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131.
Kaschula CH Egan TJ Hunter R Basilico N Parapini S Taramelli D Pasini E Monti D 《Journal of medicinal chemistry》2002,45(16):3531-3539
Antiplasmodial activities versus the chloroquine sensitive D10 strain of Plasmodium falciparum of a series of N(1),N(1)-diethyl-N(2)-(4-quinolinyl)-1,2-ethanediamines with 11 different substituents at the 7-position on the quinoline ring have been investigated in vitro. Electron-withdrawing groups at the 7-position have been shown to lower the pK(a) of both the quinoline ring nitrogen atom and the tertiary amino nitrogen in the alkyl side chain. The quinoline nitrogen pK(a) ranges from 6.28 in the nitro derivative to 8.36 in the amino derivative, while the tertiary amino nitrogen has a pK(a) ranging between 7.65 in the trifluoromethyl derivative and 10.02 in the amino derivative. Calculation suggests that the resulting pH trapping of these compounds in the parasite food vacuole ranges between about 7% of that observed in chloroquine for the NO(2) derivative and 97% in the amino derivative. A direct proportionality between antiplasmodial activity normalized for pH trapping and beta-hematin inhibitory activity was observed. Activity could not be correlated with any other observed physical parameter. The beta-hematin inhibitory activity of these derivatives appears to correlate with both the hematin-quinoline association constant and the electron-withdrawing capacity of the group at the 7-position (Hammett constant). For the compounds under investigation, the hematin association constant is in turn influenced by the lipophilicity of the group at the 7-position. 相似文献
132.
The physiological role of steroid hormones in humans is well known, and the metabolic pathway and mechanisms of action are almost completely elucidated. The role of plant steroid hormones, brassinosteroids, is less known, but an increasing amount of data on brassinosteroid biosynthesis is showing unexpected similarities between human and plant steroid metabolic pathways. Here we focus our attention on the enzyme 5alpha-reductase (5alphaR) for which a plant ortholog of the mammalian system, DET2, was recently described in Arabidopsis thaliana. We demonstrate that campestenone, the natural substrate of DET2, is reduced to 5alpha-campestanone by both human 5alphaR isozymes but with different affinities. Solanum malacoxylon, which is a calcinogenic plant very active in the biosynthesis of vitamin D-like molecules and sterols, was used to study 5alphaR activity. Leaves and calli were chosen as examples of differentiated and undifferentiated tissues, respectively. Two separate 5alphaR activities were found in calli and leaves of Solanum using campestenone as substrate. The use of progesterone allowed the detection of both activities in calli. Support for the existence of two 5alphaR isozymes in S. malacoxylon was provided by the differential actions of inhibitors of the human 5alphaR in calli and leaves. The evidence for the presence of two isozymes in different plant tissues extends the analogies between plant and mammalian steroid metabolic pathways. 相似文献
133.
Agostoni C Verduci E Massetto N Radaelli G Riva E Giovannini M 《Developmental medicine and child neurology》2003,45(4):257-261
The aims of the study were to examine the relationship between long-chain polyunsaturated fatty acid (LCPUFA) status at diagnosis of phenylketonuria (PKU) and neurodevelopment through the first 12 months of life, and to assess whether any difference exists between infants breastfed and bottlefed in the first days of life on the basis of LCPUFA status. Twenty infants with PKU were prospectively examined through the first year of life. Plasma fatty acids were measured in infants at diagnosis. Plasma phenylalanine levels were determined monthly. Main outcome measures were the Bayley Mental Developmental Index (MDI) and Psychomotor Developmental Index (PDI) at 5 and 12 months of age, and the visual function at 12 months, evaluated by P100 wave latencies with visual evoked potentials. A higher PDI score was associated with higher plasma arachidonic acid at diagnosis (adjusted correlation coefficient of PDI at 5 months, r=0.38, p=0.05). P100 wave latency at 15 minutes of arc (15') was associated with the early plasma arachidonic acid (adjusted r=-0.56, p=0.02) and phenylalanine levels at 12 months (adjusted r=0.22, p=0.05). No association was found between MDI score and any essential fatty acids. Breastfed infants exhibited higher plasma arachidonic acid (mean difference, delta, =3.4%; 95% confidence interval [CI]=1.2-5.6%) and shorter P100 wave latency at 15' (delta=-21 ms, 95%CI=-30 to -12) than bottlefed infants. Within the population of this study, a weak positive association has been found between plasma LCPUFAs at diagnosis (higher in breastfed infants) and neurodevelopmental indices through the first year of life. 相似文献
134.
135.
