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71.
恰如其分的外周髓鞘形成取决于雪旺细胞增殖与分化进程间的平衡。丝氨酸/苏氨酸激酶(mTOR)整合多种环境因素,是细胞生长、代谢、发挥作用的中枢调节者。本文报道了一种mTOR的负性调节剂——结节性硬化复合体(TSC1),通过控制细胞增殖和髓鞘稳态,建立了雪旺细胞谱系进展和髓鞘形成的阶段依赖性程序。小鼠雪旺细胞祖细胞中TSC1的解离导致mTOR信号通路激活,继而导致雪旺细胞过量增殖,分化受阻,髓鞘形成减少。转录组分析显示,TSC1突变体中的mTOR活化使得polo样激酶(PLK)依赖性通路和细胞周期调节剂上调。弱化mTOR或者对PLK进行药理抑制部分挽救了因TSC1缺失导致的外周神经发育过程中的髓鞘形成减少。相较之下,成年小鼠成熟雪旺细胞中TSC1缺失可导致髓鞘的过度增殖和过度生长。本文的发现提示了TSC1-mTOR-PLK信号轴在控制雪旺细胞的发育过程中,从增殖到分化和髓鞘内稳态中起到的阶段特异性功能。 相似文献
72.
73.
A. A. Belogurov JR. T. A. Zargarova V. I. Turobov N. I. Novikova O. O. Favorova N. A. Ponomarenko 《Autoimmunity》2013,46(4):362-364
Previously, we demonstrated that autoantibodies (AAb) in multiple sclerosis (MS) reveal site-specific binding and cleavage toward myelin basic protein (MBP) epitope library. We have found several fragments of MBP immunodominant in terms of AAb binding. Here, we applied these peptides to DA rats with induced protracted relapsing experimental allergic encephalomyelitis (EAE) most closely related to MS. DA rats with EAE induced by syngenic spinal cord homogenate in complete Freund's adjuvant were treated by nasal route with human MBP 46–62, 81–102, 124–139, 147–170, and Copaxone®. MBP 124–139 and 147–170 displayed only mild therapeutic effects but MBP 46–62 significantly reduced EAE, reflected by lower clinical scores and shorter EAE duration compared to controls. 相似文献
74.
Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe 下载免费PDF全文
JR Santos A Cozzi‐Lepri A Phillips S De Wit C Pedersen P Reiss A Blaxhult A Lazzarin M Sluzhynska C Orkin C Duvivier J Bogner P Gargalianos‐Kakolyris P Schmid G Hassoun I Khromova M Beniowski V Hadziosmanovic D Sedlacek R Paredes JD Lundgren 《HIV medicine》2018,19(5):324-338
Objectives
The aim of the study was to evaluate the long‐term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)‐, darunavir/ritonavir (DRV/r)‐, and lopinavir/ritonavir (LPV/r)‐containing regimens.Methods
Data were analysed for 5678 EuroSIDA‐enrolled patients starting a DRV/r‐, ATZ/r‐ or LPV/r‐containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART‐naïve subjects (8%) at ritonavir‐boosted protease inhibitor (PI/r) initiation; (2) ART‐experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV‐1 RNA copies/mL; and (3) ART‐experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan–Meier and multivariable Cox models were used to compare risks of failure by PI/r‐based regimen. The main analysis was performed with intention‐to‐treat (ITT) ignoring treatment switches.Results
The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log‐rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART‐naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment‐experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r‐based ART.Conclusions
Although confounding by indication and calendar year cannot be completely ruled out, in ART‐experienced subjects the long‐term effectiveness of DRV/r‐containing regimens appears to be greater than that of ATZ/r and LPV/r.75.
