demonstrate that simian virus 40 T antigen has sufficient homology to efficiently substitute for the analogous JCV protein in initiating viral DNA replication.


Sphingosine-1-Phosphate Improves the Biological Features of Mouse Bone Marrow-Derived EPCs Partially through PI3K/AKT/eNOS/NO Pathway.
Sphingosine-1-phosphate (S1P), a bioactive sphingolipid, is recognized as a critical regulator in physiological and pathophysiological processes of atherosclerosis (AS). However, the underlying mechanism remains unclear. As the precursor cells of endothelial cells (ECs), endothelial progenitor cells (EPCs) can prevent AS development through repairing endothelial monolayer impaired by proatherogenic factors. The present study investigated the effects of S1P on the biological features of mouse bone marrow-derived EPCs and the underlying mechanism. The results showed that S1P improved cell viability, adhesion, and nitric oxide (NO) release of EPCs in a bell-shaped manner, and migration and tube formation dose-dependently. The aforementioned beneficial effects of S1P on EPCs could be inhibited by the phosphatidylinositol 3-kinase (PI3K) inhibitor of LY294002 and nitric oxide synthase (NOS) inhibitor of N'-nitro-L-arginine-methyl ester hydrochloride (L-NAME). The inhibitor of LY294002 inhibited S1P-stimulated activation of phosphorylated protein kinase B (AKT) (p-AKT) and endothelial nitric oxide synthase (eNOS) (p-eNOS), and down-regulated the level of eNOS significantly. The results suggest that S1P improves the biological features of EPCs partially through PI3K/AKT/eNOS/NO signaling pathway.


Omega-3 fatty acid rich diet prevents diabetic renal disease.
Omega-3 polyunsaturated fatty acids (n-3 PUFA) show beneficial effects in cardiovascular disease, IgA, and diabetic nephropathy; however, the mechanisms underlying these benefits are unknown. The study was performed in male Sprague-Dawley rats randomly divided into four treatment groups: nondiabetic (ND), streptozotocin-induced diabetic (D), diabetic and fed a high n-3 PUFA diet (D+canola), and diabetic and fed a high n-6 (omega-6) PUFA diet (D+corn). Study treatments were carried out for 30 wk. D+canola significantly decreased diabetes-associated increases in urine albumin excretion (ND 17.8 +/- 6.4; D 97.3 +/- 9.4; D+canola 8.3 +/- 2.2 mg/day); systolic blood pressure (ND 153 +/- 9; D 198 +/- 7; D+canola 162 +/- 9 mmHg); glomerulosclerosis (ND 0.6 +/- 0.2; D 1.8 +/- 0.2; D+canola 0.8 +/- 0.1 AU); and tubulointerstitial fibrosis in the renal cortex (ND 1.2 +/- 0.2; D 2.0 +/- 0.2; D+canola 1.1 +/- 0.1) and the inner stripe of the outer medulla (ND 1.0 +/- 0.2; D 2.1 +/- 0.2; D+canola 1.1 +/- 0.2 AU). D+corn also exerted renoprotection, but not to the same degree as D+canola (urine albumin excretion, 33.8 +/- 6.1 mg/day; systolic blood pressure, D+corn 177 +/- 6 mmHg; glomerulosclerosis, D+corn 1.2 +/- 0.3 AU; cortical tubulointerstitial fibrosis, D+corn 1.6 +/- 0.1 AU; medullary tubulointerstitial fibrosis, D+corn 1.5 +/- 0.1 AU). In addition, D+canola attenuated D-associated increase in collagen type I and type IV, IL-6, MCP-1, transforming growth factor-beta, and CD68 expression. These observations indicate a beneficial effect of high dietary intake of n-3 PUFA in reducing diabetic renal disease.


Pathogenic implications, incidence, and outcomes of COVID-19 in autoimmune inflammatory joint diseases and autoinflammatory disorders.
As the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to spread rapidly, there are still many unresolved questions of how this virus would impact on autoimmune inflammatory joint diseases and autoinflammatory disorders. The main aim of this paper is to describe the main studies focusing their attention on COVID-19 incidence and outcomes of rheumatoid arthritis (RA), spondylarthritis (SpA), and autoinflammatory disease cohorts. We also revised possible pathogenic mechanisms associated with. Available data suggest that, in patients with RA and SpA, the immunosuppressive therapy, older age, male sex, and the presence of comorbidities (hypertension, lung disease, diabetes, CVD, and chronic renal insufficiency/end-stage renal disease) could be associated with an increased risk of infections and high rate of hospitalization. Other studies have shown that lower odds of hospitalization were associated with bDMARD or tsDMARDs monotherapy, driven largely by anti-TNF therapies. For autoinflammatory diseases, considering the possibility that COVID-19 could be associated with a cytokine storm syndrome, the question of the susceptibility and severity of SARS-CoV-2 infection in patients displaying innate immunity disorders has been raised. In this context, data are very scarce and studies available did not clarify if having an autoinflammatory disorder could be or not a risk factor to develop a more severe COVID-19. Taking together these observations, further studies are likely to be needed to fully characterize these specific patient groups and associated SARS-CoV-2 infection.


Health-related quality-of-life results from the randomised phase II TAVAREC trial on temozolomide with or without bevacizumab in 1p/19q intact first-recurrence World Health Organization grade 2 and 3 glioma (European Organization for Research and Treatment of Cancer 26091).
In an international randomised controlled phase II study of temozolomide (TMZ) versus TMZ in combination with bevacizumab (BEV) in locally diagnosed non-1p/19q co-deleted World Health Organization grade 2 or 3 gliomas with a first and contrast-enhancing recurrence after initial radiotherapy, and overall survival at 12 months was not significantly different (61% in the TMZ arm and 55% in the TMZ + BEV arm). Health-related quality of life (HRQoL) was a key secondary end-point in this trial, and the main objective of this study was to determine the impact of the addition of BEV to TMZ on HRQoL. HRQoL was assessed using the European Organization for Research and Treatment of Cancer QLQ-C30 (version 3) and QLQ-BN20 at baseline, and then every 12 weeks until disease progression. The pre-selected primary HRQoL end-point was the QLQ-C30 global health scale, with self-perceived cognitive functioning and pain selected as secondary HRQoL issues. Analysis was undertaken using linear mixed modelling and complemented with sensitivity analyses using summary statistics. A difference was considered clinically relevant with ≥10 points difference on a 100-point scale. Baseline compliance was high at 94% and remained above 60% until 72 weeks, limiting the analysis to 60 weeks. Compliance was similar in both arms. We found no statistically significant or clinically significant differences between the primary HRQoL end-point in both treatment arms (p = 0.2642). The sensitivity analyses confirmed this finding. The overall test for post-baseline differences between the two treatment arms also showed no statistically or clinically significant differences regarding the selected secondary end-point scales. The addition of BEV to TMZ in this patient group neither improves nor negatively impacts HRQoL.


