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1.
Marike Gabrielson Mattias Hammarström Magnus Bäcklund Jenny Bergqvist Kristina Lång Ann H Rosendahl Signe Borgquist Roxanna Hellgren Kamila Czene Per Hall 《International journal of cancer. Journal international du cancer》2023,152(11):2362-2372
Tamoxifen prevents recurrence of breast cancer and is suggested for preventive risk-reducing therapy. Tamoxifen reduces mammographic density, a proxy for therapy response, but little is known about its effects in remodelling normal breast tissue. Our study, a substudy within the double-blinded dose-determination trial KARISMA, investigated tamoxifen-specific changes in breast tissue composition and histological markers in healthy women. We included 83 healthy women randomised to 6 months daily intake of 20, 10, 5, 2.5, 1 mg of tamoxifen or placebo. The groups were combined to “no dose” (0-1 mg), “low-dose” (2.5-5 mg) or “high-dose” (10-20 mg) of tamoxifen. Ultrasound-guided biopsies were collected before and after tamoxifen exposure. In each biopsy, epithelial, stromal and adipose tissues was quantified, and expression of epithelial and stromal Ki67, oestrogen receptor (ER) and progesterone receptor (PR) analysed. Mammographic density using STRATUS was measured at baseline and end-of-tamoxifen-exposure. We found that different doses of tamoxifen reduced mammographic density and glandular-epithelial area in premenopausal women and associated with reduced epithelium and increased adipose tissue. High-dose tamoxifen also decreased epithelial ER and PR expressions in premenopausal women. Premenopausal women with the greatest reduction in proliferation also had the greatest epithelial reduction. In postmenopausal women, high-dose tamoxifen decreased the epithelial area with no measurable density decrease. Tamoxifen at both low and high doses influences breast tissue composition and expression of histological markers in the normal breast. Our findings connect epithelial proliferation with tissue remodelling in premenopausal women and provide novel insights to understanding biological mechanisms of primary prevention with tamoxifen. 相似文献
2.
Signe S?nderkaer Marianne Schmiegelow Henrik Carstensen Lars B?geskov Nielsen J?rn Müller Kjeld Schmiegelow 《Journal of clinical oncology》2003,21(7):1347-1351
PURPOSE: To evaluate the pattern of neurological late effects in patients who have received surgery only for a brain tumor in childhood and to identify possible risk factors for neurological sequelae. PATIENTS AND METHODS: The medical, histologic, and operative records were reviewed for 65 consecutive patients operated for a benign brain tumor from 1970 to 1997, and all patients were re-examined after a median length of follow-up of 10.7 years. Thirty-four patients had posterior fossa tumors, 22 patients had cerebral hemisphere tumors, and nine patients had midline tumors. RESULTS: At the time of follow-up, 20 patients (31%) had no neurological deficits, 22 patients (34%) had minor deficits that did not interfere with their daily life activities, and 23 patients (35%) had moderate or severe deficits such as severe ataxia, spastic paresis, seriously reduced vision, or epilepsy with more than two seizures per year. Fourteen of the 31 patients (45%) registered with ataxia preoperatively had recovered fully. Six of seven patients had persistence of a pre- or postoperatively developed hemiparesis. Thirteen of 23 patients had persistence of cranial nerve deficits that developed second to surgery. Fifty-five percent of the 18 patients with seizures at diagnosis were seizure-free at follow-up. At follow-up both ataxia and hemiparesis were significantly more frequent among females (P =.02 and P =.03, respectively). CONCLUSION: In patients who received operation as the only treatment for their brain tumor, there was a good chance of total or partial recovery of preoperative and postoperative neurological deficits, although only one third of the patients will have no long-term neurological deficits. 相似文献
3.
Focal ischemia of the rat brain,with special reference to the influence of plasma glucose concentration 总被引:5,自引:0,他引:5
Summary Focal cerebral ischemia was induced by occlusion of the right middle cerebral artery in hypoglycemic, normoglycemic, as well as in acute and chronic diabetic rats. The brain damage was studied after 4 days. The volume of infarction was decreased in hypoglycemia (29±19 mm3 (mean±SD) versus 58±35 mm3,P<0.0046), unaltered in acute diabetes (61±45 mm3), and increased in chronic diabetes (91±22 mm3,P<0.0463). The cortex adjacent to the infarct showed selective neuronal injury affecting the cortical layers 2 and 3. The damage was enhanced by hypoglycemia and prevented in most of the diabetic animals. The findings indicate that different mechanisms cause infarction and selective neuronal injury outside infarcts, but that both are influenced by the plasma glucose concentration. 相似文献
4.