ADRIAN J. GREENSTEIN M.B.B.Ch. F.A.C.S. F.R.C.S. F.A.C.G. DAVID A. DREILING M.D. F.A.C.S. F.A.C.G. † ARTHUR H. AUFSES JR. M.D. F.A.C.S. F.A.C.G.‡ 《The American journal of gastroenterology》1975,64(4):306-318
Retroperitoneal lumbocrural abscess occurred in 12 patients of 231 with Crohn's colitis or ileocolitis. Although all patients with this complication fell within the group of 175 ileocolitis patients, at least four originated in fistulous tracts of the colon. Eleven of the 12 abscesses developed spontaneously as the first major complication of the disease. The prominent clinical features included pain radiating down the thigh, hip joint flexion, difficulty in walking, hydronephrosis and hydroureter. Internal and external fistulas were significantly more common in the abscess group of 12 patients than in the 219 patients without retroperitoneal abscess. Radiological evidence of granulomatous disease was found in all patients; fistulous tract formation was characteristic and the development of extraperitoneal gas bubbles, in four patients, pathognomonic of abscess with gast-forming organisms. In the presence of established retroperitoneal abscess, the surgical sequence suggested is drainage synchronous with, or followed by diversion and ultimately definitive resection. Resection with anastomosis should not be carried out in the presence of an acute inflammatory process with frank abscess or free pus communicating with the peritoneal cavity. The spontaneous development of retroperitoneal abscess is a serious development in the natural history of Crohn's (ileo) colitis. It frequently heralds the first of a series of operative procedures to deal with the abscess. It sequels are enterocutaneous fistulas and further extension of the disease process. 相似文献
76.
TRANCHESI B. JR; SANTOS R. D.; CARAMELLI B.; GEBARA O.; BARBOSA V.; BELLOTTI G.; PILEGGI F. 《European heart journal》1993,14(1):90-95
The combination of captopril and nitroglycerin early after acutemyocardial infarction (AMI) could lead to a dangerous decreasein blood pressure coronary perfusion. To evaluate the safetyaspects and haemodynamic effects of this combination, we studied36 first Q wave thrombolysed anterior wall AMIpatients during the 24 h following the onset of symptoms. Afterwards, thrombolysis patients received a continuous infusionof nitroglycerin and were submitted to pulmonary artery catheterization.Those patients with mean arterial pressure (MAP) 70 mmHg, cardiacindex 2.21. min1.m2, and wedge pressure 10 mmHgwere included and randomized to receive 6.25 mg of captoprilevery 6 h on the first day and 12.5 mg qid on the second f MAP 70mmHg (group 1). A second group (group 2) received a placebo.Haemodynamic parameters were determined after 1, 6 and thenevery 6 h up to 48 h after basal measurements. Significant differenceswere observed only for the MAP and the rate-pressure product(reduction in group 1 values, P <0.05). However, MAP wasmaintained within acceptable limits. Our data support the factthat the combination of captopril and nitroglycerin in the earlyhours of a non-complicated anterior wall AMI is safe, and couldguarantee its use in large clinical trials to determine theeffects on left ventricle remodelling and survival after AMI. 相似文献
77.
A. Fortin R. Rabasa-Lhoret S. Lemieux M.-E. Labonté V. Gingras 《Nutrition, metabolism, and cardiovascular diseases : NMCD》2018,28(12):1275-1284
Background and aims
The metabolic syndrome (MS) is an emerging complication in patients with type 1 diabetes (T1D), with no preventive or therapeutic treatment reported yet. We wanted to compare the impact of two 6-month nutritional interventions, based on a Mediterranean (MED) or a low-fat diet, on waist circumference, anthropometric and metabolic outcomes in patients with both T1D and the MS.Methods and results
Participants were randomized into 2 intervention groups: 1) MED-diet or 2) low-fat diet. The 6-month study included 9 teaching sessions with a registered dietitian. Anthropometric (primary outcome: waist circumference), metabolic and nutritional assessments were performed at inclusion, 3 and 6-month. We used mixed effects models to assess the effects of both interventions. 28 participants were included (50.9 ± 10.3 years old) with a mean BMI of 30.7 ± 3.3 kg/m2 and a waist circumference of 105.5 ± 8.9 cm at inclusion. A trend towards a greater reduction of dietary fat intakes in the low-fat diet group was observed (P-interaction = 0.09). Waist circumference was reduced at 6-month in both groups (?3.5 cm low-fat; ?1.5 cm MED-diet) with no significant difference between groups (P-interaction = 0.43). Body mass index also significantly decreased in both groups (?0.7 kg/m2 low-fat; ?1.1 kg/m2 MED-diet; P-interaction = 0.56). No significant differences between groups were observed for other metabolic parameters.Conclusions
This study suggests that a 6-month non-restrictive dietary intervention in patients with T1D and MS could contribute to weight management, without significant differences between interventions for anthropometric and metabolic parameters. Further studies should investigate the long-term benefits of these diets.78.