Development of a novel xenotransplantation strategy for treatment of diabetes mellitus in rat hosts and translation to non-human primates.
Transplantation therapy for diabetes is limited by unavailability of donor organs and outcomes complicated by immunosuppressive drug toxicity. Xenotransplantation is a strategy to overcome supply problems. Implantation of tissue obtained early during embryogenesis is a way to reduce transplant immunogenicity. Insulin-producing cells originating from embryonic pig pancreas obtained very early following pancreatic primordium formation [embryonic day 28 (E28)] engraft long-term in inbred diabetic Lewis or Zucker Diabetic Fatty (ZDF) rats or rhesus macaques. Endocrine cells originating from embryonic pig pancreas transplanted in host mesentery migrate to mesenteric lymph nodes, engraft, normalize glucose tolerance in rats and improve glucose tolerance in rhesus macaques without the need for immune suppression. Engraftment of primordia is permissive for engraftment of an insulin-expressing cell component from porcine islets implanted subsequently without immune suppression. Similarities between findings in inbred rat and non-human primate hosts bode well for successful translation to humans of what could be a novel xenotransplantation strategy for the treatment of diabetes.


An internalized transmembrane protein resides in a fusion-competent endosome for less than 5 minutes.
We have used our assay for the cell-free reconstitution of vesicle fusion occurring in endocytosis to investigate the fusion competence of defined endosomal fractions containing the G protein of vesicular stomatitis virus, G protein was first implanted into the plasma membrane, and endocytosis was then allowed to proceed for defined periods of time. Endosomal fractions were prepared by "immuno-isolation" on a solid support with a monoclonal antibody against the cytoplasmic domain of the G protein. Maximal internalization of the G protein occurred within 5 min at 37 degrees C. From this early endosome the G molecules follow a branched pathway: 50% recycles to the cell surface, while 50% is transported along the endocytic route to the lysosomal compartment. The proportion of G protein following each pathway can be modulated. When the amount of implanted G protein was increased, the fraction of G molecules recycling to the cell surface was reduced. When the G molecules were cross-linked with an antibody prior to the internalization step, recycling to the cell surface was abolished. The cell-free analysis of vesicle fusion was carried out with endosomal fractions immuno-isolated after 5, 10, 15, and 30 min of G-protein internalization at 37 degrees C. Fusion competence was at a maximum with the fraction isolated 5 min after internalization and then decreased with a half-life of approximately equal to 3 min with fractions isolated at later time points. The fusion-competent compartment is the early endosome where sorting of the transmembrane G protein to recycling or degradation occurs.


[Protein-losing giant fold gastritis in childhood--a case report and differentiation from Ménétrier disease of adulthood].
We report on a 2.5-year-old boy, who presented with vomiting since one week and periorbital and pitting edema. Laboratory studies revealed hypoproteinemia and hypoalbuminemia without signs of renal or liver disease. The cause of protein loss was giant fold gastritis disclosed by upper endoscopy. Biopsies revealed foveolar hyperplasia with cystic dilatation of the glands, identical to Ménétrier's disease in adulthood. About 55 cases of hypertrophic gastropathy in children have been published. In contrast to the chronic course of Ménétrier's disease in adults, the pediatric cases are generally benign, self-limited with complete resolution typically within a few weeks. While the etiology of Ménétrier's disease is still unknown, the benign pediatric hypertrophic gastropathies have been associated with infections, primarily CMV and occasionally helicobacter pylori, herpes simplex and mycoplasma. Supportive treatment with a high-protein-diet and intravenous albumin transfusions is recommended. H2-receptor antagonists might improve symptoms.


Mitragynine 'Kratom' related fatality: a case report with postmortem concentrations.
A 24-year-old man whose medical history was significant for alcohol abuse and depression was found unresponsive in bed. He had several prior suicide attempts with 'pills' and had also been hospitalized for an accidental overdose on a previous occasion. Autopsy findings were unremarkable apart from pulmonary edema and congestion, and urinary retention. Postmortem peripheral blood initially screened positive for mitragynine 'Kratom' (by routine alkaline drug screen by gas chromatography-mass spectrometry, GC-MS), which was subsequently confirmed by a specific GC-MS selective ion mode analysis following solid-phase extraction. Concentrations were determined in the peripheral blood (0.23 mg/L), central blood (0.19 mg/L), liver (0.43 mg/kg), vitreous (<0.05 mg/L), urine (0.37 mg/L) and was not detected in the gastric. Therapeutic concentrations of venlafaxine, diphenhydramine and mirtazapine were also detected together with a negligible ethanol of 0.02% (w/v). The results are discussed in relation to previous cases of toxicity, and the lack of potential for mitragynine postmortem redistribution.


The distribution of conduction velocities (DCV) in peripheral nerves: a review.
Recent advances in digital signal processing have permitted the development of clinically relevant, noninvasive, computer-based methods for estimating the distribution of conduction velocities (DCV) in motor, sensory, and mixed populations of large myelinated nerve fibers. All currently available methods incorporate explicit and implicit assumptions about the nature of the unit impulses under study. Preliminary investigations using DCV methods have clarified some issues concerning conduction of impulses in the different fiber subpopulations of normal and diseased human nerves. In the presence of severe nerve disease, DCV analysis is usually either impractical or superfluous; additional studies are needed to define its range of clinical applicability. Extension of this technology to clinical analysis of small myelinated and unmyelinated fiber populations will require improvements in the techniques of nerve stimulation and recording.


Intelligent Bayes Classifier (IBC) for ENT infection classification in hospital environment.
Electronic Nose based ENT bacteria identification in hospital environment is a classical and challenging problem of classification. In this paper an electronic nose (e-nose), comprising a hybrid array of 12 tin oxide sensors (SnO2) and 6 conducting polymer sensors has been used to identify three species of bacteria, Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), and Pseudomonas aeruginosa (P. aeruginosa) responsible for ear nose and throat (ENT) infections when collected as swab sample from infected patients and kept in ISO agar solution in the hospital environment. In the next stage a sub-classification technique has been developed for the classification of two different species of S. aureus, namely Methicillin-Resistant S. aureus (MRSA) and Methicillin Susceptible S. aureus (MSSA). An innovative Intelligent Bayes Classifier (IBC) based on "Baye's theorem" and "maximum probability rule" was developed and investigated for these three main groups of ENT bacteria. Along with the IBC three other supervised classifiers (namely, Multilayer Perceptron (MLP), Probabilistic neural network (PNN), and Radial Basis Function Network (RBFN)) were used to classify the three main bacteria classes. A comparative evaluation of the classifiers was conducted for this application. IBC outperformed MLP, PNN and RBFN. The best results suggest that we are able to identify and classify three bacteria main classes with up to 100% accuracy rate using IBC. We have also achieved 100% classification accuracy for the classification of MRSA and MSSA samples with IBC. We can conclude that this study proves that IBC based e-nose can provide very strong and rapid solution for the identification of ENT infections in hospital environment.


