HNRNPA1-induced spliceopathy in a transgenic mouse model of myotonic dystrophy.

Studies on myotonic dystrophy type 1 (DM1) have led to the RNA-mediated disease model for hereditary disorders caused by noncoding microsatellite expansions. This model proposes that DM1 disease manifestations are caused by a reversion to fetal RNA processing patterns in adult tissues due to the expression of toxic CUG RNA expansions (CUGexp) leading to decreased muscleblind-like, but increased CUGBP1/ETR3-like factor 1 (CELF1), alternative splicing activities. Here, we test this model in vivo, using the mouse HSALR poly(CUG) model for DM1 and recombinant adeno-associated virus (rAAV)-mediated transduction of specific splicing factors. Surprisingly, systemic overexpression of HNRNPA1, not previously linked to DM1, also shifted DM1-relevant splicing targets to fetal isoforms, resulting in more severe muscle weakness/myopathy as early as 4 to 6 wk posttransduction, whereas rAAV controls were unaffected. Overexpression of HNRNPA1 promotes fetal exon inclusion of representative DM1-relevant splicing targets in differentiated myoblasts, and HITS-CLIP of rAAV-mycHnrnpa1-injected muscle revealed direct interactions of HNRNPA1 with these targets in vivo. Similar to CELF1, HNRNPA1 protein levels decrease during postnatal development, but are elevated in both regenerating mouse muscle and DM1 skeletal muscle. Our studies suggest that CUGexp RNA triggers abnormal expression of multiple nuclear RNA binding proteins, including CELF1 and HNRNPA1, that antagonize MBNL activity to promote fetal splicing patterns.

Alpha-synuclein levels in patients with multiple system atrophy: a meta-analysis.

PURPOSE: This study evaluates the relationship between multiple system atrophy and α-synuclein levels in the cerebrospinal fluid, plasma and neural tissue. METHOD: Literature search for relevant research articles was undertaken in electronic databases and study selection was based on a priori eligibility criteria. Random-effects meta-analyses of standardized mean differences in α-synuclein levels between multiple system atrophy patients and normal controls were conducted to obtain the overall and subgroup effect sizes. Meta-regression analyses were performed to evaluate the effect of age, gender and disease severity on standardized mean differences. RESULTS: Data were obtained from 11 studies involving 378 multiple system atrophy patients and 637 healthy controls (age: multiple system atrophy patients 64.14 [95% confidence interval 62.05, 66.23] years; controls 64.16 [60.06, 68.25] years; disease duration: 44.41 [26.44, 62.38] months). Cerebrospinal fluid α-synuclein levels were significantly lower in multiple system atrophy patients than in controls but in plasma and neural tissue, α-synuclein levels were significantly higher in multiple system atrophy patients (standardized mean difference: -0.99 [-1.65, -0.32]; p = 0.001). Percentage of male multiple system atrophy patients was significantly positively associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p = 0.029) whereas the percentage of healthy males was not associated with the standardized mean differences of cerebrospinal fluid α-synuclein levels (p = 0.920). CONCLUSION: In multiple system atrophy patients, α-synuclein levels were significantly lower in the cerebrospinal fluid and were positively associated with the male gender.

Neurobrucellosis.

PURPOSE: Neurobrucellosis (NB) is a rare complication of brucellosis. NB presents with avariety of clinical manifestations, and the symptoms are always atypical. Our aim was to analyze the demographic characteristics, clinical manifestations, laboratory findings, imaging findings, treatments and outcomes of patients with NB. MATERIAL AND METHOD: We retrospectively reviewed the data from 17 patients with NB hospitalized at the Chinese People's Liberation Army General Hospital between 1 January 2005 and 31 October 2016. RESULTS: The following symptoms were recorded: 10/17 (59%) patients had fever, and 9/17 (53%) patients had a disorder affecting urination and defecation. Involvement of the cranial nerves was documented in 12/17 (71%) patients. The positivity rates of the tests were as follows: serum standard tube agglutination (STA), 15/17 (88.2%); cerebrospinal fluid STA, 10/17 (59%). The radiologic findings were categorized into four types: normal, white matter changes, vascular insult and inflammatory changes. Patients were treated with different combinations of rifampicin, doxycycline, ceftriaxone sodium and sulphamethoxazole for a total of six months. Two (12%) patients deteriorated, and two (12%) patients were lost to follow-up. The remaining patients (76%) were cured, but sequelae occurred in six patients. CONCLUSIONS: NB should be kept in mind in patients with autonomic dysfunction, especially disorders of urination and defecation. Hearing loss due to vestibulocochlear nerve injury seems to be typical for NB. The high incidence of sequelae may be related to a long disease course and the involvement of the central nervous system. Early detection, diagnosis and treatment could decrease mortality and sequelae.