Background
Dietary oleic acid may prevent pancreatic ductal adenocarcinoma (PDA) by reducing hyperinsulinaemia which can otherwise promote DNA damage and tumour growth. Results from previous epidemiological studies investigating oleic acid are inconsistent. This study aims to clarify the relationship between dietary oleic acid intake and the risk of developing PDA using nutritional information from food diaries plus published serum biomarker data from HbA1c.Methods
23,658 participants, aged 40–74 years, were recruited into EPIC-Norfolk and completed 7-day food diaries which recorded; foods, brands and portion sizes to calculate nutrient intakes. Serum HbA1c was measured at recruitment in 11,147 participants (48.7% of cohort). Hazard ratios (HRs) for quintiles of dietary oleic acid intake and serum HbA1c were estimated using Cox regression. Additional analyses were made according to whether body mass index (BMI) was greater or less than 25?kg/m2 as this influences hyperinsulinaemia.Results
88 participants (55% women) developed PDA after a mean follow-up of 8.4 years (SD?=?3.9) (mean age at diagnosis?=?72.6 years, SD?=?8.8). A decreased risk of PDA was associated with increased dietary oleic acid intake (highest vs lowest quintile, HR?=?0.29, 95% CI?=?0.10–0.81, P trend across quintiles?=?0.011), with statistical significance maintained when BMI>25?kg/m2 but not if BMI<25?kg/m2. An elevated serum HbA1c was associated with increased risk of disease (highest vs lowest quintiles, HR?=?6.32, 95% CI?=?1.38–28.89, P for trend?=?0.004).Conclusions
The data supports a protective role of oleic acid against development of PDA in those with higher BMIs possibly through influencing hyperinsulinaemia. Oleic acid intake should be accurately measured in future aetiological studies. 相似文献79.
ADRIAN J. GREENSTEIN M.B.B.Ch. F.A.C.G. F.A.C.S. F.R.C.S. STEPHEN A. GELLER M.D. † DAVID A. DREILING M.D. F.A.C.G. F.A.C.S. † ARTHUR H. AUFSES JR. M.D. F.A.C.G. F.A.C.S. 《The American journal of gastroenterology》1975,64(3):191-199
Using accepted diagnostic criteria we have selected, for study, 160 patients with Crohn's disease involving the colon. There is a remarkable discrepancy between the clinical diagnosis prior to or at the time of initial admission to this hospital and the diagnosis following definitive investigation and observation of the progression of disease.
The peak age incidence occurred in the second decode The colitis group showed a greater percentage of patients over 30 years of age. Although histopathology was not obtained in all patients, there appeared to be sparing of the ascending colon in a small percentage (9%) of patients with ileocolitis.
