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61.
Carlos R Ferreira Dillon Kavanagh Ralf Oheim Kristin Zimmerman Julian Stürznickel Xiaofeng Li Paul Stabach R Luke Rettig Logan Calderone Colin MacKichan Aaron Wang Hunter A Hutchinson Tracy Nelson Steven M Tommasini Simon von Kroge Imke AK Fiedler Ethan R Lester Gilbert W Moeckel Björn Busse Thorsten Schinke Thomas O Carpenter Michael A Levine Mark C Horowitz Demetrios T Braddock 《Journal of bone and mineral research》2021,36(5):942-955
Inactivating mutations in human ecto-nucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1) may result in early-onset osteoporosis (EOOP) in haploinsufficiency and autosomal recessive hypophosphatemic rickets (ARHR2) in homozygous deficiency. ARHR2 patients are frequently treated with phosphate supplementation to ameliorate the rachitic phenotype, but elevating plasma phosphorus concentrations in ARHR2 patients may increase the risk of ectopic calcification without increasing bone mass. To assess the risks and efficacy of conventional ARHR2 therapy, we performed comprehensive evaluations of ARHR2 patients at two academic medical centers and compared their skeletal and renal phenotypes with ENPP1-deficient Enpp1asj/asj mice on an acceleration diet containing high phosphate treated with recombinant murine Enpp1-Fc. ARHR2 patients treated with conventional therapy demonstrated improvements in rickets, but all adults and one adolescent analyzed continued to exhibit low bone mineral density (BMD). In addition, conventional therapy was associated with the development of medullary nephrocalcinosis in half of the treated patients. Similar to Enpp1asj/asj mice on normal chow and to patients with mono- and biallelic ENPP1 mutations, 5-week-old Enpp1asj/asj mice on the high-phosphate diet exhibited lower trabecular bone mass, reduced cortical bone mass, and greater bone fragility. Treating the Enpp1asj/asj mice with recombinant Enpp1-Fc protein between weeks 2 and 5 normalized trabecular bone mass, normalized or improved bone biomechanical properties, and prevented the development of nephrocalcinosis and renal failure. The data suggest that conventional ARHR2 therapy does not address low BMD inherent in ENPP1 deficiency, and that ENPP1 enzyme replacement may be effective for correcting low bone mass in ARHR2 patients without increasing the risk of nephrocalcinosis. © 2021 American Society for Bone and Mineral Research (ASBMR). 相似文献
62.
63.
Notfall + Rettungsmedizin - Das akute Koronarsyndrom ist der häufigste Grund für einen Rettungsdiensteinsatz in Deutschland. So resultieren in etwa 20–25 % aller Einsätze... 相似文献
64.
Interaction with 14-3-3 proteins promotes functional expression of the potassium channels TASK-1 and TASK-3 总被引:11,自引:0,他引:11
Sindhu Rajan Regina Preisig-Müller Erhard Wischmeyer† Ralf Nehring† Peter J. Hanley Vijay Renigunta Boris Musset Günter Schlichthörl Christian Derst reas Karschin† Jürgen Daut 《The Journal of physiology》2002,545(1):13-26
The two-pore-domain potassium channels TASK-1, TASK-3 and TASK-5 possess a conserved C-terminal motif of five amino acids. Truncation of the C-terminus of TASK-1 strongly reduced the currents measured after heterologous expression in Xenopus oocytes or HEK293 cells and decreased surface membrane expression of GFP-tagged channel proteins. Two-hybrid analysis showed that the C-terminal domain of TASK-1, TASK-3 and TASK-5, but not TASK-4, interacts with isoforms of the adapter protein 14-3-3. A pentapeptide motif at the extreme C-terminus of TASK-1, RRx(S/T)x, was found to be sufficient for weak but significant interaction with 14-3-3, whereas the last 40 amino acids of TASK-1 were required for strong binding. Deletion of a single amino acid at the C-terminal end of TASK-1 or TASK-3 abolished binding of 14-3-3 and strongly reduced the macroscopic currents observed in Xenopus oocytes. TASK-1 mutants that failed to interact with 14-3-3 isoforms (V411*, S410A, S410D) also produced only very weak macroscopic currents. In contrast, the mutant TASK-1 S409A, which interacts with 14-3-3-like wild-type channels, displayed normal macroscopic currents. Co-injection of 14-3-3ζ cRNA increased TASK-1 current in Xenopus oocytes by about 70 %. After co-transfection in HEK293 cells, TASK-1 and 14-3-3ζ (but not TASK-1ΔC5 and 14-3-3ζ) could be co-immunoprecipitated. Furthermore, TASK-1 and 14-3-3 could be co-immunoprecipitated in synaptic membrane extracts and postsynaptic density membranes. Our findings suggest that interaction of 14-3-3 with TASK-1 or TASK-3 may promote the trafficking of the channels to the surface membrane. 相似文献
65.
