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21.
Oleg S Gorbatyuk Shoudong Li Frederic Nha Nguyen Fredric P Manfredsson Galina Kondrikova Layla F Sullivan Craig Meyers Weijun Chen Ronald J Mandel Nicholas Muzyczka 《Molecular therapy》2010,18(10):1758-1768
We present genetic evidence that an in vivo role of α-synuclein (α-syn) is to inhibit phospholipase D2 (PLD2), an enzyme that is believed to participate in vesicle trafficking, membrane signaling, and both endo- and exocytosis. Overexpression of PLD2 in rat substantia nigra pars compacta (SNc) caused severe neurodegeneration of dopamine (DA) neurons, loss of striatal DA, and an associated ipsilateral amphetamine-induced rotational asymmetry. Coexpression of human wild type α-syn suppressed PLD2 neurodegeneration, DA loss, and amphetamine-induced rotational asymmetry. However, an α-syn mutant defective for inhibition of PLD2 in vitro also failed to inhibit PLD toxicity in vivo. Further, reduction of PLD2 activity in SNc, either by siRNA knockdown of PLD2 or overexpression of α-syn, both produced an unusual contralateral amphetamine-induced rotational asymmetry, opposite to that seen with overexpression of PLD2, suggesting that PLD2 and α-syn were both involved in DA release or reuptake. Finally, α-syn coimmunoprecipitated with PLD2 from extracts prepared from striatal tissues. Taken together, our data demonstrate that α-syn is an inhibitor of PLD2 in vivo, and confirm earlier reports that α-syn inhibits PLD2 in vitro. Our data also demonstrate that it is possible to use viral-mediated gene transfer to study gene interactions in vivo. 相似文献
22.
Barduagni P Ahmed AS Curtale F Raafat M Soliman L 《Tropical medicine & international health : TM & IH》2003,8(7):615-618
Our aim was to compare the performance of the Sahli and Colour Scale methods in diagnosing anaemia in school children, where the prevalence of anaemia is low and the haemoglobin level ranges from mild to moderate (8-11 g/dl). The study was conducted in February 2001, in Qena Governorate, Upper Egypt. The haemoglobin level measured by the two methods in each child were compared with the result obtained by using a portable haemoglobin photometer 'HemoCue'. A total of 149 school children were included in the study. Using HemoCue, 17.4% children were anaemic; using the Sahli method (SM), 66.4% children were anaemic; and using the Haemoglobin Colour Scale (HCS) method, 57.7% children were anaemic. Neither method detected any cases of severe anaemia (Hb < 7 g/dl). Both the Sahli and Colour Scale methods are sensitive but have low specificity, giving a high rate of false positive results. Both methods perform perform very similarly in haemoglobin measurement; they fulfil many of the criteria for their use at primary health care level and detect almost all cases of anaemia in a given population, even if the level of anaemia is mild. Standards for collection, handling and disposal of blood samples are guaranteed more easily by the HCS than the SM. Moreover, lay people can easily manage the HCS with success after brief training. We suggest to gradually replace the SM by the HCS method in primary health care (PHC) centres. Where anaemia levels are moderate to mild, the use of SM and HCS as tools to define anaemia prevalence might be limited, as they often label healthy individuals as anaemic. Both methods remain a useful diagnostic tool to confirm the diagnosis of clinically suspected anaemia in areas where the prevalence of anaemia is low and the haemoglobin level ranges from mild to moderate. 相似文献
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24.
Many behavioral effects of nicotine result from activation of nigrostriatal and mesolimbic dopaminergic systems. Nicotine regulates dopamine release not only by stimulation of nicotinic acetylcholine receptors (nAChRs) on dopamine cell bodies within the substantia nigra and ventral tegmental area (SN/VTA), but also on presynaptic nAChRs located on striatal terminals. The nAChR subtype(s) present on both cell bodies and terminals is still a matter of controversy. The purpose of this study was to use double-labeling in situ hybridization to identify nAChR subunit mRNAs expressed within dopamine neurons of the SN/VTA, by using a digoxigenin-labeled riboprobe for tyrosine hydroxylase as the dopamine cell marker and (35)S-labeled riboprobes for nAChR subunits. The results reveal a heterogeneous population of nAChR subunit mRNAs within midbrain dopamine neurons. Within the SN, almost all dopamine neurons express alpha2, alpha4, alpha5, alpha6, beta2, and beta3 nAChR mRNAs, with more than half also expressing alpha3 and alpha7 mRNAs. In contrast, less than 10% express beta4 mRNA. Within the VTA, a similar pattern of nAChR subunit mRNA expression is observed except that most subunits are expressed in a slightly lower percentage of dopamine neurons than in the SN. Within the SN, alpha4, beta2, alpha7, and beta4 mRNAs are also expressed in a significant number of nondopaminergic neurons, whereas within the VTA this only occurs for beta4. The heterogeneity in the expression of nAChR subunits within the SN/VTA may indicate the formation of a variety of different nAChR subtypes on cell bodies and terminals of the nigrostriatal and mesolimbic pathways. 相似文献
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26.