Comparison of the clinical features of granulomatous disease limited to the colon and granulomatous ileocolitis shows a significantly greater incidence of extraintestinal symptoms and overt bleeding in the former. Nausea, vomiting, subacute obstruction, abdominal mass and internal fistulas were substantially more common in ileocolitis but the difference was not statistically significant. In this series retroperitoneal abscess did not occur in patients with disease localized to the colon. In the 10 patients with ileocolitis who developed an abscess, however, the site of fistula was the colon in four patients. In one of these, the abscess was left-sided. 相似文献
The peak age incidence occurred in the second decode The colitis group showed a greater percentage of patients over 30 years of age. Although histopathology was not obtained in all patients, there appeared to be sparing of the ascending colon in a small percentage (9%) of patients with ileocolitis.
Comparison of the clinical features of granulomatous disease limited to the colon and granulomatous ileocolitis shows a significantly greater incidence of extraintestinal symptoms and overt bleeding in the former. Nausea, vomiting, subacute obstruction, abdominal mass and internal fistulas were substantially more common in ileocolitis but the difference was not statistically significant. In this series retroperitoneal abscess did not occur in patients with disease localized to the colon. In the 10 patients with ileocolitis who developed an abscess, however, the site of fistula was the colon in four patients. In one of these, the abscess was left-sided. 相似文献
80.
Emily L. Doolittle Bruno Gingras Dominik M. Endres W. Tecumseh Fitch 《Proceedings of the National Academy of Sciences of the United States of America》2014,111(46):16616-16621
Many human musical scales, including the diatonic major scale prevalent in Western
music, are built partially or entirely from intervals (ratios between adjacent
frequencies) corresponding to small-integer proportions drawn from the harmonic
series. Scientists have long debated the extent to which principles of scale
generation in human music are biologically or culturally determined. Data from animal
“song” may provide new insights into this discussion. Here, by
examining pitch relationships using both a simple linear regression model and a
Bayesian generative model, we show that most songs of the hermit thrush
(Catharus guttatus) favor simple frequency ratios derived from
the harmonic (or overtone) series. Furthermore, we show that this frequency selection
results not from physical constraints governing peripheral production mechanisms but
from active selection at a central level. These data provide the most rigorous
empirical evidence to date of a bird song that makes use of the same mathematical
principles that underlie Western and many non-Western musical scales, demonstrating
surprising convergence between human and animal “song cultures.”
Although there is no evidence that the songs of most bird species follow the overtone
series, our findings add to a small but growing body of research showing that a
preference for small-integer frequency ratios is not unique to humans. These findings
thus have important implications for current debates about the origins of human
musical systems and may call for a reevaluation of existing theories of musical
consonance based on specific human vocal characteristics.Many human musical scales, including the diatonic major scale
prevalent in Western music, are built partially or entirely from intervals (ratios between
adjacent frequencies) corresponding to small-integer ratios drawn from the harmonic series
(1). A long-running debate concerns the extent to
which principles underlying the structure of human musical scales derive from biological
aspects of auditory perception and/or vocal production or are historical cultural
“accidents” (2–4). The songs of nonhuman
animals, such as birds or whales, potentially offer a valuable perspective on this debate.
