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61.
Collins FS; Boehm CD; Waber PG; Stoeckert CJ Jr; Weissman SM; Forget BG; Kazazian HH Jr 《Blood》1984,64(6):1292-1296
Hereditary persistence of fetal hemoglobin (HPFH) is a genetically heterogeneous and clinically benign condition characterized by persistent expression of fetal hemoglobin (Hb F) into adulthood. In the G gamma beta + type, no major deletions in the globin gene cluster occur; adult heterozygotes produce approximately 20% Hb F, which results from overproduction of G gamma chains, with no apparent increase in production from the adjacent A gamma gene. We have recently described a point mutation 202 base pairs 5' to the cap site of the G gamma gene in an individual with G gamma beta + HPFH. This mutation abolishes a normal ApaI restriction endonuclease site, and thus can be detected by blotting of genomic DNA. We present here further data on the ApaI mutation: (1) It occurs in six of seven families with G gamma beta + HPFH. (2) In three families, detailed haplotype analysis using 11 polymorphic restriction sites in the beta globin cluster has been done. The two that carry the missing ApaI site are identical but the third, which has a normal ApaI pattern, differs from the other two in at least two sites, one of which is a new polymorphic Nco I site between the delta and beta globin genes. This suggests the possibility of a different HPFH mutation in the third family. (3) The haplotype of the G gamma beta + HPFH chromosome carrying the ApaI mutation is different from that of 108 beta A chromosomes of black individuals that have been tested. (4) The G gamma ApaI site is normal in 61 beta A and 109 beta S alleles from non-HPFH black individuals, including 22 who share the same haplotype for the intragenic G gamma, A gamma HindIII polymorphisms. These data add support to the possibility that the -202 mutation is actually causative of the G gamma beta + HPFH phenotype. 相似文献
62.
Susan Hrisos Martin P Eccles Jill J Francis Marije Bosch Rob Dijkstra Marie Johnston Richard Grol Eileen FS Kaner Ian N Steen 《BMC health services research》2009,9(1):140
Background
Long term management of patients with Type 2 diabetes is well established within Primary Care. However, despite extensive efforts to implement high quality care both service provision and patient health outcomes remain sub-optimal. Several recent studies suggest that psychological theories about individuals' behaviour can provide a valuable framework for understanding generalisable factors underlying health professionals' clinical behaviour. In the context of the team management of chronic disease such as diabetes, however, the application of such models is less well established. The aim of this study was to identify motivational factors underlying health professional teams' clinical management of diabetes using a psychological model of human behaviour. 相似文献63.
AM Alazami SA Schneider D Bonneau L Pasquier M Carecchio M Kojovic K Steindl M De Kerdanet MM Nezarati KP Bhatia B Degos E Goh FS Alkuraya 《Clinical genetics》2010,78(6):585-590
Alazami AM, Schneider SA, Bonneau D, Pasquier L, Carecchio M, Kojovic M, Steindl K, de Kerdanet M, Nezarati MM, Bhatia KP, Degos B, Goh E, Alkuraya FS. C2orf37 mutational spectrum in Woodhouse–Sakati syndrome patients. Woodhouse–Sakati syndrome (WSS) is a rare autosomal recessive disorder that encompasses hypogonadism, deafness, alopecia, mental retardation, diabetes mellitus and progressive extrapyramidal defects. The syndrome is caused by mutation of the C2orf37 gene. Here we studied a cohort of seven new cases from three ethnic backgrounds, presenting with the hallmarks of WSS, in an effort to extend the mutational spectrum of this disorder. Genetic analysis revealed a novel mutation in each of the four families investigated, of which three were nonsense mutations and the fourth was a splice site ablation. We also examined a separate collection of 11 cases presenting with deafness and dystonia, two constituents of WSS, but found no pathogenic changes. This study doubles the number of known mutations for this disorder, confirms that truncating mutations in C2orf37 are the only known cause of WSS, and suggests that mutations in this gene do not contribute significantly to cases presenting with isolated elements of WSS such as deafness and dystonia. The lack of correlation between clinically expressivity of WSS and the site of the eight truncating mutations strongly supports that they are equally null, while the intrafamilial variability argues for an important role of modifiers in this disease. 相似文献
64.
65.