Analogs of alpha-conotoxin MII are selective for alpha6-containing nicotinic acetylcholine receptors
McIntosh JM Azam L Staheli S Dowell C Lindstrom JM Kuryatov A Garrett JE Marks MJ Whiteaker P 《Molecular pharmacology》2004,65(4):944-952
Neuronal nicotinic acetylcholine receptors (nAChRs) both mediate direct cholinergic synaptic transmission and modulate synaptic transmission by other neurotransmitters. Novel ligands are needed as probes to discriminate among structurally related nAChR subtypes. Alpha-conotoxin MII, a selective ligand that discriminates among a variety of nAChR subtypes, fails to discriminate well between some subtypes containing the closely related alpha3 and alpha6 subunits. Structure-function analysis of alpha-conotoxin MII was performed in an attempt to generate analogs with preference for alpha6-containing [alpha6(*) (asterisks indicate the possible presence of additional subunits)] nAChRs. Alanine substitution resulted in several analogs with decreased activity at alpha3(*) versus alpha6(*) nAChRs heterologously expressed in Xenopus laevis oocytes. From the initial analogs, a series of mutations with two alanine substitutions was synthesized. Substitution at His9 and Leu15 (MII[H9A;L15A]) resulted in a 29-fold lower IC(50) at alpha6beta4 versus alpha3beta4 nAChRs. The peptide had a 590-fold lower IC(50) for alpha6/alpha3beta2 versus alpha3beta2 and a 2020-fold lower IC(50) for alpha6/alpha3beta2beta3 versus alpha3beta2 nAChRs. MII[H9A;L15A] had little or no activity at alpha2beta2, alpha2beta4, alpha3beta4, alpha4beta2, alpha4beta4, and alpha7 nAChRs. Functional block by MII[H9A;L15A] of rat alpha6/alpha3beta2beta3 nAChRs (IC(50) = 2.4 nM) correlated well with the inhibition constant of MII[H9A;L15A] for [(125)I]alpha-conotoxin MII binding to putative alpha6beta2(*) nAChRs in mouse brain homogenates (K(i) = 3.3 nM). Thus, structure-function analysis of alpha-conotoxin MII enabled the creation of novel selective antagonists for discriminating among nAChRs containing alpha3 and alpha6 subunits. 相似文献
27.
Dental unit water lines harbour considerable amounts of bacteria, derived from the biofilm on their inner surfaces, and the continuous reservoir of bacteria carries the potential to infect patients and dental workers alike. This article reviews the different methods of control and provides recent recommendations for ensuring that water of satisfactory quality is delivered to the patient. 相似文献
28.
Layla Diab-Cáceres Rosa María Girón-Moreno María Teresa Pastor-Sanz Esther Quintana-Gallego Isabel Delgado-Pecellín Marina Blanco-Aparicio Luis Maiz Marta María García-Clemente Carmen Luna-Paredes Pedro Mondéjar-López Marta Ruiz-de-Valbuena Ofelia Fernández Maribel Barrio Maribel González Alejandro López-Neyra María Cols-i-Roig Alexandre Palou-Rotger Francisco Javier Gómez-de-Terreros-Caro 《Archivos de bronconeumología》2018,54(12):614-618
Background
The most common cystic fibrosis (CF)-causing mutation is deltaF508 (F508del), which is present in 28% of CF Spanish patients. While the literature based on real-life studies on CF patients homozygous F508del treated with lumacaftor/ivacaftor is limited, it demonstrates the need for better strategies to prevent related adverse events (AEs) as well as the development of newer drugs.Methods
We conducted a multicenter, retrospective, observational study to describe the effects of lumacaftor/ivacaftor treatment in real-life in Spain. 20 CF patients were included, all aged 6 and upwards and presented with ppFEV1 < 40%, chosen from CF units country-wide. For the purposes of the study, they were treated with lumacaftor/ivacaftor 200/125 mg two tablets twice a day on a compassionate use programme throughout 2016. The primary endpoint was measured in all of the sample patients. Data were analysed from ppFEV1 at baseline and was measured every 6 months.Results
The mean age was 26.65 (range of 10–45), while the mean ppFEV1 before the treatment was 32.4% and mean BMI was 19.9 kg/m2. We analysed the changes in ppFEV1 and BMI from baseline during the treatment with lumacaftor/ivacaftor, but no differences were found. However, a moderate association between days of intravenous antibiotic needed and the use of lumacaftor/ivacaftor (p = 0.001) was established. Indeed, under the lumacaftor/ivacaftor, patients required 5.8 days of intravenous antibiotic treatment compared to 14.9 days prior to study. Also, severe pulmonary exacerbations requiring hospitalisation were statistically fewer under lumacaftor/ivacaftor treatment (p = 0.003). Finally, 75% of the sample presented with AEs, which led 35% of the subjects to discontinue the treatment.Conclusions
While treatment with lumacaftor/ivacaftor resulted in an improvement in the number of pulmonary severe exacerbations, no improvement in ppFEV1 or BMI was found. 相似文献29.