Gerd Geerling Norbert Koop Andreas Tüngler Ralf Brinkmann Christopher Wirbelauer Reginald Birngruber Horst Laqua 《Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft》1999,96(5):306-311
Purpose: Pulsed holmium lasers are currently used to correct hyperopia by means of laser thermokeratoplasty (LTK). Series of μs laser
pulses are applied with a high repetition rate to induce shrinkage of corneal collagen fibers. The pulsed energy application
results in intrastromal temperature peaks of up to 200 °C. A continuously emitting laser diode can – as we demonstrated recently
in an invivo study on minipigs – be used for LTK and may be of advantage because the temperature rise is more steady. The
aim of this study was to examine the safety, amount, and stability of hyperopic correction of diode LTK on blind human eyes.
Methods: We used a laserdiode that was set to continuously emit light at λ = 1.854 μm/μa = 1.04 mm–1(group I, n = 4) or 1.87 μm/μa = 1.92 mm–1 (group II, n = 4). Radiation energy was 100 to 150 mW for 10 s per coagulation. Eight coagulations on a single ring (group I) and 16 coagulations
on a double ring (group II) diameter were applied in the cornea concentric to the entrance pupil by means of a vacuum-fixed
application mask (group I = conjunctival fixation; group II = corneal fixation) and a handpiece with a focusing optic. Preoperatively
as well as 1 week, 1, 2, 3, 6 12 and 18 months postoperative ophthalmologic controls were performed and the corneal refractive
power was measured.
Results: In group I initial refractive changes of up to + 4.9 D were achieved (1 week postoperative). However, due to the great penetration
depth of the laser irradiation, large endothelial defects resulted beneath the stromal coagulations. In group II an initial
refractive change of up to + 6.8 D was achieved and as a result of the reduced penetration depth, the endothelial cell damage
was much reduced. Partial regression of the refractive effect occured in all subjects, which continued in higher refractive
changes during the 2nd postoperative year. The refractive effect at 12 months was + 0.6 to + 1.5 D in group I and + 0.9 to + 5.7 D in group II.
At 12 months the induced astigmatism was 0.5 to 2.2 D in group I and 0.3 to 1.6 D in group II. No serious adverse effects
were noticed.
Conclusion: A continously emitting laser diode working at a wavelength of 1.87 μm can be used to correct hyperopia by means of LTK safely
and effectively. Regression occurs predominantly in the first 6 postoperative months. Further studies must be conducted to
determine the importance of patient inherent parameters such as age in establishing a nomogram.
相似文献
66.
Friedrich Gönner Ralf Baumgartner Daniel Schüpbach M. C. G. Merlo 《Psychopharmacology》1999,144(4):416-418
Neuroleptic malignant syndrome (NMS) is a rare but potentially fatal side-effect of antipsychotic drug therapy, especially
of dopamine receptor antagonists. As a dose relationship has been postulated, low dose neuroleptization would be expected
to help to avoid this side-effect. In contrast, we report on a 21-year-old female following low dose fluphenazine treatment
with 2.5 mg/day. The patient recovered from NMS after 3 days of dantrolene administration. Eventually, remission from psychotic
symptoms was achieved with clozapine. At 8-month follow-up, psychopathology remained stable and there were no more signs of
NMS.
Received: 8 July 1998 / Final version: 6 November 1998 相似文献
67.