Posterior subgluteal approach to block the sciatic nerve: description of the technique and initial clinical experiences 总被引:4,自引:0,他引:4
BACKGROUND AND OBJECTIVE: A new posterior approach to the sciatic nerve in the subgluteal region was developed. We describe our clinical experiences on 135 consecutive patients. METHODS: All blocks were performed with a nerve stimulator (stimulation frequency 2 Hz; intensity from 1 reduced to < or = 0.5 mA before application). A line was drawn from the greater trochanter to the ischial tuberosity of the femur; then, from the mid-point of this line, a second line was drawn perpendicularly and extended caudally for 4 cm: the end of this line represented the entry point of the needle. Sciatic stimulation was elicited at < or = 0.5 mA; then ropivacaine 0.75% 20 mL was injected. An independent observer recorded the time from needle insertion to successful sciatic nerve stimulation (performance time), the depth of appropriate sciatic stimulation and the number of needle redirections, as well as the quality of nerve block, the discomfort during the procedure and patient acceptance. RESULTS: The performance time was 41 +/- 25 s (mean +/- SD) and the mean (SD) depth at which the sciatic nerve stimulation was found was 45 +/- 10 mm. The median (range) number of needle redirections required to find the proper sciatic stimulation was 2 (1-5). The tibial response was observed in 77 patients (57%), while the common peroneal response was observed in 58 patients (43%). The degree of discomfort reported was very low and only 16 patients (12%) reported severe pain during placement of the block. The onset time (mean +/- SD) of sensory and motor block was 7 +/- 4 and 17 +/- 13 min respectively, and the surgical procedure was completed with only the peripheral nerve block in 127 patients (94%). The same anaesthesia procedure was acceptable by 127 patients (94%) and only eight patients (6%) would prefer a different anaesthesia technique in the future. CONCLUSIONS: The study demonstrated that the sciatic nerve can be easily blocked using this new posterior subgluteal approach, suggesting that it represents a safe and effective alternative to block the sciatic nerve at a proximal level, with the potential for reducing the discomfort experienced by the patient during block placement. 相似文献
136.
137.
A randomised controlled trial of intravenous immunoglobulin in IgM paraprotein associated demyelinating neuropathy 总被引:3,自引:0,他引:3
Comi G Roveri L Swan A Willison H Bojar M Illa I Karageorgiou C Nobile-Orazio E van den Bergh P Swan T Hughes R Aubry J Baumann N Hadden R Lunn M Knapp M Léger JM Bouche P Mazanec R Meucci N van der Meché F Toyka K;Inflammatory Neuropathy Cause Treatment Group 《Journal of neurology》2002,249(10):1370-1377
This multicentre randomised double blind crossover trial tested the short term efficacy of intravenous immunoglobulin (IVIg)
2.0 g/kg given over 24 or 48 hours in patients with paraproteinaemic demyelinating neuropathy (PDN). Twenty-two patients were
randomised and completed the trial. After 2 weeks, the overall disability grade decreased during both IVIg treatment and placebo
but neither change was significant nor was the mean difference between the treatment effects. After 4 weeks the overall disability
decreased by a mean of 0.55 [0.67] grades during the IVIg period (p = 0.001) while it was substantially unmodified during
the placebo period. The mean difference between the treatment effects was significant (p = 0.05). Overall during the IVIg
period 10 patients improved and 11 were stable and one got worse. During the placebo period 4 patients improved, 4 deteriorated
and 14 were stable. Many secondary outcome measures, including Rankin scale, time to walk 10 metres, grip strength, sensory
symptoms score were significantly better during IVIg treatment. Two serious adverse events occurred during the trial, both
during placebo treatment. In conclusion the trial showed some short-term benefit of IVIg in about half of the patients confirming
previous observation.
Received: 6 August 2001, Received in revised form: 6 March 2002, Accepted: 12 March 2002
RID="*"
ID="*"The other members of the INCAT group are Jacques Aubry PhD, Institut de Biologie, INSERM Unit 463, 9 Quai Moncousu,
44 035 Nantes, France; Nicole Baumann MD, InSERM Unit 495, Salpetriere Hospital, 75 651 Paris, Cedex 13 France; Robert Hadden
PhD, Michael Lunn, MD, Department of Neuroimmunology, Guy's, King's and St. Thomas' School of Medicine, Guy's Hospital, London
SE1 9 UL, UK; Martin Knapp Phd, Personal Social Services Research Unit, London School of Economics and Political Science,
Houghton Street, London WC2A 1AE, UK; Jean-Marc Léger MD, Pierre Bouche MD, Service d'Eplorations Functionelles de la Salpetriere,
47 Boulevard de l'Hospital, 75 651 Paris, Cedex 13, France; Radim Mazanec CSc, Charles University, 2nd Medical School, University Hospital, V uvalu 84, Prague 5, Czech Republic; Nicoletta Meucci MD, Institute of Clinical Neurology,
University of Milan, Ospedale Maggior-Policlinico, via Sforza, 20 122 Milan, Italy; Frans van der Meché PhD, Department of
Neurology, Erasmus Medical Center Rotterdam, dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands; and Klaus Toyka PhD,
Universitat Würzburg, Josef-Schneider Strasse 2, 97 080 Würzburg, Germany
Correspondence to Giancarlo Comi, MD 相似文献
138.