Changes in terminal sprout formation in rat sternocostalis muscle during chronic intoxication with 2,5 hexanedione.
Qualitative and quantitative morphological studies of the sternocostalis muscle innervation were made on rats chronically intoxicated with 2,5 hexanedione (2,5 HD) using the zinc iodide-osmium (ZIO) technique. Two distinct phases were seen in the events at the motor endplate. First, the number of motor endplates forming spontaneous terminal sprouts was found to increase linearly with time and, from the third week onward, the sprouts appeared to become progressively elongated. This latter change was associated with the appearance of swollen axons within intramuscular nerve bundles. Second, from the sixth week onward, wallerian degeneration of nerve fibers was seen and terminal sprouts began to make new arborizations on muscle fibers. By the eighth week, this occurred in as many as 66% of the rats, and collateral sprouting was also observed at this time. The occurrence of increased spontaneous terminal sprouting due to altered neuromuscular function is discussed in the light of axonal changes resulting from neurofilament accumulation following 2,5 HD intoxication.


Differential S1P Receptor Profiles on M1- and M2-Polarized Macrophages Affect Macrophage Cytokine Production and Migration.
Introduction. Macrophages are key players in complex biological processes. In response to environmental signals, macrophages undergo polarization towards a proinflammatory (M1) or anti-inflammatory (M2) phenotype. Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid that acts via 5 G-protein coupled receptors (S1P1-5) in order to influence a broad spectrum of biological processes. This study assesses S1P receptor expression on macrophages before and after M1 and M2 polarization and performs a comparative analysis of S1P signalling in the two activational states of macrophages. Methods. Bone marrow derived macrophages (BMDM) from C57 BL/6 mice were cultured under either M1- or M2-polarizing conditions. S1P-receptor expression was determined by quantitative RT-PCR. Influence of S1P on macrophage activation, migration, phagocytosis, and cytokine secretion was assessed in vitro. Results. All 5 S1P receptor subclasses were expressed in macrophages. Culture under both M1- and M2-polarizing conditions led to significant downregulation of S1P1. In contrast, M1-polarized macrophages significantly downregulated S1P4. The expression of the remaining three S1P receptors did not change. S1P increased expression of iNOS under M2-polarizing conditions. Furthermore, S1P induced chemotaxis in M1 macrophages and changed cytokine production in M2 macrophages. Phagocytosis was not affected by S1P-signalling. Discussion. The expression of different specific S1P receptor profiles may provide a possibility to selectively influence M1- or M2-polarized macrophages.


Neural-network-based online HJB solution for optimal robust guaranteed cost control of continuous-time uncertain nonlinear systems.
In this paper, the infinite horizon optimal robust guaranteed cost control of continuous-time uncertain nonlinear systems is investigated using neural-network-based online solution of Hamilton-Jacobi-Bellman (HJB) equation. By establishing an appropriate bounded function and defining a modified cost function, the optimal robust guaranteed cost control problem is transformed into an optimal control problem. It can be observed that the optimal cost function of the nominal system is nothing but the optimal guaranteed cost of the original uncertain system. A critic neural network is constructed to facilitate the solution of the modified HJB equation corresponding to the nominal system. More importantly, an additional stabilizing term is introduced for helping to verify the stability, which reinforces the updating process of the weight vector and reduces the requirement of an initial stabilizing control. The uniform ultimate boundedness of the closed-loop system is analyzed by using the Lyapunov approach as well. Two simulation examples are provided to verify the effectiveness of the present control approach.


Development of multiwavelength-range fine-resolution spectrometer for hydrogen emissions and its application to large helical device periphery plasmas.
We developed a spectrometer specialized for simultaneous observation of the hydrogen Balmer-alpha, -beta, -gamma lines and the Fulcher-alpha v(')=v(")=2 rovibronic transition band. The spectrometer was optimized for the light input coupled by nine optical fibers having 400 microm core diameters. The spectral resolutions were 0.02-0.03 nm for these wavelength ranges at the entrance slit width of 20 microm. The polarization resolved spectra of these emissions from the peripheral region of large helical device (LHD) plasmas were measured simultaneously and showed the polarization dependence coming from the magnetic field in the LHD plasma.


Cross-resistance and Inheritance of Resistance to Emamectin Benzoate in Spodoptera exigua (Lepidoptera: Noctuidae).
Beet armyworm, Spodoptera exigua (Hübner), is a worldwide pest of many crops. Chemical insecticides are heavily used for its control in China, and serious resistance has been evolved in the field to a variety of insecticides including emamectin benzoate. Through repeated backcrossing to a susceptible strain (WH-S) and selection with emamectin benzoate, the trait conferring resistance to emamectin benzoate in a field-collected population of S. exigua (moderately resistant to emamectin benzoate and strongly resistant to pyrethroids and indoxacarb) was introgressed into WH-S to generate a near-isogenic resistant strain (WH-EB). Compared with WH-S, the WH-EB strain developed a 1,110-fold resistance to emamectin benzoate and a high level of cross-resistance to abamectin (202-fold), with low levels of cross-resistance to cypermethrin (10-fold) and chlorfluazuron (7-fold), but no cross-resistance to representatives of another six different classes of insecticides (chlorantraniliprole, chlorfenapyr, indoxacarb, spinosad, tebufenozide, and chlorpyrifos). Resistance to emamectin benzoate in WH-EB was autosomal, incompletely dominant, and polygenic. Limited cross-resistance in WH-EB indicates that emamectin benzoate can be rotated with other classes of insecticides to which it does not show cross-resistance to delay the evolution of resistance in S. exigua. The incompletely dominant nature of resistance in S. exigua may explain the rapid evolution of resistance to emamectin benzoate in the field, and careful deployment of this chemical within a resistance management program should be considered.