FS Chung S Eyal M Muzi JM Link DA Mankoff A Kaddoumi F O'Sullivan P Hsiao JD Unadkat 《British journal of pharmacology》2010,159(2):394-404
Background and purpose:
Changes in tissue P-glycoprotein (P-gp) activity during pregnancy could affect the pharmacokinetics and thus the efficacy and toxicity of many drugs. Therefore, using positron emission tomography (PET) imaging, we tested whether gestational age affects tissue P-gp activity in the pregnant non-human primate, Macaca nemestrina.Experimental approach:
Mid-gestational (day 75 ± 13, n= 7) and late-gestational (day 150 ± 10, n= 5) age macaques were imaged after administration of a prototypic P-gp substrate, 11C-verapamil (13.7–75.4 MBq·kg−1), before and during intravenous infusion of a P-gp inhibitor, cyclosporin A (CsA) (12 or 24 mg·kg−1·h−1). Accumulation of radioactivity in the fetal liver served as a reporter of placental P-gp activity. P-gp activity was expressed as CsA-induced percent change in the ratio of the area (0–9 min) under the 11C-radioactivity concentration–time curve in the tissue (AUCtissue) to that in the maternal plasma (AUCplasma).Key results:
The CsA-induced change in AUCfetal liver/AUCmaternalplasma of 11C-radioactivity significantly increased from mid- (35 ± 25%) to late gestation (125 ± 66%). Likewise, the CsA-induced change in AUCmaternal brain/AUCplasma increased from mid- (172 ± 80%) to late gestation (337 ± 148%). The AUC ratio for the other maternal tissues was not significantly affected. Neither the CsA blood concentrations nor the level of circulating 11C-verapamil metabolites were significantly affected by gestational age.Conclusions and implications:
P-gp activity at the blood–brain barrier and the placental barrier in the macaque increased with gestational age. If replicated in humans, the exposure of the fetus and maternal brain to P-gp substrate drugs, and therefore their efficacy and toxicity, will change during pregnancy. 相似文献66.
肛管直肠超声可用来诊断多种肛管直肠良、恶性疾病。近几年来.该技术取得了长足进步.其应用360度旋转高频(6.16MHZ)探头(焦距2.8~6.2cm),无需转动探头便可获得高清晰的肛管直肠三维结构图。位于探头远端的换能晶片向近端边旋转边移动,持续55S.可获得长约6cm的图像。这个图像是将连续的0.2mm层厚轴向切面通过容积再现技术合成的高清晰的三维数字立体图像。其拥有多个视角(同时4~6个视野).可同时观察多个解剖平面.进行低亮度、高对比度调整,可形成半透明暗腔。 相似文献
67.
Bioactivation of the mushroom hydrazine, agaritine, to intermediates that bind covalently to proteins and induce mutations in the Ames test 总被引:1,自引:0,他引:1
The present study was undertaken to establish whether liver and kidney
enzyme systems, from rat and mouse, have the potential to metabolise and
bioactivate agaritine, beta-N-(gamma-L(+)glutamyl)-4-
(hydroxymethyl)phenylhydrazine, the most abundant hydrazine present in the
edible mushroom Agaricus bisporus. Agaritine was weakly mutagenic, in the
absence of an activation system, in Salmonella typhimurium strain TA104.
Rat kidney homogenates, characterised by high gamma- glutamyl
transpeptidase activity, enhanced the mutagenic response. In contrast,
hepatic microsomes, having very low gamma-glutamyl transpeptidase activity,
did not influence the mutagenicity of agaritine. However, hepatic
microsomes could further potentiate the mutagenic response induced by the
kidney. Agaritine was a good substrate for purified gamma-glutamyl
transpeptidase, being converted to a major metabolite,
4-(hydroxymethyl)phenylhydrazine, formed as a result of the loss of the
glutamyl moiety. Kidney homogenates from the rat and mouse also catalysed
this reaction, the former being the more effective. Metabolism of agaritine
was suppressed by serine-borate, an inhibitor of gamma-glutamyl
transpeptidase. Kidney homogenates from rat and mouse could metabolise
agaritine to intermediate(s) that bound covalently to proteins, with the
rat preparations being the more effective; covalent binding was inhibited
by glutathione. In contrast, hepatic preparations alone were ineffective in
producing such covalent binding but did further increase the covalent
binding mediated by the kidney preparations. It is concluded that rat and
mouse kidney homogenates catalyse the removal of the glutamyl group from
agaritine to yield the reactive free hydrazine, which is further converted
to the highly reactive diazonium ion by hepatic microsomes.
相似文献
68.
Yen CC; Hsieh RK; Chiou TJ; Liu JH; Fang FS; Wang WS; Tung SL; Tzeng CH; Chen PM 《Japanese journal of clinical oncology》1998,28(2):129-133
The anti-emetic efficacy of a combination of tropisetron and dexamethasone
was studied in 33 patients who underwent bone marrow transplantation.