The cognitive functioning of 27 female patients with congenital adrenal hyperplasia (CAH) (aged 11–41 yrs) and 13 of their healthy sisters (13–31 yrs) was compared using short versions of age-appropriate Wechsler scales. In contrast to other studies, neither a higher than average IQ level for CAH patients (mean: 99.0) nor for their sisters (97.7) was found. Unexpectedly, and in contrast to other reports, the subgroup of salt-wasting (SW) patients>16 yrs (N=6; mean score: 111.5) differed from their sisters as well as from simple-virilizing (SV) patients in full IQ (p<0.05) and subtest scorings for Information, Similarities, and Picture Completion (p<0.05–<0.10). SW patients displayed more masculine behaviour (vs. SV patients and sisters) which, in turn, was related to differential prenatal hormonal influences. No clear-cut relationships between IQ/cognitive (subtest) findings and gender-role behaviour were found.
Zusammenfassung 27 Patientinnen mit dem Adrenogenitalen Syndrom (AGS) (11–41 J.) und 13 ihrer Schwestern (13–31 J.) wurden hinsichtlich intellektueller Funktionen verglichen (Kurzformen von HAWIK, HAWIE). Im Unterschied zu den meisten früheren Untersuchungen wurden weder für Patientinnen (mean: 99.0) noch für Kontrollen (97.7) über dem Durchschnitt liegende IQ-Werte gefunden. Im Gegensatz zur Literatur unterschied sich die Teilgruppe der Salzverlust-Patientinnen (SW)>16 J. (N=6, mean: 111.5) von den Schwestern und den Patientinnen mit einfachem AGS (SV) im Gesamt-IQ (p<0.05) und in den Untertests Allgemeines Wissen, Gemeinsamkeiten und Bilderergänzen (p<0.05–<0.10). SW-Patientinnen hatten signifikant männlichere Verhaltensmuster gezeigt (vs. SV-Patientinnen und Schwestern), die auf differentielle Hormoneffekte pränatal bezogen worden waren. Es fanden sich aber keine klaren Zusammenhänge zwischen IQ-bzw. Untertest-Resultaten und Ergebnissen für Geschlechtsrollenverhalten.
Résumé Le fonctionnement cognitif de 21 patientes avec une hyperplasie congénitale surrénale (âgée de 11 à 41 ans) et de 13 de leurs soeurs saines (13–31 ans) a été comparé au moyen de versions raccourcies de l'échelle de Wechsler appropriée à l'âge. En contraste avec d'autres études, il n'a été retrouvé un Q.I. plus haut que la moyenne ni pour les patientes (moyenne 99.0) ni pour leurs soeurs (moyenne 97.7). De façon inattendue, et en contraste avec d'autres études, le sous-groupe de patientes déprivées en sel (SW)>16 ans (N=6), moyenne score: 111.5) différait de leurs soeurs aussi bien en tant que patientes présentant des signes de virilsation (SV) pour le Q.I. complet (p<0.05) et les scores aux subtests d'information, de similarité et de complément d'images (p<0.05–0.10). Les patientes déprivées en sel (SW) montraient un comportement plus masculin (vs. SV et leurs soeurs) qui en retour était relié aux influences hormonales prénatales différentes. Il n'y avait pas de relation de différences nettes entre les résultats aux sous-tests cognitifs du Q.I. et le comportement de genre.相似文献
68.
Maria Korte Ralf Stahlmann Malgorzata Kubicka-Muranyi Ernst Gleichmann Diether Neubert 《Archives of toxicology》1991,65(8):656-660
We used a modified version of the popliteal lymph node assay in rats to investigate the immunosuppressive potential of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In 10 months we conducted 3 experimental series. Animals were treated with single s.c. injections of TCDD and 7 days later human red blood cells (HRBC) were injected s.c. into the right hind footpad of the rat. Another 7 days later, both popliteal lymph nodes were prepared, weighed, the cell number was counted and the quotients (index) of these variables from the treated and the untreated side were determined. The doses applied in three experimental series were 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt. In the first experimental series only the three highest doses were tested, in a second experimental series doses of 60, 6, 0.6, 0.06 ng TCDD/kg body wt were applied. Combining the results of these two experimental series, a statistically significant difference was found in the cell number index between the controls and the two highest doses tested (60 and 600 ng/kg body wt;p <0.01). This result was recently published as an abstract (Korte et al. 1990). However, with slight methodological changes in the third series of experiments (doses applied: 600, 60, 6, 0.6, and 0.06 ng TCDD/kg body wt) and using a greater number of animals we could not confirm these preliminary results. No difference was seen in the immune response to the antigen challenge in controls and in any of the treatment groups. We conclude that TCDD does not clearly influence the immune response as observed in the popliteal lymph node assay under our experimental conditions. 相似文献
69.