[National plan for the prevention and control "influenza pandemic"].
France has developed a national plan for the prevention and control of an influenza pandemic with the aim of reducing its health impact and its consequences on the economic and social life of the country. The main objectives of the plan are to prepare the country to face an epizootic of avian influenza due to a highly pathogenic virus, to detect the first manifestation of a new flu virus, to curb its spread by adopting early and appropriate public health measures and to protect the French population, as well as French citizens abroad. Ensuring that the population has the best possible access to prevention and care, through the organisation and adaptation of the health system facing a pandemic, is one of the major goals of the plan. The plan, and organisation associated to it, forms the foundation of a coherent and adaptable system which every citizen should feel ownership of.


Cholesterol interacts with lactosyl and maltosyl cerebrosides but not with glucosyl or galactosyl cerebrosides in mixed monolayers.
Pure and mixed monolayers of mono- and dihexoside cerebrosides with cholesterol have been characterized at the air/water interface. Cholesterol oxidase was used as a reporter enzyme for the cholesterol-cerebroside interaction in the mixed monolayers. The cerebrosides either were derived from bovine brain extracts or were synthetic. The dihexoside cerebrosides were synthesized by coupling of the hepta-O-acetyl-alpha-lactosyl- or maltosylphosphoramidates with D-erythro-N-acylceramides in dichloromethane, in the presence of trimethylsilyl triflate and molecular sieves, followed by hydrolysis of the acetate-protecting groups. All of the bovine-brain-derived cerebrosides [galactosyl cerebroside (GalCer, types I and II), glucosyl cerebroside (GlcCer), and lactosyl cerebroside (LacCer)] had very condensed force-area isotherms (compressibility values of 3-5 x 10(-3) m/mN at 20 mN/m), as did the synthetic N-stearoylmaltosylceramide (N-18:0 MaltCer). Shorter-chain synthetic cerebrosides (N-8:0 LacCer and N-8:0 MaltCer) had more expanded isotherms, with compressibility values of 15-17 x 10(-3) m/mN. When cholesterol was included in mixed monolayers of monohexoside cerebroside, it did not induce significant condensation of packing (indicating that cholesterol did not increase the order of the acyl chains). However, with dihexoside cerebrosides, a cholesterol-induced condensing effect was observed, which amounted to a 11-19% reduction in the observed mean molecular area. When cholesterol oxidase was used to titrate the stoichiometry of cholesterol/cerebroside in mixed monolayers, at which pure cholesterol clusters appeared, it was observed that in monohexoside cerebroside monolayers cholesterol clusters were present even below a 1:1 molar stoichiometry.(ABSTRACT TRUNCATED AT 250 WORDS)


Spectrally resolved femtosecond two-color three-pulse photon echoes: study of ground and excited state dynamics in molecules.
We report the use of spectrally resolved femtosecond two-color three-pulse photon echoes as a potentially powerful multidimensional technique for studying vibrational and electronic dynamics in complex molecules. The wavelengths of the pump and probe laser pulses are found to have a dramatic effect on the spectrum of the photon echo signal and can be chosen to select different sets of energy levels in the vibrational manifold, allowing a study of the dynamics and vibrational splitting in either the ground or the excited state. The technique is applied to studies of the dynamics of vibrational electronic states in the dye molecule Rhodamine 101 in methanol.


Occurrence of Escherichia coli O157:H7 and other enterohemorrhagic Escherichia coli in the environment.
Enterohemorrhagic Escherichia coli (EHEC) (O157 and other serotypes) are zoonotic pathogens linked with severe human illnesses. The main virulence factors of EHEC are the Shiga toxins, among others. Most of the genes coding for these toxins are bacteriophage-encoded. Although ruminants are recognized as their main natural reservoir, water has also been documented as a way of transmission of EHEC. E. coli O157:H7 and other EHEC may contaminate waters (recreational, drinking or irrigation waters) through feces from humans and other animals. Indeed, the occurrence of EHEC carrying the stx2 gene in raw municipal sewage and animal wastewater from several origins has been widely documented. However, the evaluation of the persistence of naturally occurring EHEC in the environment is still difficult due to methodological problems. Methods proposed for the detection and isolation of stx-encoding bacteria, ranging from the classic culture-based methods to molecular approaches, and their application in the environment, are discussed here. Most virulence factors associated with these strains are linked to either plasmids or phages, and consequently they are likely to be subject to horizontal gene transfer between species or serotypes. Moreover, the presence of infectious stx-phages isolated as free particles in the environment and their high persistence in water systems suggest that they may contribute to the spread of stx genes, as they are directly involved in the emergence of new pathogenic strains, which might have important health consequences.


The Association Between Dietary Inflammatory Potential and Sex Hormones in Male Children and Adolescents Aged 6-19 Years.
This study aimed to assess the relationship between dietary inflammatory index (DII) and sex hormones in male children and adolescents aged 6-19 years. We obtained data from the 2013-2016 National Health and Nutrition Examination Survey (NHANES). Male participants aged 6-19 years old with the complete data of DII and sex hormones were included. Weighted multiple regression analysis and subgroup analysis were preformed to estimate the independent relationship between DII and sex hormones. A total of 1717 male participants with the average age of 13.02 ± 3.82 years were enrolled, of whom 41.3% (n=713) were children and 58.47% (n=1004) were adolescents. In children, mean DII was 0.18 ± 1.67, with scores ranging from -4.53 to 4.08. As for adolescents, the mean DII was 0.36 ± 1.98, mean total testosterone (TT) was 376.94 ± 206.69 ng/dl overall. A negative association between DII with TT and estradiol (E2) was observed (TT: β=-11.97, P=0.0006; E2: β=-0.45, P=0.0108) in male adolescent. Subgroup analysis and interaction test results indicated that this association was similar in male adolescents with different body mass index. No statistically significant association was observed in children. Pro-inflammatory diet was associated with lower TT and E2 level in male adolescent, while no association with statistical significance between them was observed in male children. However, more studies are still needed to validate the causal relationship between DII and sex hormones.