Cerebral aspergillosis: a retrospective analysis of eight cases.

PURPOSE: Aspergillosis of the central nervous system is very rare. However with recent increases in the use of immunosuppressive agents and antibiotics, its incidence is increasing. We evaluated the demographics, clinical manifestations, laboratory findings, diagnosis, underlying conditions, treatment regimens and outcomes of patients with cerebral aspergillosis (CA). METHODS: We retrospectively reviewed data from eight patients with CA hospitalized at a Chinese general hospital from 1 January 2005 to 30 September 2015. RESULTS: Common clinical manifestations included headache and cranial nerve involvement. Four patients underwent biopsy and were pathologically diagnosed with Aspergillus hyphae. One patient was proved to have Aspergillus infection via autopsy. One patient had positive cerebrospinal fluid fungal cultures. The lesion locations were: the cavernous sinus (n = 5, 62.5%), frontal lobe (n = 1, 12.5%), temporosphenoid lobe (n = 1, 12.5%) and cerebellum (n = 1, 12.5%). At the end of follow-up, three patients were cured and five patients had died (mortality rate, 62.5%). CONCLUSIONS: Most patients with CA had no significant immunosuppression-related conditions in our study. Aspergillus spp. can infect the central nervous system through several pathways and CA has an atypical clinical manifestation. The use of local tissue puncture, surgery or other invasive means to obtain diseased tissue containing higher levels of Aspergillus, followed by culture or histological examination, can contribute to an early diagnosis of CA and timely therapeutic intervention. The prognosis of CA is poor, but early and adequate use of antifungal drugs with high transfer across the blood-brain barrier and radical surgery to remove lesions can improve the survival rate.

Incidence and risk factors of pleural effusions in patients with POEMS syndrome.

Information regarding the characteristics of pleural effusions in patients with POEMS syndrome is limited. The aim of this study was to describe the incidence and risk factors of pleural effusions in patients with POEMS syndrome and characterize the pleural fluid biochemistry in those patients. A retrospective review of 96 patients with POEMS syndrome was conducted. The patients were divided into groups with and without pleural effusions. The clinical data were obtained from medical charts. Risk factors were studied with univariate and multivariate analysis. The median age at the time of diagnosis of POEMS syndrome was 45.1 years, and the median disease duration was 30.4 months. Pleural effusions were detected in 41 (42.7%) of the 96 patients. Increased serum vascular endothelial growth factor (VEGF), complement component 3 (C3), Lambda light chain, tumour necrosis factor (TNF)-α, interleukin (IL)-6 levels and low albumin as well as cardiac disease were found to be significantly correlated with pleural effusions. By multivariate logistic regression, independent risk factors for pleural effusions in POEMS syndrome were VEGF [odds ratio (OR): 2.46, 95% confidence interval (CI): 1.720-3.414, p = 0.01], TNF-α (OR: 3.64, 95% CI: 1.073-4.338, p = 0.04) and C3 (OR: 3.77, 95% CI: 1.225-3.591, p = 0.02) levels. Pleural effusions are the most common thoracic involvement findings in patients with POEMS syndrome, and all the pleural fluids are exudates. Serum VEGF, TNF-α and C3 levels are identified as important risk factors for presence of pleural effusions in POEMS syndrome.

Characteristics of CADASIL in Chinese mainland patients.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) has been reported in many geographical regions. However, relatively few reports about CADASIL in Chinese were reported. MATERIALS AND METHODS: We retrospectively collected and analyzed clinical characteristics, magnetic resonance (MRI) features and genetic data of 52 Chinese mainland CADASIL patients. RESULTS: Mean age of onset was 42.43 years. The primary clinical manifestations included: Ischemic stroke/transient ischemic attack (62.5%), primary intracerebral hemorrhage (25%), vertigo (25%), migraine (39.58%), dementia (18.75%) and emotional disturbance (20.83%). The most frequently observed MRI abnormalities were hyperintensity in the cerebral white matter on T2-weighted images and multiple infarcts, high-signal lesions on T2 images in anterior temporal lobes and external capsule were uncommon. The highest mutation frequency was in exon regions, 4 and 3, followed by exon 11. Granular osmiophilic material (GOM) was identified in 66.67% of the cases examined with biopsy. CONCLUSIONS: Most characteristics of Chinese mainland CADASIL patients are similar to those of CADASIL patients living in other regions. However, the prevalence of primary intracerebral hemorrhage and vertigo is much higher in Chinese mainland CADASIL patients. Significant leukoaraiosis in anterior temporal poles on T2-weighted image are uncommon. Exons 3 and 4 are the mutation hotspots.

