TSC1-mTOR-PLK轴以阶段特异性方式调节从施旺细胞增殖到髓鞘形成的内稳态开关

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。     

The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development

BACKGROUND: During development, the homeobox gene Cdx2 exerts a homeotic function, providing the positional information necessary for correct specification of the midgut endoderm. This is illustrated by the non-neoplastic gastric-type heteroplasias present at birth in the pericaecal region of Cdx2(+/-) mice. Furthermore, intestinal expression of Cdx2 continues throughout life but diminishes in colorectal cancers compared with adjacent normal tissue, suggesting a role in tumorigenesis. Aim: To investigate the consequence of altered Cdx2 expression on colon tumour initiation and/or progression. METHODS: Heterozygous Cdx2(+/-) mice were analysed for spontaneous malignant tumours and for tumour development after treatment with a DNA mutagen, azoxymethane. RESULTS: Cdx2(+/-) mice did not spontaneously develop malignant tumours. After azoxymethane treatment, the gastric-like heteroplasias in the pericaecal region did not evolve into cancer indicating that they are not precancerous lesions. However, azoxymethane treated Cdx2(+/-) mice developed tumours specifically in the distal colon 12 weeks after azoxymethane treatment whereas no tumours were found in wild-type littermates at this stage. Histopathological and molecular analyses indicated that these tumours were invasive adenocarcinomas that recapitulated the malignant sequence observed in the majority of sporadic colorectal cancers in human. In addition, we found that the colonic epithelium was less sensitive to radiation induced apoptosis in Cdx2(+/-) than in wild-type mice. CONCLUSION: This study provides the first experimental evidence that Cdx2 is a tumour suppressor gene involved in cancer progression in the distal colon. This action in adults is functionally and geographically distinct from its homeotic role during gut development.     

Exploring the utility of whole‐exome sequencing as a diagnostic tool in a child with atypical episodic muscle weakness

The advent of whole‐exome next‐generation sequencing (WES) has been pivotal for the molecular characterization of Mendelian disease; however, the clinical applicability of WES has remained relatively unexplored. We describe our exploration of WES as a diagnostic tool in a 3½‐year old female patient with a 2‐year history of episodic muscle weakness and paroxysmal dystonia who presented following a previous extensive but unrevealing diagnostic work‐up. WES was performed on the proband and her two parents. Parental exome data was used to filter potential de novo genomic events in the proband and suspected variants were confirmed using di‐deoxy sequencing. WES revealed a de novo non‐synonymous mutation in exon 21 of the calcium channel gene CACNA1S that has been previously reported in a single patient as a rare cause of atypical hypokalemic periodic paralysis. This was unexpected, as the proband's original differential diagnosis had included hypokalemic periodic paralysis, but clinical and laboratory features were equivocal, and standard clinical molecular testing for hypokalemic periodic paralysis and related disorders was negative. This report highlights the potential diagnostic utility of WES in clinical practice, with implications for the approach to similar diagnostic dilemmas in the future.     

Suppression of ongoing experimental allergic encephalomyelitis in DA rats by novel peptide drug,structural part of human myelin basic protein 46–62

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.     

Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

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.

     

Crohn''s Disease of the Colon

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.     

Early administration of captopril and nitroglycerin in combination after acute myocardial infarction: an invasive haemodynamic study

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. min^–1.m^–2, 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.