Changes in the thyroid hormone profiles in children with nephrotic syndrome.
We compared thyroid hormone profiles in children with nephrotic syndrome (NS) during the nephrotic phase and after remission. This study included 31 pediatric NS patients. The thyroid hormone profiles included serum levels of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and free T4. Of the 31 patients, 16 (51.6%) showed abnormal thyroid hormone profiles: 6 had overt hypothyroidism, 8 had subclinical hypothyroidism, and 2 had low T3 syndrome. The mean serum T3, T4, and free T4 levels in the nephrotic phase and after remission were 82.37±23.64 and 117.88±29.49 ng/dL, 5.47±1.14 and 7.91±1.56 µg/dL, and 1.02±0.26 and 1.38±0.23 ng/dL, respectively; the levels were significantly lower in the NS nephrotic phase (P=0.0007, P<0.0001, and P=0.0002). The mean serum TSH levels during the nephrotic phase and after remission were 8.05±3.53 and 4.08±2.05 µIU/ mL, respectively; they were significantly higher in the nephrotic phase (P=0.0005). The urinary protein/ creatinine ratio during the nephrotic phase was significantly correlated with serum T3, T4, and free T4 levels (r=-0.5995, P=0.0032; r=-0.5797, P=0.0047; r=-0.5513, P=0.0078) as well as with TSH levels (r=0.5022, P=0.0172). A significant correlation was found between serum albumin and serum T3 levels during the nephrotic phase (r=0.5385, P=0.0018) but not between serum albumin and T4, TSH, or free T4 levels. These significant correlations all disappeared after remission. Abnormal thyroid hormone profile findings were observed in 51.6% of pediatric patients with NS. Thyroid hormone levels normalized after remission, regardless of levothyroxine therapy.


Enhanced membrane fusion in sterol-enriched vacuoles bypasses the Vrp1p requirement.
Organization of lipids into membrane microdomains is a vital mechanism of protein processing. Here we show that overexpression of ERG6, a gene involved in ergosterol synthesis, elevates sterol levels 1.5-fold on the vacuole membrane and enhances their homotypic fusion. The mechanism of sterol-enhanced fusion is not via more efficient sorting, but instead promotes increased kinetics of fusion subreactions. We initially isolated ERG6 as a suppressor of a vrp1Delta growth defect selective for vacuole function. VRP1 encodes verprolin, an actin-binding protein that colocalizes to vacuoles. The vrp1Delta mutant has fragmented vacuoles in vivo and isolated vacuoles do not fuse in vitro, indicative of a Vrp1p requirement for membrane fusion. ERG6 overexpression rescues vrp1Delta vacuole fusion in a cytosol-dependent manner. Cytosol prepared from the vrp1Delta strain remains active; therefore, cytosol is not resupplying Vrp1p. Las17p (Vrp1p functional partner) antibodies, which inhibit wild-type vacuole fusion, do not inhibit the fusion of vacuoles from the vrp1Delta-ERG6 overexpression strain. Vacuole-associated actin turnover is decreased in the vrp1Delta strain, but recovered by ERG6 overexpression linking sterol enrichment to actin remodeling. Therefore, the Vrp1p/Las17p requirement for membrane fusion is bypassed by increased sterols, which promotes actin remodeling as part the membrane fusion mechanism.


Study of blood lipids, cortisol and haemodynamic variations under stress in male adults.
Increased cholesterol in blood plays the role in atherosclerosis formation. It is observed that stress increases cholesterol level. Most of previous studies were conducted on biological risk factors like blood lipids under stress in middle aged persons who remained under investigations for heart problems. The study was conducted to evaluate the changes in blood lipids and blood cortisol along with sympatheo-adnergic responses determined by selected haemodynamic parameters during psychological stress. Male participants (n = 114) were randomly selected. They were examined two times, for stress task of viva-voce (degree examination) and during non-stress period. Final selection of participants was depending on stress assessment and their well being. Cortisol, systolic and diastolic blood pressures (SBP and DBP) and heart rate (HR) were significantly increased during stress period with p < 0.001 for each parameter. But different blood lipids levels (TC, LDL-C, HDL-C and TG) were detected with different significant levels. The correlations of changed lipids with raised findings of haemodynamics and cortisol were also evaluated. Further studies in our population are needed to evaluate the relation of changes in various biological risk factors including IL-9 and sympatho-adernergic activities with stress factors related to our social/ environmental problems, especially genetically based psychological factors.


Commentary: Demystifying Doppler - revisiting a vital diagnostic tool.
Doppler is the most commonly utilised vascular assessment tool by podiatrists in Australia and the United Kingdom. Doppler is a key component of many international guidelines for vascular assessment. Used alongside pressure measurements such as ankle and toe-brachial indices, Doppler assists podiatrists to diagnose, triage and subsequently manage patients with peripheral arterial disease. This commentary aims to clarify the importance, technique, and interpretation of continuous wave handheld Doppler in podiatry practice. This commentary presents discussion on the equipment and optimal test conditions for use of Doppler, and guidance on the technique required in podiatry clinical practice. Furthermore, there is a focus on interpretation of the output from Doppler including both audio and visual output. There is in depth discussion about identifying pathology and integration into the clinical management plan.


High-dose therapy and autologous peripheral stem cell transplantation for patients with bone marrow metastases and relapsed lymphoma: an alternative to bone marrow purging.
Throughout a 4-year period, we reinfused autologous peripheral stem cells rather than purged autologous bone marrow following high-dose therapy to 57 patients with relapsed lymphoma and bone marrow metastases. Approximately 7 x 10(8) circulating mononuclear cells/kg patient weight were collected for each patient with 6-19 4-h apheresis procedures while hemopoiesis was unperturbed. Following collection, the cells were cryopreserved. Administration of high-dose therapy, which included either combination chemotherapy or combination chemotherapy plus total body irradiation, was followed by i.v. administration of the thawed autologous stem cells. The rate of hemopoietic recovery varied with the specific high-dose therapy administered. Sixty-two percent of 50 evaluable patients had a clinical complete response. The actuarial event-free survival for these patients 4 years after transplantation was 30%, and the projected survival at 4 years was 51%. Patients with relapsed lymphoma and bone marrow metastases who receive high dose therapy followed by peripheral stem cell transplantation can experience long-term event-free survival. Whether similar patients would fare as well with the same high-dose therapy followed by a purged autologous bone marrow transplantation would require a randomized prospective study.


Primary care physician attitudes and values toward end-of-life care and physician-assisted death.
This study explores how primary care physician attitudes toward physician-assisted death (PAD) are related to their personal values toward end-of-life care and PAD. A group of 810 Michigan family physicians, internists, and general practitioners, divided into 4 typology groups by their intention toward participating in PAD, rated their attitudes toward PAD, along with their values and preferences for their own end-of-life care. Respondents who most objected to PAD were less likely to have executed an advance directive and more likely to have values promoting continued life-sustaining treatment in their own terminal care. Furthermore, a significant number of physicians, who had strong values against their own withdrawal of treatment in terminal care, were opposed to the withdrawing or withholding of life-sustaining treatment in patient care. Considerations of personal physician values are relevant in the discussion of PAD and the withdrawal of treatment in terminal care.