Novel Triazolopyridine-Based BRD4 Inhibitors as Potent HIV-1 Latency Reversing Agents.

Bromodomain-containing protein 4 (BRD4) inhibitors have been proven to be a promising option for anti-HIV-1 latency therapeutics. We herein describe the design, synthesis, and anti-HIV-1 latency bioevaluation of triazolopyridine derivatives as BRD4 inhibitors. Among them, compound 13d displayed favorable HIV-1 reactivation and prominent safety profile without triggering abnormal immune activation. It exerted strong synergism when combined with the PKC activator prostratin and has the same BRD4-targeting latency mechanism as observed with JQ1, by stimulating Tat-dependent HIV-1 elongation. Besides, it neither affected the antiviral efficacies of antiviral drugs nor caused secondary infections to uninfected cells and the latency reversing potency of 13d, in turn, was not affected by different classes of antiviral drugs.

The characteristics of ascites in patients with POEMS syndrome.

The characteristics of ascites in patients with POEMS syndrome, which comprise polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes, are unknown. We described the frequency of ascites at presentation of POEMS syndrome and further evaluated for the pathogenesis and nature of the ascites. One hundred and six consecutive patients with POEMS syndrome in Chinese PLA General Hospital were evaluated for the presence of ascites, and the cellular and biochemical characteristics of the ascitic fluids were assessed. Serum levels of complement, cytokines, and clinical chemistry parameters were analyzed in peripheral blood samples of the patients with POEMS syndrome. Ascites was observed in 42 of 106 (39.6 %) patients with POEMS syndrome. Patients with ascites had significantly high serum levels of C3 and C4 complement components and TNF-α (all p < 0.01). In 31 (73.8 %) patients who underwent paracentesis, the ascitic fluids had low serum ascites albumin gradients (SAAG), indicating non-portal hypertension. Spontaneous bacterial peritonitis was not observed. Ascites is a common complication of POEMS syndrome and has characteristics of non-portal hypertension, based on low SAAG. Increased immune activation and inflammatory status could contribute to the pathogenesis of ascites in POEMS syndrome.

[Electrophysiological features of patients with myotonic dystrophy type 1].

OBJECTIVE: To explore the electromyography (EMG) and nerve conduction (NC) features of patients with myotonic dystrophy type 1 (DM1). METHODS: Routine PCR and triplet primed-PCR (TP-PCR) were performed for 33 clinically diagnosed DM1 cases at our clinic from June 2009 to June 2012. The EMG and NC results of 30 patients with a genetic diagnosis of DM1 were collected and analyzed. RESULTS: Myotonic discharges were found in all patients and EMG revealed myogenic changes in 29 patients. Among all 123 muscles examined, the incidence of myotonic discharges was, a little higher than that of myogenic changes (91.87% vs 90.24%). The rate of myotonic discharges in distal muscles was higher than that of myotonic discharges in proximal muscles (100% vs 83.61%). And the difference was statistically significant. No difference existed in myogenic changes between distal and proximal muscles.(87.10% vs 93.44%) Nerve conduction was all normal. CONCLUSIONS: Myotonic discharges and myogenic changes are important EMG features in DM1. In early stage of DM1, myotonic discharges may be the isolated EMG abnormality. Myotonic discharges are predominantly detected in distal muscles. The involved regions detected by EMG are wider than those of clinical findings. EMG is an important screening tool for subclinical or early atypical DM1 patients.

Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment.

Latent reservoir persistence remains a major obstacle for curing human immunodeficiency virus type 1 (HIV-1) infection. Thus, strategies for the elimination of latent HIV-1 are urgently needed. As a bromodomain and extra-terminal (BET) inhibitor, BMS-986158 has been used in clinical trials for advanced solid tumors and hematological malignancies. Here, we found that BMS-986158 reactivated latent HIV-1 in three types of HIV-1 latency cells in vitro, and in combination antiretroviral therapy (cART)-treated patient-derived peripheral blood mononuclear cells ex vivo, without influencing global immune cell activation. BMS-986158 reactivated latent HIV-1 by increasing phosphorylation of CDK9 at Thr186 and promoting recruitment of CDK9 and RNA polymerase II to the HIV-1 long terminal repeat in J-Lat cells. Furthermore, BMS-986158 exerted strong synergism in reactivating latent HIV-1 when combined with prostratin and vorinostat and enhanced the antiviral activity of anti-HIV-1 drugs. Finally, BMS-986158 showed antiviral activity in an HIV-1 acute infection model, possibly by arresting the cell cycle in infected cells. Thus, these results suggest that BMS-986158 is a potential candidate for AIDS/HIV-1 therapy.