Abstract: The main aim of the present investigation was to study systematically the passive and stimulation-evoked release of 3H-5-hydroxytryptamine (3H-5-HT) from rabbit isolated aorta. This was accomplished by preloading rings of aorta with 3H-5-HT (10–6M) and then monitoring by fractional collection the basal 3H-outflow and stimulation-evoked 3H-overflow. The basal 3H-outflow from aorta preloaded with 10–6M of either 3H-5-HT or (-)-3H-noradrenaline (3H-NA) leveled off about 100 min. after the onset of wash-out and remained almost constant thereafter (100–240 min.). The basal 3H-outflow from tissue preloaded with 3H-5-HT was almost 3-fold higher (70–240 min.) than that seen after preloading with 3H-NA. Cocaine (3x10–5M) did not alter the basal 3H-outflow (15–240 min.) from tissue preloaded with 3H-5-HT, while pargyline (5X10–4M) decreased it by about 66% (100–240 min.). Electrical-field stimulation (S1S7, 200 mA, 600 pulses, 0.5 msec, 3 Hz) were applied to the tissue. The initial stimulation-evoked 3H-overflow from aorta preloaded with 3H-5-HT was higher than the subsequent ones (S1-S7: 100, 35, 35, 35, 35, 37, and 40%). Similar results to these were obtained with tissues preloaded with 3H-NA. The stimulation (S1-S7; 200 mA; 600 pulses, 0.5 msec, 3 Hz)-evoked 3H-overflow increased in an apparent linear manner with the amount of current used (50–200 mA). This was also the case for number of pulses (100–900) in the stimulus. The stimulation-evoked 3H-overflow depended in part on the stimulation frequency: unchanged at 2–4 Hz; small increase at 8 Hz; and a 15-fold increase at 16 Hz relative to 2 Hz. Tetrodotoxin (10–6M) decreased the stimulation-evoked 3H-overflow from aorta preloaded with 3H-5-HT (S2-S6) by about 60%, while S1 was not affected. The inhibitory effect of tetrodotoxin was fully reversed by washing the aorta with drug-free salt solution. Omission of Ca2+ from the salt solution reduced the stimulation 3H-overflow by 47–57% (S2-S6) while S1 was unaffected. 6-Hydroxydopamine markedly increased the stimulation-evoked 3H-overflow from 3H-5-HT preloaded rings (180–323% of control). Pargyline (5x10–4M), cocaine (3x10–5M) and removal of endothelium did not alter the stimulation-evoked 3H-overflow evoked by stimulation (S1-S6) of aorta preloaded with 3H-5-HT. It is concluded that 3H-5-HT can be released by electrical-field stimulation as a “false transmitter'’from rabbit isolated aorta. Most of the release is probably of neuronal origin. However, some of the stimulation-evoked 3H-overflow is derived from extraneuronal sites. 相似文献
5.
Jan Abrahamsen Ove A. Nedergaard 《Naunyn-Schmiedeberg's archives of pharmacology》1989,339(3):281-287
Summary The purpose of this investigation was to study the effect of adrenaline on presynaptic adrenoceptors by recording the release of 3H-noradrenaline evoked by electrical-field stimulation. Adrenaline (10–10–3 × 10–9 mol/l) had no effect on the 3H-overflow evoked by stimulation of aorta preloaded with 3H-noradrenaline. At 10–8 and 3 × 10–8 mol/l, the 3H-overflow was decreased by up to 47%. The maximum decrease was more marked in the presence of either cocaine (3 × 10–5 mol/l) plus corticosterone (4 × 10–5 mol/l), cocaine (3.3 × 10–6 mol/l) plus normetanephrine (4 × 10–5 mol/l), or desipramine (10–6 mol/l) plus normetanephrine (10–5 mol/l). The relationship between adrenaline-induced decrease and stimulation-frequency was dependent on the experimental design: either the decrease was the same at all frequencies (1–16 Hz) or it was more marked, the lower the frequency (1 > 3 > 8 Hz). Phentolamine and rauwolscine (both 10–6 mol/l) antagonized the inhibitory effect of adrenaline (10 – 8–10–6 mol/l). Phenoxybenzamine (10–6 mol/l), prevented the inhibitory effect. No enhancing effect of adrenaline (10–9–10–6 mol/l) was observed in the presence of these three -adrenoceptor antagonists. Our results suggest that adrenaline activates inhibitory 2-adrenoceptors, but not facilitatory -adrenoceptors on postganglionic sympathetic nerve terminals in rabbit aorta.
Send offprint requests to J. Abrahamsen at the above address 相似文献
6.