[Influence of acute alcohol intoxication on the synthesis of RNA and proteins in the liver of rats at various times of the day].
An acute alcoholic poisoning occurring 12 hours after intragastric administration of a 40 degrees ethanol (1.5 ml/kg) produced at 9 and 21 hours an inhibitory action on the incorporation of H3-uridine in the nuclei and cytoplasm, as well as of S35-methionine in the cytoplasm of the hepatic cells in rats. An alcohol inhibition of the RNA and protein synthesis at different time of the day proved dissimilar. Intact animals demonstrated significant diurnal variations in the intensity of the isotopes incorporation in the nuclei and cytoplasm of hepatocytes which continued after the action of alcohol, with the incorporation maximum at 21 and minimum at 9 hours.


How should we address the inevitable harms from non-negligent variant reclassification in predictive genetic testing?
The process of interpreting genetic variants, in which experts use all available evidence to determine whether an identified variant is associated with a current or future disease, is both scientific and nevertheless subjective. In this paper, we summarize the existing evidence that any given variant could be reclassified and that such a reclassification could lead to harm. Furthermore, the racial gap in genetic databases could lead to a higher likelihood of harm for non-white patients. We also review recent legal analyses indicating it is unlikely that an individual who sues for restitution would be successful, especially in the absence of evidence of lab negligence. We then propose a compensation program for medical genetic tests to ensure that individuals who experience demonstrable harm due to a variant reclassification can be made whole financially. We conclude by discussing outstanding questions that must be answered for such a program to be feasible.


Exploring drinking dynamics using interactive voice response technology.
Neurocognitive models of alcohol use and mathematical models of drinking patterns suggest that levels of drinking on one day should affect probabilities of drinking on subsequent days. However, there has been no demonstration in the alcohol literature that these structured temporal dependencies appear in daily patterns of alcohol use. A model of daily drinking is presented that relates probabilities of drinking on any day to amounts consumed 1 day and 1 week before. It is assumed that positive and negative experiences with alcohol shape drinking levels and probabilities of subsequent drinking. The model predicts that nonmonotonic functions will relate drinking levels to subsequent drinking probabilities. Maxima of these functions represent optimal drinking levels that provide greatest positive returns from any drinking occasion for each drinker. Interactive Voice Response technology was used to obtain annual time series of daily drinking levels from 33 drinkers sampled from public establishments in Vermont. Two predictions from the model were tested: (1) Temporal dependencies exist between the onset of drinking events over time; and (2) these dependencies are nonmonotonically related to prior drinking levels. Dynamics were separately assessed for each drinker using bootstrapped logistic regression models. Thirty respondents provided data suitable for analysis. Time series data from five of these respondents exhibited no temporal dynamics (17%). Data from 25 respondents exhibited either daily or weekly dynamics (83%). Data from 18 respondents exhibited the expected nonmonotonic relationship between drinking levels and subsequent drinking events (60%). Daily probabilities of drinking were conditional upon and nonmonotonically related to prior drinking levels among a majority of respondents. The results of the study support models of daily drinking in which positive and negative experiences with alcohol shape daily drinking patterns.


Periodontics, Implantology, and Prosthodontics Integrated: The Zenith-Driven Rehabilitation.
A customized treatment plan is important to reach results that will satisfy the patient providing esthetics, function, and long-term stability. This type of oral rehabilitation requires professionals from different dental specialties where communication is a major key point. Digital Smile Design allows the practitioners to plan and discuss the patient's condition to establish the proper treatment plan, which must be driven by the desired zenith position. The ideal gingival position will guide the professionals and determine the need to perform surgical procedures or orthodontic movement before placing the final restorations. In this article, the zenith-driven concept is discussed and a challenging case is presented with 4-year follow-up where tooth extraction, immediate implant placement, bone regeneration, and a connective tissue graft were performed.


[Detection of regional lymph node micrometastasis and its impact on long-term survival of non-small cell lung cancer (NSCLC) patients].
Regional lymph node micrometastasis, which can not be found by routine pathologic examination, may be detected by immunohistochemistry after radical operation of tumors. This study was to investigate regional lymph node micrometastasis in non-small cell lung cancer (NSCLC) and its impact on prognosis. The expressions of cytokeratin (CK) in 684 specimens from 78 stage pT1-2N0M0 NSCLC patients, treated from Jan. 1996 to Dec. 2003, were detected by EnVision method using anti-CK antibody AE1/AE3. The correlation of CK expression to prognosis was analyzed. The overall detection rate of CK was 26.9%û the detection rates were 5.9% in stage p-IA patients and 32.8% in stage p-IB patients. The 1-, 3-, 5-, and 8-year survival rates were significantly higher in non-micrometastasis group than in micrometastasis group (90.80% vs. 60.00%, 69.70% vs. 48.48%, 55.76% vs. 29.09%, and 37.17% vs. 0, P=0.008)û the median survival time were 87 months and 23 months, respectively. CK and KPS score were independent prognostic factors of NSCLC (P=0.014, P<0.001). Compared with surgery alone, surgery plus postoperative radiochemotherapy prolonged survival, but the difference was not significant (P=0.063). The detection rate of lymph node micrometastases may be increased with the progression of NSCLC. Micrometastasis is an independent prognostic factor of NSCLC.


[Complications after replacement of a knee joint endoprosthesis with a cementless "low contact stress" prosthesis].
Total endoprosthesis of the knee joint of the LCS type reduce due to the mobile placement of the menisci and rotatable components the mechanical demands on anchoring in bone and thus contribute to satisfactory biological integration. During the period between June 1, 1989 and December 31, 1991 in the orthopaedic department of the general hospital in Zwettel 41 patients had 42 total endoprostheses (LCS) of the knee joint implanted. The group comprised 34 women and 7 men. All patients were checked and evaluated according to Hungerdorf's schema. The age range was 62 to 79 years with an average of 65.8 years. The follow-up period was 8 to 38 months, mean 21 months. The results as regards pain, stability, mobility, axis of the extremity and ability to walk were evaluated as very good and good. The authors discuss also postoperative complications. They did not observe loosening of cement-free components.