Missense and splice site mutations in SPG4 suggest loss-of-function in dominant spastic paraplegia 总被引:3,自引:0,他引:3
Patrono C Casali C Tessa A Cricchi F Fortini D Carrozzo R Siciliano G Bertini E Santorelli FM 《Journal of neurology》2002,249(2):200-205
We studied nine Italian families with a pure form of autosomal dominant spastic paraplegia (ADHSP) to assess the frequency
of mutations in the SPG4 gene. We observed marked intrafamilial variability in both age-at-onset and clinical severity, ranging
from severe congenital presentation to mild involvement after age 55 years to healthy carriers of the mutation after age 70.
Four of nine probands harboured SPG4 mutations, We identified three new SPG4 mutations, all predicting a loss-of-function
with apparently important consequences for spastin function. RT-PCR studies predict loss-of-function as a possible mechanism
leading to spastin-related HSP. The current study expands the spectrum of allelic variants in SPG4, confirming their pathological
significance in pure AD-HSP and suggesting implications for the presumed function of spastin.
Received: 15 December 2000, Received in revised form: 29 May 2001, Accepted: 18 June 2001 相似文献
139.
Bertini G Peng ZC Fabene PF Grassi-Zucconi G Bentivoglio M 《Brain research bulletin》2002,57(5):631-638
It has been repeatedly reported that Fos is spontaneously induced in several brain structures, including the cerebral cortex, during wakefulness. To ascertain whether cortical interneurons are involved in this state-dependent oscillation of gene regulation, we combined Fos immunocytochemistry with immunostaining of either parvalbumin or calbindin, known markers of cortical interneurons. Immunopositive neurons were examined in the sensorimotor and cingulate cortex. In rats perfused in basal conditions, a minor proportion (around 8%) of Fos-immunoreactive neurons in the parietal cortex were also parvalbumin- or calbindin-immunoreactive; these double immunostained cells accounted for 13% of the parvalbumin- and 34% of the calbindin-labeled neurons. Colocalization of Fos with either calcium-binding protein was instead not observed in the cingulate cortex. In rats stimulated by novel environmental cues during the period of wakefulness preceding perfusion, Fos-positive neurons increased markedly relative to unstimulated animals, and involved the majority of the calbindin- or parvalbumin-labeled cell populations (60-75% and over 95%, respectively). In the neuronal populations in which Fos was induced by exposure to the enriched environment, the proportion of calbindin- and parvalbumin-labeled cells was larger than in the unstimulated cases, and the increment was statistically significant in the cingulate cortex. The results demonstrate that Fos induction occurring in the cortex during undisturbed wakefulness in a familiar environment involves a minor proportion of interneurons. Furthermore, the findings indicate that the addition of novel environmental stimuli results in an increase of Fos-expressing neurons whose recruitment, at least in the cingulate cortex, involves a higher proportion of interneurons than of projection neurons. 相似文献
140.
Viegi A Cotrufo T Berardi N Mascia L Maffei L 《The European journal of neuroscience》2002,16(10):1925-1930
Total lack of visual experience (dark rearing, DR) is known to affect development of mammalian visual cortex (VC) and to prolong the critical period of visual cortical plasticity. Neurotrophins (NTs) have been proposed to play a relevant role in activity dependent processes important for the final shaping of cortical visual connections. Neurotrophin supply or antagonism of endogenous NT action profoundly affect visual cortical development and plasticity; in particular, exogenous supply of NTs counteracts DR effects on VC development. However, the effects of DR on NT expression are still debated and mounting evidence reports a mismatch between BDNF mRNA and protein expression in DR animals. To gain insight into the effects of DR on expression of nerve growth factor (NGF) and the functional state of NT signalling pathways, we assessed the phosphorylation state of Trk receptors in light-reared animals (LR), in dark-reared animals (DR), in DR animals briefly exposed to light and in DR animals with exogenous supply of NTs [NGF, brain-derived neurotrophic factor (BDNF) and NT-4] in the VC. We report that DR increases the expression of NGF but reduces the phosphorylation of TrkA and TrkB receptors with respect to LR; normal phosphorylation is rapidly rescued by a brief exposure to light. Exogenous supply of NGF, BDNF or NT4 in DR animals also rescues the phosphorylation of their receptors. 相似文献