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71.
Frataxin is reduced in Friedreich ataxia patients and is associated with mitochondrial membranes 总被引:17,自引:8,他引:17
Campuzano V; Montermini L; Lutz Y; Cova L; Hindelang C; Jiralerspong S; Trottier Y; Kish SJ; Faucheux B; Trouillas P; Authier FJ; Durr A; Mandel JL; Vescovi A; Pandolfo M; Koenig M 《Human molecular genetics》1997,6(11):1771-1780
Friedreich ataxia is a progressive neurodegenerative disorder caused by
loss of function mutations in the frataxin gene. In order to unravel
frataxin function we developed monoclonal antibodies raised against
different regions of the protein. These antibodies detect a processed 18
kDa protein in various human and mouse tissues and cell lines that is
severely reduced in Friedreich ataxia patients. By immunocytofluorescence
and immunocytoelectron microscopy we show that frataxin is located in
mitochondria, associated with the mitochondrial membranes and crests.
Analysis of cellular localization of various truncated forms of frataxin
expressed in cultured cells and evidence of removal of an N-terminal
epitope during protein maturation demonstrated that the mitochondrial
targetting sequence is encoded by the first 20 amino acids. Given the
shared clinical features between Friedreich ataxia, vitamin E deficiency
and some mitochondriopathies, our data suggest that a reduction in frataxin
results in oxidative damage.
相似文献
72.
Recessively inherited L-DOPA-responsive parkinsonism in infancy caused by a point mutation (L205P) in the tyrosine hydroxylase gene 总被引:4,自引:0,他引:4
73.
Cellular effects of deep brain stimulation: model-based analysis of activation and inhibition 总被引:14,自引:0,他引:14
Deep brain stimulation (DBS) is an effective therapy for medically refractory movement disorders. However, fundamental questions remain about the effects of DBS on neurons surrounding the electrode. Experimental studies have produced apparently contradictory results showing suppression of activity in the stimulated nucleus, but increased inputs to projection nuclei. We hypothesized that cell body firing does not accurately reflect the efferent output of neurons stimulated with high-frequency extracellular pulses, and that this decoupling of somatic and axonal activity explains the paradoxical experimental results. We studied stimulation using the combination of a finite-element model of the clinical DBS electrode and a multicompartment cable model of a thalamocortical (TC) relay neuron. Both the electric potentials generated by the electrode and a distribution of excitatory and inhibitory trans-synaptic inputs induced by stimulation of presynaptic terminals were applied to the TC relay neuron. The response of the neuron to DBS was primarily dependent on the position and orientation of the axon with respect to the electrode and the stimulation parameters. Stimulation subthreshold for direct activation of TC relay neurons caused suppression of intrinsic firing (tonic or burst) activity during the stimulus train mediated by activation of presynaptic terminals. Suprathreshold stimulation caused suppression of intrinsic firing in the soma, but generated efferent output at the stimulus frequency in the axon. This independence of firing in the cell body and axon resolves the apparently contradictory experimental results on the effects of DBS. In turn, the results of this study support the hypothesis of stimulation-induced modulation of pathological network activity as a therapeutic mechanism of DBS. 相似文献
74.
75.
Cameron OG 《Psychosomatic medicine》2001,63(5):697-710
OBJECTIVE: To comprehend psychosomatic processes, it will be necessary to understand the brain's influences on bodily functions and also the body's afferent sensory input to the central nervous system, including the effects of this input on behavior and cognitive functions, especially emotion. The objective of this Presidential Address is to review what is known circa the year 2000 of the processes and mechanisms of visceral sensory psychobiology, often called interoception. METHODS: Over 1000 publications that have appeared since the 19th century were reviewed to prepare this review, including a group that are specifically cited here. RESULTS: Factors and data were reviewed that were identified as germane to understanding interoception. These included definitional issues, historical roots, the neural basis, studies and results in the cardiovascular-respiratory and alimentary-gastrointestinal systems, studies of emotion, and studies in people with mental disorders. Drug and hormone effects, pain, proprioception, and phantom limb or organ factors, and the role of awareness were briefly described. Methodological issues, methods of study including functional imaging, and possible future directions for study were identified. CONCLUSIONS: Understanding the physical basis of psychosomatic processes, including the so-called mind-body problem, will require a detailed understanding the psychobiology of interoception. 相似文献
76.
The platelet-derived growth factor (PDGF) antagonist, trapidil, which also blocks the thromboxane and/or PG-endoperoxide receptor and is an inhibitor of thromboxane synthetase, was administered during rabbit accelerated nephrotoxic nephritis; the clinical and histological evolution was studied as well as urinary immunoreactive thromboxane (i-TXB2) and immunoreactive prostaglandin E2 (i-PGE2) excretion. Although the dose we used has been shown to be effective in vivo, and it inhibited the urinary i-TXB2 excretion on days 5 and 10, it neither inhibited the enhanced production of i-TXB2 on day 1, nor prevented the glomerular influx of monocytes on days 5 and 10. All clinical and histological data tend to be worse rather than better in trapidil-treated animals on days 5 and 10. 相似文献
77.
78.