The Effect of a 12-Week Beta-hydroxy-beta-methylbutyrate (HMB) Supplementation on Highly-Trained Combat Sports Athletes: A Randomised, Double-Blind, Placebo-Controlled Crossover Study.
The aim of this study was to verify the effect of beta-hydroxy-beta-methylbutyrate (HMB) supplementation on physical capacity, body composition and the value of biochemical parameters in highly-trained combat sports athletes. Forty-two males highly-trained in combat sports were subjected to 12 weeks of supplementation with HMB and a placebo in a randomized, placebo controlled, double-blind crossover manner. Over the course of the experiment, aerobic and anaerobic capacity was determined, while analyses were conducted on body composition and levels of creatine kinase, lactate dehydrogenase, testosterone, cortisol and lactate. Following HMB supplementation, fat-free mass increased (p = 0.049) with a simultaneous reduction of fat mass (p = 0.016) in comparison to placebo. In turn, after HMB supplementation, the following indicators increased significantly in comparison to the placebo: the time to reach ventilatory threshold (p < 0.0001), threshold load (p = 0.017) and the threshold HR (p < 0.0001), as well as anaerobic peak power (p = 0.005), average power (p = 0.029), maximum speed (p < 0.001) and post-exercise lactate concentrations (p < 0.0001). However, when compared to the placebo, no differences were observed in blood marker levels. The results indicate that supplying HMB promotes advantageous changes in body composition and stimulates an increase in aerobic and anaerobic capacity in combat sports athletes.


Influence of physically crosslinked gelatins on the vasculature in the avian chorioallantoic membrane.
Gelatins functionalized with desaminotyrosine (DAT) or desaminotyrosyl tyrosine (DATT) form physically crosslinked hydrogels, due to the interactions between the introduced aromatic moieties and gelatin triple helices, whose extent depends on the thermal treatment of the material. The G-modulus of these hydrogels can be tailored to the range of the natural extracellular matrix by adjusting the degree of crosslinking. While these gelatin-based materials have been shown to be not angiogenic, the aim of the study was to evaluate whether these biomaterials influence the regulation of blood vessels when positioned on the chorionallantoic membrane (CAM) of fertilized eggs. The results clearly indicate that the DAT-functionalized gelatin led to an increase of the diameter of the blood vessels in the CAM, which at the same time is probably associated with an increased blood flow in these CAM vessels. The vessel diameters of the four groups (DAT-functionalized gelatin, DATT-functionalized gelatin, plain gelatin, control group without gelatin, each n = 10) differed significantly (p < 0.0001). Vessels in the CAM exposed to the DAT-functionalized gelatin showed with 36.4 μm ± 3.4 μm the largest mean diameters compared to the mean diameters of the samples exposed to DATT gelatin (16.0 μm ± 0.8 μm; p < 0.05) and the plain gelatin (21.2 μm ± 1.0 μm; p < 0.05), which both did not differ significantly from the vessels of the control group. The biocompatibility of the materials in vitro motivates the exploration of their application as matrix in local drug-release systems with short half-life times (one hour up to several days).


DDAVP in the treatment of bleeding disorders.
Hemophilia A and von Willebrand's disease are hereditary disorders associated with qualitative and quantitative abnormalities of clotting factor VIII. A major clinical feature is excessive or abnormal bleeding often necessitating the use of transfusions of pooled blood products to achieve hemostasis. Exposure to blood products places the recipient at risk for infection by the hepatitis B virus or the human immunodeficiency virus. A synthetic analog of arginine vasopressin, 1-desamino-8-D-arginine vasopressin, has been shown to increase the plasma levels of factor VIII coagulant activity and von Willebrand's factor, and clinically to improve abnormal bleeding, obviating the need to use blood products.


Population pharmacokinetics and pharmacodynamics of busulfan with GSTA1 polymorphisms in patients undergoing allogeneic hematopoietic stem cell transplantation.
A population pharmacokinetic (PPK) analysis was conducted to describe the influence of GSTA1 polymorphisms on intravenous busulfan in adults undergoing allogeneic hematopoietic stem cell transplantation. A PPK model was developed from 36 patients by a one-compartment model with first-order elimination. The typical value of clearance and volume of distribution were 11.0 l/h and 42.4 l, respectively. Clearance decreased by 15% and area under the concentration-time curves (AUCs) increased with GSTA1 variants compared with wild-type (both p < 0.05). Subtherapeutic AUCs were seen only in wild-type patients. To our knowledge, this is the first PPK study to suggest that GSTA1 polymorphisms in adults are associated with busulfan PK.


The Relationship Between Dental Students' Assessment Ability and Preclinical and Academic Performance in Operative Dentistry.
Self-assessment is a critical skill for health care professionals. Because these professionals must be lifelong, self-directed learners and self-regulating practitioners, the ability to self-assess is essential for them. The aims of this study were to measure how dental students self-assessed and peer-assessed their performance in preclinical operative procedures and to evaluate any relationship between their assessment ability and preclinical skills or academic performance. The study was conducted from 2015 to 2016. Third-year students at Harvard School of Dental Medicine self-assessed their work on four preclinical practical exams: Class II amalgam preparation, Class II amalgam restoration, Class III composite preparation, and Class III composite restoration. Three faculty members graded the same preparations and restorations. The difference between the students' self-assessment and the mean faculty assessment was calculated as the student-faculty (S-F) gap. An absolute S-F gap was also calculated with absolute values of differences. A total of 71 students completed these practical exams: 36 in the Class of 2016 and 35 in the Class of 2017. All 71 self-assessments for each of the four practical exams were collected for a response rate of 100%. The results showed that the mean S-F gap ranged from 2% to 8%, and the absolute S-F gap ranged from 7% to 12%. Preclinical performance was correlated with self-assessment accuracy. Low-performing students significantly overestimated their self-assessments compared to the rest of the class. High-performing students had more accurate self-assessments and tended to underestimate themselves. Overall, these results showed that the students had room for improving the accuracy of their self-assessments.


Responses of photosynthesis to NaCl in gametophytes of Acrostichum aureum.
Gametophytes of Acrostichum aureum were cultured in 0.0 to 1.0% NaCl solutions or in NaCl-free solution and then transferred to 1.0% NaCl solution. Photosynthetic light-response curves, efficiency of the primary photochemical reaction, relative electron transport rate, and photochemical and non-photochemical quenching at steady state were determined by photosynthetic O2 evolution and in vivo chlorophyll fluorescence. Results obtained showed that the chlorophyll fluorescence parameters, Fv /Fm and F'v /F'm and αO2 (the initial linear slope of the photosynthetic light-response curve) increased in gametophytes grown in NaCl. Linear electron transport rate was stimulated by NaCl. Based on the chlorophyll content, light-saturated photosynthesis in gametophytes grown in 0.2 to 0.7% NaCl increased slightly; it decreased in gametophytes grown in 1.0% NaCl. Photochemical quenching decreased in NaCl-grown gametophytes at all photosynthetic photon flux density (PPFD) levels measured, but there was no increase in non-photochemical quenching. The chlorophyll a/b ratio increased with increasing NaCl concentration in culture solutions. These results indicated that NaCl enhanced photochemical efficiency of photosystem II (PSII) and photosynthetic linear electron transport, thus resulting in the development of an excitation pressure in PSII. Such excitation pressure might act as a signal for photosynthetic acclimation to salt stress, thus allowing the gametophytes to grow in their natural habitats.


