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41.
Functional consequences of ROMK mutants linked to antenatal Bartter's syndrome and implications for treatment 总被引:4,自引:0,他引:4
The antenatal variant of Bartter's syndrome is an autosomal recessive
kidney disease characterized by polyhydramnios, premature delivery,
hypokalemic alkalosis and hypercalciuria. It is genetically heterogeneous,
having been linked recently to mutations in an ATP- sensitive, renal outer
medullary K+channel, ROMK, and earlier to mutations in the Na-K-2Cl
co-transporter, NKCC2. We characterized four of the mutations reported in
three heterozygous ROMK variants of antenatal Bartter's and found that each
expressed a distinct phenotype in Sf9 cells. One mutation expressed normal
function and appears to be an allelic polymorphism. The other three
mutations produced channels with significantly reduced K+fluxes. However,
the mechanisms in each case were different and reflected abnormalities in
phosphorylation, proteolytic processing or protein trafficking. The
different mechanisms may be important in the design of appropriate therapy
for patients with this disease.
相似文献
42.
A model of corrective gene transfer in X-linked ichthyosis 总被引:5,自引:0,他引:5
Freiberg RA; Choate KA; Deng H; Alperin ES; Shapiro LJ; Khavari PA 《Human molecular genetics》1997,6(6):927-933
Single gene recessive genetic skin disorders offer attractive prototypes
for the development of therapeutic cutaneous gene delivery. We have
utilized X-linked ichthyosis (XLI), characterized by loss of function of
the steroid sulfatase arylsulfatase C (STS), to develop a model of
corrective gene delivery to human skin in vivo. A new retroviral expression
vector was produced and utilized to effect STS gene transfer to primary
keratinocytes from XLI patients. Transduction was associated with
restoration of full-length STS protein expression as well as steroid
sulfatase enzymatic activity in proportion to the number of proviral
integrations in XLI cells. Transduced and uncorrected XLI keratinocytes,
along with normal controls, were then grafted onto immunodeficient mice to
regenerate full thickness human epidermis. Unmodified XLI keratinocytes
regenerated a hyperkeratotic epidermis lacking STS expression with
defective skin barrier function, effectively recapitulating the human
disease in vivo. Transduced XLI keratinocytes from the same patients,
however, regenerated epidermis histologically indistinguishable from that
formed by keratinocytes from patients with normal skin. Transduced XLI
epidermis demonstrated STS expression in vivo by immunostaining as well as
a normalization of histologic appearance at 5 weeks post-grafting. In
addition, transduced XLI epidermis demonstrated a return of barrier
function parameters to normal. These findings demonstrate corrective gene
delivery in human XLI patient skin tissue at both molecular and functional
levels and provide a model of human cutaneous gene therapy.
相似文献
43.
44.
Mutational analysis of the SOX9 gene in campomelic dysplasia and autosomal sex reversal: lack of genotype/phenotype correlations 总被引:9,自引:1,他引:9
Meyer J; Sudbeck P; Held M; Wagner T; Schmitz ML; Bricarelli FD; Eggermont E; Friedrich U; Haas OA; Kobelt A; Leroy JG; Van Maldergem L; Michel E; Mitulla B; Pfeiffer RA; Schinzel A; Schmidt H; Scherer G 《Human molecular genetics》1997,6(1):91-98
It has previously been shown that, in the heterozygous state, mutations in
the SOX9 gene cause campomelic dysplasia (CD) and the often associated
autosomal XY sex reversal. In 12 CD patients, 10 novel mutations and one
recurrent mutation were characterized in one SOX9 allele each, and in one
case, no mutation was found. Four missense mutations are all located within
the high mobility group (HMG) domain. They either reduce or abolish the
DNA-binding ability of the mutant SOX9 proteins. Among the five nonsense
and three frameshift mutations identified, two leave the C-terminal
transactivation (TA) domain encompassing residues 402-509 of SOX9 partly or
almost completely intact. When tested in cell transfection experiments, the
recurrent nonsense mutation Y440X, found in two patients who survived for
four and more than 9 years, respectively, exhibits some residual
transactivation ability. In contrast, a frameshift mutation extending the
protein by 70 residues at codon 507, found in a patient who died shortly
after birth, showed no transactivation. This is apparently due to
instability of the mutant SOX9 protein as demonstrated by Western blotting.