Y chromosome deletions in azoospermic and severely oligozoospermic men undergoing intracytoplasmic sperm injection after testicular sperm extraction 总被引:11,自引:16,他引:11
Silber SJ; Alagappan R; Brown LG; Page DC 《Human reproduction (Oxford, England)》1998,13(12):3332-3337
Y chromosome deletions encompassing the AZFc region have been reported in
13% of azoospermic men and 7% of severely oligozoospermic men. We examined
the impact of these Y deletions on the severity of testicular defects in 51
azoospermic men undergoing intracytoplasmic sperm injection (ICSI) after
testicular sperm extraction (TESE) and 30 men with severe oligozoospermia
undergoing ICSI after ejaculation of spermatozoa. In addition, five
azoospermic patients shown previously to have Y chromosome deletions
underwent histological evaluation of their previously obtained testis
biopsy specimens. A further 27 azoospermic men underwent TESE-ICSI, but not
Y chromosome DNA testing. Ten of 51 azoospermic men (20%) who underwent
TESE-ICSI and Y-DNA testing were found to be deleted for portions of the Y
chromosome AZFc region. Of these 10, five had spermatozoa retrievable from
the testis, and in two cases the wives became pregnant. Of the 41
azoospermic men with no Y chromosome deletion, 22 (54%) had spermatozoa
retrievable from the testis, and in 12 cases (29%) the wives became
pregnant. Four of 30 (13%) severely oligozoospermic patients were found to
be deleted for AZFc and in three (75%) of these pregnancy was achieved. The
other 26 severely oligozoospermic couples who had no AZFc deletions
underwent ICSI, and 12 (46%) have an ongoing or delivered pregnancy. The
embryo implantation rate was not significantly different for azoospermic
(22%), oligozoospermic (16%), Y-deleted (14%) or Y-intact (18%) men. Of the
total of 19 infertile men who had Y chromosome deletions, 14 had deletions
within Y chromosome intervals 6D-6F, in the AZFc region. Twelve of those 14
had some spermatozoa (however few in number) in the ejaculate or testis.
Five of the Y-deleted men had deletions that extended more proximally on
the Y chromosome, and in none of these could any spermatozoa be observed in
either ejaculate or testis. These results support the concept that, in
azoospermic or oligozoospermic men with Y chromosome deletions limited to
intervals 6D-6F (AZFc), there are generally very small numbers of
testicular or ejaculated spermatozoa. Larger Y deletions, including and
extending beyond the AZFc region and encompassing more Y genes, tend to be
associated with a total absence of testicular spermatozoa. In those cases
where spermatozoa were retrieved, the presence of Y deletions had no
obvious impact on fertilization or pregnancy rate.
相似文献
79.
M Tascilar G J Offerhaus R Altink P Argani T A Sohn C J Yeo J L Cameron M Goggins R H Hruban R E Wilentz 《American journal of clinical pathology》2001,116(6):831-837
We immunohistochemically labeled 72 biopsy specimens from the extrahepatic biliary tree and pancreas for Dpc4 protein and correlated expression with histologic diagnosis and patient follow-up. Specimens were classified histologically as follows: nonneoplastic, 35; neoplastic, 22; atypical, 15. Loss of expression of Dpc4 protein was identified in 12 specimens; 11 were histologically diagnostic of carcinoma. The 12th specimen was from a patient whose biopsy specimen initially was diagnosed as "atypical," but clinical follow-up revealed adenocarcinoma. Of the 12 atypical biopsy specimens with intact expression for Dpc4, follow-up later revealed that 10 were adenocarcinoma. Loss of expression of Dpc4 protein was never identified in a benign specimen. Immunohistochemical labeling for the Dpc4 gene product is a specific marker of carcinoma in biopsy specimens of the pancreas and extrahepatic bile ducts and is marginally helpful in classifying atypical specimens. The sensitivity for carcinoma is low. This latter finding is not unexpected, because the DPC4 tumor suppressor gene is inactivated in only about half of pancreatic and biliary malignant neoplasms. Importantly, loss of Dpc4 expression has been reported in in situ carcinomas, suggesting that loss of expression should not be equated with invasive carcinoma. 相似文献
80.
Mercan R; Mayer JF; Walker D; Jones S; Oehninger S; Toner JP; Muasher SJ 《Human reproduction (Oxford, England)》1997,12(9):1886-1889
The aim of this study was to compare the efficacy of pure follicle
stimulating hormone (FSH) with that of FSH/human menopausal gonadotrophin
(HMG) combination in downregulated cycles. A total of 357 patients was
evaluated retrospectively. Sixty percent of patients in the FSH group and
55% in the FSH/HMG group were new; the others were repeat patients.
Ovulation was suppressed with leuprolide acetate in all patients, followed
by either FSH (n = 218) or FSH/HMG (n = 119). There was no difference in
patients' age, infertility factors, number of ampoules used, length of
stimulation, oestradiol levels on day of human chorionic gonadotrophin
(HCG) administration, number of oocytes recovered or the number of embryos
transferred. Also, nuclear maturity at aspiration and fertilization rates
were not different between the two groups. FSH stimulation resulted in a
significantly higher percentage of mature oocytes that showed the typical
'mature' morphological characteristics (P < 0.0001). The clinical
pregnancy rates per transfer were 40 and 28% in patients stimulated with
pure FSH and FSH/HMG respectively (P < 0.05). The significantly higher
number of immature oocytes matured in vitro in the FSH/HMG group (P =
0.001) suggests a possible effect on in-vitro maturation, due to
luteinizing hormone present in HMG. The difference in mature oocyte quality
may be an important determinant in the higher pregnancy rates for the FSH-
stimulated patients.
相似文献