Novel mode of interference with nuclear factor of activated T-cells regulation in T-cells by the bacterial metabolite n-butyrate.
The transcription factor nuclear factor of activated T-cells (NF-AT) plays an essential role in the activation of many early immune response genes. A dynamic equilibrium between calcineurin and cellular kinases controls its phosphorylation and thus regulates its activity by determining its subcellular localization. Here, we demonstrate that T-cell activation in the presence of the bacterial metabolite n-butyrate, which leads to inhibition of interleukin-2 transcription, is characterized by the maintenance of the activity of counter-regulatory kinases glycogen synthase kinase 3 and protein kinase A as well as persistence of intracellular cAMP levels, whereas calcium response and mitogen-activated protein kinase activation were indistinguishable from cells stimulated in the absence of n-butyrate. Nuclear binding of NF-AT was decreased but other transcription factors implicated in interleukin-2 expression such as AP1 and nuclear factor kappaB were unaffected. The effect on NF-AT binding appeared to be the result of increased nuclear export because the export inhibitor leptomycin B completely restored nuclear binding of NF-AT. We, therefore, provide first evidence for interference with NF-AT regulation alternative to the currently understood inhibition of nuclear import. This mechanism might represent a bacterial strategy to subvert host defense, which could be of particular clinical importance in the gastrointestinal tract where high amounts of n-butyrate are physiologically present.


Recent advances in understanding the pathogenesis of obstructive sleep apnea.
The pathogenesis of obstructive sleep apnea (OSA) is incompletely understood. Historically it was believed that patients with OSA have a small upper airway (often due to obesity) that is kept patent during wakefulness by the activity of upper airway dilating muscles. With the reduction in muscle tone at sleep onset, the airway collapses and causes apnea. While this appears to be the case for many patients with OSA, other patients show no major airway anatomic defects or minimal obesity. This has led to the concept that other factors such as unstable ventilatory control and changes in lung volume during sleep may be involved in the pathogenesis of OSA. Recently there have been several advances in our understanding of how these mechanisms are involved in OSA pathogenesis. A more complete understanding of apnea pathogenesis may improve therapeutic techniques and reduce the consequences of OSA.


Tandem stem-loops in roX RNAs act together to mediate X chromosome dosage compensation in Drosophila.
Dosage compensation in Drosophila is an epigenetic phenomenon utilizing proteins and long noncoding RNAs (lncRNAs) for transcriptional upregulation of the male X chromosome. Here, by using UV crosslinking followed by deep sequencing, we show that two enzymes in the Male-Specific Lethal complex, MLE RNA helicase and MSL2 ubiquitin ligase, bind evolutionarily conserved domains containing tandem stem-loops in roX1 and roX2 RNAs in vivo. These domains constitute the minimal RNA unit present in multiple copies in diverse arrangements for nucleation of the MSL complex. MLE binds to these domains with distinct ATP-independent and ATP-dependent behavior. Importantly, we show that different roX RNA domains have overlapping function, since only combinatorial mutations in the tandem stem-loops result in severe loss of dosage compensation and consequently male-specific lethality. We propose that repetitive structural motifs in lncRNAs could provide plasticity during multiprotein complex assemblies to ensure efficient targeting in cis or in trans along chromosomes.


Plk1 regulates contraction of postmitotic smooth muscle cells and is required for vascular homeostasis.
Polo-like kinase 1 (PLK1), an essential regulator of cell division, is currently undergoing clinical evaluation as a target for cancer therapy. We report an unexpected function of Plk1 in sustaining cardiovascular homeostasis. Plk1 haploinsufficiency in mice did not induce obvious cell proliferation defects but did result in arterial structural alterations, which frequently led to aortic rupture and death. Specific ablation of Plk1 in vascular smooth muscle cells (VSMCs) led to reduced arterial elasticity, hypotension, and an impaired arterial response to angiotensin II in vivo. Mechanistically, we found that Plk1 regulated angiotensin II-dependent activation of RhoA and actomyosin dynamics in VSMCs in a mitosis-independent manner. This regulation depended on Plk1 kinase activity, and the administration of small-molecule Plk1 inhibitors to angiotensin II-treated mice led to reduced arterial fitness and an elevated risk of aneurysm and aortic rupture. We thus conclude that a partial reduction of Plk1 activity that does not block cell division can nevertheless impair aortic homeostasis. Our findings have potentially important implications for current approaches aimed at PLK1 inhibition for cancer therapy.


Maintained expression of genes associated with metabolism in the ventromedial hypothalamic nucleus despite development of leptin resistance during pregnancy in the rat.
Hyperphagia and weight gain to acquire energy stores for development and growth of the fetus and to prepare for the demands of lactation are important adaptations to support a healthy pregnancy. As a consequence, hypothalamic leptin resistance develops to enable maintenance of a positive energy state. During pregnancy there is a decrease in leptin receptor expression and reduced leptin-induced phospho signal transducer and activator of transcription 3 (pSTAT3) in the ventromedial nucleus of the hypothalamus (VMN), suggesting that the VMN is a key site of pregnancy-induced modification in the control of energy homeostasis. The aim of this study was to investigate expression levels of known gene targets, which are involved in metabolic regulation and glucosensing, within the VMN during pregnancy. Using in situ hybridization, pituitary adenylate cyclase-activated polypeptide (Pacap), brain-derived neurotrophic factor (Bdnf), and glucokinase messenger ribonucleic acid (mRNA) expression were localized in the hypothalamus of nonpregnant and day 14 pregnant rats, then expression levels were compared by quantitative polymerase chain reaction (qPCR) using laser capture microdissection of the VMN and arcuate nucleus. Despite significantly elevated plasma leptin and insulin concentrations, and lower blood glucose levels, during pregnancy, no significant changes in gene expression of Pacap, Bdnf, or glucokinase were detected between nonpregnant and day 14 pregnant groups. These data suggest that loss of leptin and insulin sensitivity in the VMN might allow gene expression to be maintained at normal/control levels in this nucleus, despite marked changes in the levels of these important regulatory hormones. These data provide further evidence for development of leptin resistance in the VMN as an adaptive response during pregnancy.