On the one hand, features of human music that are culturally bound, or dependent on
specific characteristics of the human voice or auditory system, should be absent in animal
vocalizations. On the other hand, aspects of human music observed in the vocalizations of
other species seem likely to be partially determined by general physical or biological
constraints rather than solely by cultural practices. Such shared features would complement
recent research suggesting that common motor constraints shape both human song and that of
some bird species (5).The physical principles underlying vocal production in songbirds are well understood (6–10) and do not differ fundamentally from those of other vertebrates. Sound is
produced by tissue vibrations in the syrinx, a bird-specific organ located at the base of
the trachea. Flow-driven vibrations of fleshy membranes within the syrinx (in songbirds,
the medial and lateral labia) generate a periodic source signal that is filtered by the air
column within the trachea and mouth and then emitted to the environment. These principles
are important in formulating various alternative hypotheses considered below.Naturalists have long wondered whether birdsong could be said to have musical properties
(11–13). However, early studies on pitch selection tended
to be anecdotal, based on a small sample size, or lacking in analytical rigor. Two more
recent studies specifically comparing pitch selection in bird song and human musical scales
concluded that birdsong does not make preferential use of musical intervals found in
commonly used Western musical scales (14, 15). However, because these studies each only examined
one species [the white-throated sparrow (Zonotrichia albicollis) and the
nightingale wren (Microcerculus philomela), respectively], a conclusion
that birdsong in general does not exhibit musical properties seems premature. Indeed, other
studies have shown preferential use of consonant intervals in tropical boubou shrikes
(Laniarius aethiopicus) (16) and
musician wrens (Cyphorhinus arada) (17), although in the first case no rigorous statistical analysis was
presented.Here, we investigated songs of the hermit thrush (Catharus guttatus), a
medium-sized North American songbird whose famously “musical”-sounding song
has attracted the attention of ornithologists and musicians alike (18) but has not yet been subjected to detailed pitch analysis. Its
songs are composed of elements (the smallest unit of song construction, seen as continuous
uninterrupted traces on spectrograms) that may exhibit either a variable pitch, such as
trills and slides, or a stable pitch—pure, non-frequency-modulated,
“flutelike” sounds. These stable sounds, which we refer to as
“notes” (Fig. 1), are characterized
by strong fundamental frequencies and very weak higher harmonics, making them ideally
suited for an analysis of pitch relationships (15).
Males typically sing 6–10 different song types, defined as nearly identical
sequences of elements, durations, and frequencies. In a number of early- and
mid-20th-century studies, hermit thrush song was variously attributed with use of major,
minor, and pentatonic scales (19, 20) and claimed to follow the overtone series (21). However, these early studies again suffered from
small sample sizes and anecdotal reporting and were not based on rigorous acoustic
analysis. More recent hermit thrush studies have focused on regional differences and
song-type ordering, rather than pitch selection (22, 23).Open in a separate windowFig. 1.Song of the hermit thrush (C. guttatus). One song type of a single
male hermit thrush, illustrating the various elements that can be observed in songs
of this species. Only “notes” (elements with stable pitch) were
analyzed in this study because the other element types have no clearly defined or
measurable pitch.Here we tested the overtone hypothesis, which predicts that the frequencies of the
individual song notes are integer multiples (harmonics) of an implied (but not actually
sung) base frequency (hereafter fi). This hypothesis seems
plausible because, unlike some previous claims, it does not attribute human-specific
music-theoretical concepts to hermit thrush song. Moreover, the subjective impression of
trained musicians listening to hermit thrush songs (played at one-sixth of the original
speed to shift the speed and frequency of the songs into a range more suitable for human
hearing) was that most notes indeed seemed to follow an overtone series (see Fig. 2 and Audio File S1 for the corresponding sound example). However,
determining whether a set of notes are harmonics of a frequency not present in the set
requires a rigorous procedure to estimate and evaluate fi. To
this end, we used two different statistical approaches, an ordinary least-squares
regression model and a generative Bayesian estimator. Both approaches were used to test the
hypothesis that a song is an exchangeable sequence of frequencies that are integer
multiples of some implied fi, versus the null hypothesis that
songs are generated by drawing frequencies out of a random log-normal distribution (see
Materials and Methods for
details). By using a Bayesian approach in addition to the least-squares regression model we
evaluate whether our analyses represent a rigorous test of our overtone hypothesis and not
simply a post hoc explanation that minimizes an error measure by “memorizing”
the data. These properties make the Bayesian evaluation statistically more rigorous than
least-squares fitting.Open in a separate windowFig. 2.Frequency distribution of a hermit thrush song compared with an overtone series.
(A) Notes of a hermit thrush song. (B) The same
notes rearranged in ascending order to show how they correspond to overtones 3, 4, 5,
and 6 of an overtone series fitted to the frequencies corresponding to these notes
(the complete stacked overtone series is shown on the right). 相似文献