Smad4 overexpression causes germ cell ablation and leydig cell hyperplasia in transgenic mice
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Narula A Kilen S Ma E Kroeger J Goldberg E Woodruff TK 《The American journal of pathology》2002,161(5):1723-1734
Members of the transforming growth factor-beta (TGF-beta) superfamily play a variety of important roles in testicular development and function. The tumor suppressor gene, Smad4, is a common mediator of TGF-beta, activin, and bone morphogenetic protein-mediated signaling pathways. To investigate the role of the Smad4 gene during testicular development and function, transgenic mice were generated using a Flag-tagged Smad4 gene driven by 180-bp fragment of the Mullerian inhibiting substance upstream promoter sequence. Three Smad4 transgenic founders (A, B, and G) were detected by Southern blot analysis; line B showed the highest expression of the Smad4 transgene and was further studied. The fertility in F1 generation (B) and F2 generation (BB) of the Smad4 transgenic mice was not impaired. However, in the F3 generation (B2x) all animals were impacted by the overexpression of the Smad4 transgene and two kinds of phenotypes were observed. In one group animals were completely infertile, while in the other group animals were fertile and sired the normal number of pups/litter. These groups are designated as infertile and fertile in the text. Histological evaluation of the testes from the infertile group showed variable degrees of Leydig cell hyperplasia, apoptosis of germ cells, spermatogenic arrest, seminiferous tubule degeneration, and infertility. In the fertile group, there was no apparent change in the histology of the testis except for a slight increase in the number of Leydig cells. Serum follicle-stimulating hormone levels in the adult animals of both groups of Smad4 transgenic male mice were not significantly different from normal littermates; however, testosterone levels in both groups were significantly (P < 0.05) increased. These results suggest that overexpression of Smad4 leads to testicular abnormalities and infertility supporting the hypothesis that the TGF-beta signaling pathways are carefully orchestrated during testicular development. In the absence of normal levels of Smad4 testicular function is compromised. 相似文献
7.
Nine brain autopsy cases of small old cerebral infarcts were selected for neuropathological studies. Eight of the patients had cortical infarcts, in two cases with extension into the striate body. In one case the infarct involved the striate body only. The density of neurons and glial cells was measured in the coronal and the horizontal planes at various distances from the margin of the infarct. Corresponding counting points in the contralateral hemisphere served as control. On light microscopy, the infarcted cortex was irregularly shaped, but on serial sections the bulging parts appeared to be cut off from the infarcted tissue ("pseudo-infarct islands"). The zone of transition from infarcted to normal brain tissue was less than a few mm wide. In one patient, tomographic measurements of the cerebral blood flow (CBF) and a CT scan could be compared with the neuropathological findings. In this patient, CBF in the surroundings of the infarct was decreased despite a normal neuronal density. The study supports the traditional view held by pathologists that a sharp transition exists between infarcted and normal brain tissue and suggests that the hypoperfusion zone surrounding the region of complete infarction may be due to mechanisms other than selective loss of neurons. 相似文献
8.
9.
Jan Abrahamsen Ove A. Nedergaard 《Naunyn-Schmiedeberg's archives of pharmacology》1991,343(2):161-165
Summary The aim of the present investigation was to examine whether or not presynaptic facilitatory -adrenoceptors are detectable on the postganglionic nerves in the rabbit isolated ear artery. Strips of rabbit central ear artery were incubated with 3H-noradrenaline (10–7 mol/l; 30 min or 10–6 mol/l; 60 min). Subsequently, they were washed repeatedly with physiological salt solution. The strips were subjected to electrical-field stimulation (S1–S8) and the resultant 3H-overflow was determined.When the ear artery was stimulated with 150 pulses (0.5 ms; 3 Hz; 225 mA), isoprenaline (10–9–10–6 mol/l) either alone or in the presence of either rauwolscine (10–6 mol/l) or phentolamine (10–6 mol/l) did not alter the stimulation-evoked 3H-overflow. This was also the case in the presence of rauwolscine (10–6 mol/l) plus either the selective phosphodiesterase inhibitor ICI 63 197 (3 × 10–5 mol/l) or forskolin (10–6 mol/l). When the ear artery was stimulated with 300 pulses (1 ms; 5 Hz; 225 mA), isoprenaline had no effect on the stimulation-evoked 3H-overflow. This was also the case when phentolamine (10–6 mol/l) was present. Propranolol (10–7–10–5 mol/l) did not alter the stimulation-evoked 3H-overflow. In some experiments, the stimulation current was reduced to 175 mA in order to obtain similar reference release (S3) values despite the presence of rauwolscine (150 pulses; 0.5 ms; 3 Hz). Even then, isoprenaline (10–9–10–6 mol/l) did not change stimulation-evoked 3H-overflow. The results suggest that postganglionic sympathetic nerves in rabbit central ear artery do not possess presynaptic facilitatory -adrenoceptors.
Send offprint requests to J. Abrahamsen at the above address 相似文献