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41.
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
42.
43.
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
44.
Gyrgy Stuber Gerhard H. Leder Walter J. Storkus Michael T. Lotze Susanne Modrow Lszl Szkely Hans Wolf Eva Klein Klas Krre George Klein 《European journal of immunology》1994,24(3):765-768
Mutations of the p53 gene are the most frequently observed genetic changes in human cancers; often leading to an overexpression of the wild-type (wt) p53 protein. Demonstrable T cell reactivity against tumor cells overexpressing wt or mutant p53-derived peptides could support the application of such epitopes in cancer immunotherapies. As the binding of peptide to MHC class I molecules is a prerequisite for antigen-specific T cell recognition, we evaluated the ability of wt and mutant p53 peptides to bind to HLA-A2.1 using two independent flow cytometry-based assay systems, the T2 major histocompatibility complex (MHC) class I peptide stabilization assay (stabilization assay) and the peptide-induced MHC class I reconstitution assay (reconstitution assay). The twenty selected wt sequences each conformed to the previously reported HLA-A2.1 peptide binding motif. Seven of the wt p53 and 2/13 mutant p53 peptides derived from the previously chosen wt peptides bound to HLA-A2.1 in both the stabilization and the reconstitution assays. An additional six wt and six mutant p53 peptides, presumably exhibiting lower affinity for HLA-A2.1, were identified only in the reconstitution assay. Those p53 peptides binding HLA-A2.1 may provide useful immunogens for the generation of HLA-A2.1-restricted cytolytic T lymphocytes in vitro and in vivo. 相似文献
45.
David W Dempster Hua Zhou Sudhaker D Rao Chris Recknor Paul D Miller Benjamin Z Leder Miriam Annett Michael S Ominsky Bruce H Mitlak 《Journal of bone and mineral research》2021,36(4):644-653
Anabolic osteoporosis drugs improve bone mineral density by increasing bone formation. The objective of this study was to evaluate the early effects of abaloparatide on indices of bone formation and to assess the effect of abaloparatide on modeling-based formation (MBF), remodeling-based formation (RBF), and overflow MBF (oMBF) in transiliac bone biopsies. In this open-label, single-arm study, 23 postmenopausal women with osteoporosis were treated with 80 μg abaloparatide daily. Subjects received double fluorochrome labels before treatment and before biopsy collection at 3 months. Change in dynamic histomorphometry indices in four bone envelopes were assessed. Median mineralizing surface per unit of bone surface (MS/BS) increased to 24.7%, 48.7%, 21.4%, and 16.3% of total surface after 3 months of abaloparatide treatment, representing 5.5-, 5.2-, 2.8-, and 12.9-fold changes, on cancellous, endocortical, intracortical, and periosteal surfaces (p < .001 versus baseline for all). Mineral apposition rate (MAR) was significantly increased only on intracortical surfaces. Bone formation rate (BFR/BS) was significantly increased on all four bone envelopes. Significant increases versus baseline were observed in MBF on cancellous, endocortical, and periosteal surfaces, for oMBF on cancellous and endocortical surfaces, and for RBF on cancellous, endocortical, and intracortical surfaces. Overall, modeling-based formation (MBF + oMBF) accounted for 37% and 23% of the increase in bone-forming surface on the endocortical and cancellous surfaces, respectively. Changes from baseline in serum biomarkers of bone turnover at either month 1 or month 3 were generally good surrogates for changes in histomorphometric endpoints. In conclusion, treatment with abaloparatide for 3 months stimulated bone formation on cancellous, endocortical, intracortical, and periosteal envelopes in transiliac bone biopsies obtained from postmenopausal women with osteoporosis. These increases reflected stimulation of both remodeling- and modeling-based bone formation, further elucidating the mechanisms by which abaloparatide improves bone mass and lowers fracture risk. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). 相似文献
46.
Three to four million women suffer from urinary incontinence (UI) in Germany. This number will rise further as life expectancy increases, and there is an annual incidence of newly occurring UI of about 1%. Two thirds of all women with UI suffer additional symptoms of fecal incontinence. The type of incontinence present is diagnosed on the basis of the patient's history, clinical findings, and functional testing. The findings should be interpreted in an age-adjusted manner to avoid overrating (e.g. urethral closure pressure at rest=100?age in cm H2O). The management of elderly patients focuses on conservative approaches with bladder and intestinal training as well as dietary measures serving to counteract the age-related loss of intellectual abilities. Local estrogen application has a positive effect on all forms of incontinence. Surgical approaches aim at improving symptoms since forced restoration of continence in elderly patients frequently induces voiding disorders. 相似文献
47.
Ampullary but not periampullary duodenal diverticula are an etiologic factor for chronic pancreatitis 总被引:2,自引:0,他引:2
BACKGROUND: Duodenal diverticula are common incidental findings. Although a definite treatment is rarely required, an association with biliary and pancreatic diseases is often suggested. Our aim was to determine the frequency of complications in relation to the location of the diverticulum. METHODS: We reviewed 64 patients with extraluminal duodenal diverticula. In 24 of these patients the diverticulum was treated surgically. The incidence of symptoms and complications is analyzed and follow-up in 88% of operated patients is presented. RESULTS: Thirty-one patients presented with ampullary, 36 patients with periampullary diverticula. Three patients had both types of diverticula. The indication for surgery in 24 patients was chronic pancreatitis (n = 12), chronic pain (n = 6), diverticular perforation (n = 3), bleeding (n = 2), or jaundice (n = 1). In 7 out of 31 patients with ampullary and none out of 36 patients with periampullary diverticula, chronic pancreatitis was considered to be induced by the diverticulum. Morbidity in 24 operated patients was 17%, no patient died. At follow-up all patients were free of symptoms. CONCLUSION: Extraluminal duodenal diverticula are frequently found. They rarely cause symptoms and need no surgical treatment. While ampullary duodenal diverticula can cause chronic pancreatitis, periampullary duodenal diverticula are no etiologic factor. 相似文献
48.
49.
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
50.
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