Amino acid substitutions and nonsense mutations are found in patients with
and without XY sex reversal, indicating that sex reversal in CD is subject
to variable penetrance. Finally, none of 18 female patients with XY gonadal
dysgenesis (Swyer syndrome) showed an altered SOX9 banding pattern in SSCP
assays, providing evidence that SOX9 mutations do not usually result in XY
sex reversal without skeletal malformations.
相似文献
45.
Tartaro A. Onofrj M. Delli Pizzi C. Bonomo L. Thomas A. Fulgente T. Gambi D. 《The Italian Journal of Neurological Sciences》1996,17(1):35-42
Magnetic resonance images of optic nerves were obtained in 20 patients with acute optic neuritis (ON), and assessed by means of clinical, visual field and visual evoked potential evaluations; the imaging was repeated 1 year later. The results of the conventional Short Tau Inversion Recovery (STIR) sequence obtained using short time echo (STE-STIR: 22 msec) were compared with those of the long time echo sequence (LTE-STIR: 80 msec). The conventional STE-STIR sequence revealed lesions in 57.2% cases of acute ON and in 42.9% of the optic nerves affected by previous ON: the LTE-STIR sequence was diagnostic in 95.2% of acute ON cases and in 85% of patients with previous ON. The calculated length of the optic nerve lesions was significantly longer in the images obtained using the LTE-STIR sequence than in those obtained using conventional STE-STIR sequences.
Sommario Si descrivono i risultati ottenuti con indagini di Risonanza Magnetica (RM) dei nervi ottici (eseguite all'esordio e 12 mesi dopo) in 20 pazienti affetti da Neurite Ottica (NO) acuta, valutata in funzione della sintomatologia clinica e delle alterazioni campimetriche e del potenziale evocato visivo.Sono state analizzate le immagini RM in Short Tau Inversion Recovery (STIR) mettendo a confronto i rilievi ottenuti con sequenza Short Time Echo (STE-STIR: 22 msec) rispetto a quelli ottenuti con Long Time Echo (LTE-STIR: 20 msec). Mentre con la convenzionale STE-STIR è stato possibile rilevare lesioni a carico dei nervi ottici nel 57.2% delle Neuriti Acute e nel 42.9% delle Neuriti Pregresse, la metodica LTE-STIR è risultata diagnostica nel 95.2% delle Neuriti Acute e nel 85% delle Neuriti Pregresse.Sia nelle NO acute che nelle pregresse, la lunghezza delle lesioni a carico dei nervi ottici sono risultate significativamente maggiori rispetto a quelle ottenute con la convenzionale metodica STE-STIR.相似文献
46.
P. Rossi M. Bezzi F. M. Salvatori L. Broglia F. Maccioni G. Pizzi S. Abbondanza G. Bonomo 《European radiology》1996,6(5):741-747
The aim of our study was to evaluate the performance and efficacy of a new self-expanding stent (nitinol Strecker stent) in the transjugular intrahepatic portosystemic shunt (TIPS) procedure. We have successfully placed 64 nitinol Strecker stents in 48 patients. The average portosystemic gradient decreased from 22 to 11 mm Hg. Balloon dilatation was necessary in 12 of 35 angiographically controlled cases at 5 days (34%), because of incomplete stent expansion, small thrombi within the stent or obstruction. At 1–6 months stent malfunctions occurred in 8 of 23 patients who underwent control angiography (34%) and at 6–24 months in 6 of 7 patients (85%). Rebleeding occurred in 2 of 39 patients (follow-up > 1 month) (5%) and temporary crises of de novo encephalopathy were observed in 11 of 48 patients (23%). Refractory ascites completely resolved in 4 of 6 patients (66%) and improved in the remaining 2 cases. Compared with other self-expanding stents, nitinol Strecker stents seem to be equally effective in TIPS; no increase in complication rate was observed, either clinical or stent-related.
Correspondence to: P. Rossi 相似文献
47.
Molsidomine antagonizes L-NAME-induced acquisition deficits in a recognition memory task in the rat.
Nikolaos Pitsikas Antonello E Rigamonti Sara M Bonomo Silvano G Cella Eugenio E Muller 《Pharmacological research》2003,47(4):311-315
The present study was designed to investigate the role of nitric oxide (NO) on the acquisition of a recognition memory task in the rat. For this purpose, the effects on memory exerted by pre-training administration of the NO synthase inhibitor L-NAME (N(omega)-nitro-L-arginine methyl ester) and the NO donor molsidomine (N-[ethoxycarbonyl]-3-[4-morpholinosydnomine]) were assessed by using the object recognition task, a working memory paradigm based on the differential exploration of a new and familiar object. In a first dose-response study, it was found that L-NAME (10, 30, and 60 mg kg(-1), i.p.) at 30 but not at 10 mg kg(-1) disrupted animals performance, whereas the dose of 60 mg kg(-1) induced side effects. Molsidomine (2 and 4 mg kg(-1), i.p.) at 4 but not at 2 mg kg(-1), antagonized the L-NAME-induced performance deficits. These results indicate that NO is involved in the acquisition of a recognition memory task. 相似文献
48.