Ibrahim Chahoud Ralf Krowke Gerd Bochert Brigitte Bürkle Diether Neubert 《Archives of toxicology》1991,65(1):27-31
Possible effects on the next generation after long-term exposure (subcutaneous administration) of male rats to very high doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) were studied. Two dose regimes were applied: TCDD-25 (initial dose: 25 g/kg body wt; maintenance dose: 5 g/kg body wt, once weekly) and TCDD-75 (initial dose: 75 g/kg body wt; maintenance dose: 15 g/kg body wt). Male rats were treated for 10 weeks before mating and then throughout the entire 12 week mating period. They were mated to unexposed virgin females. One group of pregnant females was used for teratological evaluations, and another group was allowed to deliver. No significant differences were observed in the number of implantations or fetuses per litter, and resorption rate, and fetal weight between the controls and TCDD-treated groups. No gross-structural anomalies occurred in any of the fetuses sired by TCDD-treated males. In the TCDD-25 group an increased frequency of two types of variations was observed which also occur in controls: incompletely ossified fingers (TCDD-25=5.1%, controls=2.6%), and incompletely ossified ossa zygomatica (TCDD-25=1.8%, controls=0.5%). In the TCDD-25 group a slight but statistically significant increase was observed in the rate of stillbirths (TCDD-25=1.3%, controls=0.1%), apparently due to an unusually low frequency occurring in the controls (overall historical controls=0.6%). There was no difference in postnatal mortality (TCDD-25=1.3%, controls=1.3%). Taken together, despite the very high doses of TCDD used, the data do not provide evidence for biologically significant paternally-mediated developmental toxicity in the fetuses and newborn. 相似文献
70.
Ralf Schneggenburger Arthur Konnerth 《Pflügers Archiv : European journal of physiology》1992,421(4):364-373
Patch-clamp recording techniques were applied to thin slices of the rat pituitary gland in order to study synaptic transmission between hypothalamic nerve terminals and neuroendocrine cells of the intermediate lobe. Inhibitory postsynaptic currents (IPSCs) could be evoked by electrical stimulation of afferent neuronal fibres in the surrounding tissue of the slice. The IPSCs could be evoked in an all-or-nothing mode depending on the stimulus intensity, suggesting that single afferent fibres were stimulated. They had a chloride-dependent reversal potential and were blocked by bicuculline (K
d=0.1 M), indicating that they were mediated by -aminobutyric acid A (GABAA) receptors. In symmetrical chloride solutions the current/voltage relation of the IPSC peak amplitudes was linear. The IPSCs were characterized by a fast (1–2 ms) rise time and a biexponential decay, with time constants of 21±4 ms and 58±14 ms at a holding potential of –60 mV (n=6 cells). Both decay time constants increased with depolarization in an exponential manner. Spontaneously occurring IPSCs had a time course that was similar to that of evoked IPSCs. These miniature IPSCs, recorded in 1 M tetrodotoxin, displayed an amplitude distribution that was well fitted by single Gaussian functions, with a mean value of its maxima of 18.1±2.3 pA (n=4 cells). Amplitude histograms of evoked IPSCs were characterized by multiple peaks with a modal amplitude of about 18 pA (n=6 cells). These findings indicate the quantal nature of GABAergic synaptic transmission in this system, with a quantal conductance step of about 280 pS. Single-channel currents underlying the IPSCs were studied by bath application of GABA to outside-out patches excised from intermediate lobe cells. Such GABA-induced currents revealed two conductance levels of 14 pS and 26 pS. In conclusion, GABAergic synaptic transmission in neuroendocrine cells of the pituitary has properties that are quite similar to those observed in neurones of the central nervous system. 相似文献