Another 50 patients receiving conventional anti-emetic therapies in bone
marrow transplantation served as control. On the first and second days of
preconditioning chemotherapy, 51% and 36% respectively of patients in the
tropisetron and dexamethasone group did not experience vomiting, compared
with only 12% and 10% of control group patients (P < 0.001). The mean
number of episodes of vomiting in the tropisetron and dexamethasone group
was also significantly lower than in the control group (0.97+/-1.65 vs
3.50+/-2.45 and 1.30+/-1.40 vs 4.44+/-2.91 respectively, both P <
0.001). Control of vomiting in the two groups was not significantly
different during days 3-6. Analysis of patients receiving busulfan and
cyclophosphamide as the preconditioning regimen still showed better
anti-emetic control in the tropisetron and dexamethasone group than in the
control group on the first two days of treatment (total control rate 33.3%
vs 6.5% and 44.4% vs 12.9% respectively, P < 0.001). Patients given
tropisetron and dexamethasone combination more frequently suffered from
dizziness and burning sensation of the chest. However, diarrhea and
extrapyramidal symptoms were the most frequent adverse effects seen after
using conventional anti-emetic combination. The combination of tropisetron
and dexamethasone was thus superior to conventional anti-emetic
combinations in preventing vomiting during preconditioning period of bone
marrow transplantation. The adverse effects of this combination were
minimal and well tolerated by patients.
相似文献
69.
Chiou TJ; Tung SL; Hsieh RK; Wang WS; Yen CC; Fan FS; Liu JH; Chen PM 《Japanese journal of clinical oncology》1998,28(5):318-322
BACKGROUND: The efficacy of the treatment of advanced gastric cancer is not
very good. The response rate to the original
etoposide--leucovorin--5-fluorouracil (ELF) treatment is 53% with tolerable
side effects. Whether increasing the dose intensity by prolonging the
duration of infusion with 5-fluorouracil (5-FU) and leucovorin (LV) from 3
to 5 days for advanced or metastatic gastric cancer patients would enhance
the efficacy but not increase side effects is still unknown. METHODS:
Thirty-six advanced or metastatic gastric cancer and chemotherapy-naive
patients with measurable or evaluable diseases were scheduled to receive
intravenous etoposide 100 mg/m2/day on days 2-4, LV 300 mg/m2/day
intravenously and 5-FU 500 mg/m2/day intravenously on days 1-5, every 4
weeks. All patients who received at least two courses of chemotherapy were
evaluated for tumor response, survival and response duration and toxicity
according to the WHO criteria. RESULTS: Thirteen patients showed a
response, including five with complete response (CR). The overall response
rate was 36% (95% confidence interval, CI, 20-52%) in the whole group and
46% (95% CI 28-66%) in the 28 patients with measurable disease. The median
progression-free interval and overall median survival time were 5 and 7
months, respectively. The most frequent toxicity was alopecia (grade I/II
56.3%). The incidence of grade III or greater myelosuppression was 5.9%. No
treatment-related death occurred. CONCLUSIONS: The efficacy of the modified
ELF by increasing the dosages of 5-FU and LV is not superior to the results
of the original regimen, yet it is a relatively safe and tolerable
combination regimen for advanced gastric cancer.
相似文献
70.
Human sperm non-nuclear progesterone receptor expression is a novel marker for fertilization outcome 总被引:1,自引:0,他引:1
Jacob A; Hurley I; Mandel FS; Hershlag A; Cooper GW; Benoff S 《Molecular human reproduction》1998,4(6):533-542
In a prospective, blind study, we have examined the relationship among the
expression of human sperm surface progesterone receptors, the ability to
undergo a mannose-stimulated acrosome reaction and the rate of
fertilization in vitro. Individual aliquots of motile spermatozoa were
surface-labelled with progesterone and/or mannose-fluoresceinated ligands.
Spontaneous acrosome loss and the increase in acrosome reactions following
exposure of spermatozoa to mannose ligands were assessed using rhodaminated
Pisum sativum agglutinin. Progesterone fluoresceinated ligand binding was
observed to occur in two patterns: (i) a uniform distribution of labelling
over the acrosome cap (pattern II), and (ii) labelling limited to the
equatorial and postacrosomal regions of the human sperm head (pattern III).
A conversion of pattern II to pattern III binding was observed and was
associated with the acrosome reaction. Pattern III binding was highly
correlated with both fertilization potential and the ability to undergo a
mannose-stimulated acrosome reaction (P < 0.001). In contrast, normal
sperm mannose receptor expression was seen in five men whose abnormal
progesterone receptor expression/function and inability to acrosome react
after mannose treatment were correlated with their reduced fertility in
vitro. In conclusion, surface progesterone receptor aggregation enhances
the mannose ligand-stimulated acrosome reaction. Such detection of
defective sperm surface progesterone receptor expression/function may be
useful in the evaluation and management of male infertility.
相似文献