Objective: To identify factors that influence a woman's decision to breast-feed.
Methodology: Five hundred and fifty-six women were recruited from the maternity wards of two Perth hospitals. Data were collected from a self-administered questionnaire completed by participants prior to discharge. Logistic regression analysis was used to determine factors influencing the initiation of breast-feeding.
Results: At discharge from hospital 83.8% of women were breast-feeding, including 6% who were giving complementary formula feeds. After controlling for potentially confounding demographic and biomedical factors, the father's reported preference for breast-feeding was found to be the most important factor influencing a woman's decision to breast-feed (OR 10.18).
Conclusion: Fathers participate in and influence the choice of infant feeding method and should be included in breast-feeding discussions. 相似文献
Methodology: Five hundred and fifty-six women were recruited from the maternity wards of two Perth hospitals. Data were collected from a self-administered questionnaire completed by participants prior to discharge. Logistic regression analysis was used to determine factors influencing the initiation of breast-feeding.
Results: At discharge from hospital 83.8% of women were breast-feeding, including 6% who were giving complementary formula feeds. After controlling for potentially confounding demographic and biomedical factors, the father's reported preference for breast-feeding was found to be the most important factor influencing a woman's decision to breast-feed (OR 10.18).
Conclusion: Fathers participate in and influence the choice of infant feeding method and should be included in breast-feeding discussions. 相似文献
49.
OBJECTIVE: Most neonatologists include an apnea-free period in the criteria for the discharge of preterm infants. However, the length of time one should wait after the cessation of apnea before sending an infant home without a monitor is debated. We undertook this study in an attempt to define a minimal and safe observation period between the time of the last apnea episode and discharge. METHODS: We reasoned that in infants with idiopathic apnea of prematurity, the intervals between days on which apnea occurs gradually increase until some point at which clinically significant apnea ceases. Therefore, knowledge about the intervals between days on which apnea occurred just before the last apnea would provide a reasonable estimate of the minimal safe observation interval between the last apnea and discharge. We reviewed the charts of 266 infants born in 1993 and 1994 at =32 weeks' gestational age or weighing =1500 g at birth from two institutions to determine the intervals between the day on which the last apnea occurred and the previous two days on which apnea occurred. One hundred seventy-five infants were excluded because they never experienced apnea, or data about the last apnea was missing, or they were on xanthines during the period encompassing the last 3 apnea days, or they weighed <1500 g or were <34 weeks' postmenstrual age at the time of the last apnea. Of the 91 remaining infants, gestational age at birth, birth weight, 1- and 5-minute Apgar scores, and discharge weight were not different between the two institutions. For each infant we determined the longest of the intervals between the 2 days on which apnea occurred previous to the day of the last apnea (MAXINT for maximum interval). The infants were then ordered by MAXINT and, starting at the longest MAXINT, the medical records of each infant were carefully examined for other conditions known to be associated with apnea (eg, recovering from anesthesia, sepsis, chronic lung disease, and so forth). The minimal safe observation period was then defined as the longest MAXINT in which there was at least 1 infant with no other explanation for the apnea other than prematurity. RESULTS: The median duration of the intervals between the 2 days on which apnea occurred previous to the day on which the last apnea occurred were 3. 0 and 2.0 days and the median duration of the MAXINT was 4.0 days. On careful examination of the charts, it was determined that each of 13 infants with a MAXINT preceding the day on which the last apnea occurred of greater than 8 days had some other condition that might result in apnea, including residual lung disease, sepsis, surgery, and so forth. In contrast, among the group of infants with a MAXINT of =8 days, at least 1 infant at each MAXINT (eg, 1 to 8) had significant apnea with no other explanation other than prematurity. CONCLUSIONS: We conclude that otherwise healthy preterm infants continue to have apneas separated by as many as 8 days before the last apnea before discharge. Conversely, infants with longer apnea intervals often have identifiable risk factors other than apnea of prematurity. 相似文献
50.