Potash JB Toolan J Steele J Miller EB Pearl J Zandi PP Schulze TG Kassem L Simpson SG Lopez V;NIMH Genetics Initiative Bipolar Disorder Consortium MacKinnon DF McMahon FJ 《The American journal of psychiatry》2007,164(8):1229-1237
OBJECTIVE: The purpose of this study was to assemble and validate a database of phenotypic variables that were collected from families with bipolar disorder as a resource for genetic and other biological studies. METHOD: Participants were ascertained for two bipolar disorder genetic linkage studies: the University of Chicago, Johns Hopkins, and National Institute of Mental Health (NIMH) Intramural Program (CHIP) Collaboration and the NIMH Genetics Initiative project. All participants underwent detailed, phenotypic assessment with either the Schedule for Affective Disorders and Schizophrenia-Lifetime Version or one of four versions of the Diagnostic Interview for Genetic Studies. Clinicians reviewed the interview items and derived variable definitions that were used to extract data from the original datasets. The combined data were subjected to range and logic assessments, and a subset was re-verified against the original data. Inconsistent data and variables that were deemed unreliable were excluded. Several of the resulting variables were characterized in the total cohort and tested for familial clustering, heritability, and statistical power in genetic linkage and association studies. RESULTS: The combined database of phenotypic variables contained 197 variables on 5,721 subjects in 1,177 families. Deoxyribonucleic acid (DNA) samples are available for 5,373 of these subjects. The clinical presentation of bipolar disorder varied markedly. Most subjects suffered from serious and often disabling illness. Many phenotypic variables are strongly familial, and some quantitative variables are highly heritable. The cohort assembled in this study offers substantial power to carry out genetic linkage and association studies that use specific clinical features as covariates or as primary phenotypes. CONCLUSIONS: This is the largest database of phenotypic variables yet assembled for bipolar disorder, and it is now available to the research community. Researchers and clinicians can use this database to explore the connections between phenomenology and genetics in a cohort that is adequately powered to detect even modest genetic effects in bipolar disorder. 相似文献
30.
Layla Al-Nakkash Nicholas L. Simmons Jennifer M. Lingard Barry E. Argent 《Journal of gastrointestinal cancer》1996,19(1):39-47
Summary
Conclusion
BxPC-3, Hs 766T, Capan-2, Panc-1, and Capan-1 cells possess receptors for VIP and β-adrenergic agonists that are functionally
coupled to adenylate cyclase. In this respect, they resemble pancreatic duct cells. However, we speculate that the process
of neoplastic transformation has either downregulated the expression of secretin receptors or led to a defect in the receptor
itself, placing a question mark over the usefulness of these adenocarcinoma cell lines as models of the pancreatic ductal
epithelium.
Background Because of the importance of ducts in pancreatic disease, we wished to establish which duct cells receptors are functional
on adenocarcinoma cell lines.
Methods We investigated the expression of agonist-stimulated adenylate cyclase activity in six human pancreatic adenocarcinoma cell
lines. Known stimulants of pancreatic ductal secretion, VIP, PHI, secretin, β-adrenergic, and dopamine, were tested.
Results For responsive cell lines, VIP was the most effective stimulant followed by adrenaline, isoprenaline, PHI, and secretin. Dopamine
was without effect. Since high concentrations of PHI and secretin were required to stimulate cyclase activity, their effect
is probably mediated by VIP receptors. Based on the degree of stimulation observed with the individual agonists, Hs 766T and
BxPC-3 were the most responsive cell lines, followed by Capan-2 and Capan-1, and finally Panc-1. MIAPaCa-2 cells did not respond
to any of the agonists tested. 相似文献