2016年 · 第129卷第09期

The last Monday in February is the "Rare Disease Day" every year. This year the theme of it is "Join us in making the voice of rare diseases heard", proposed by World Health Organization (http://www.rarediseaseday.org). Rare diseases are a group of serious chronic diseases, with a high morbidity and mortality rates. Most of the rare diseases (about 80%) are caused by genetic variants.^[1]A specific rare disease generally has a low prevalence, which is about 0.10-0.75% in the United States and the European Union definition; however, with a great variety of rare diseases (about 6000-8000 reported in http://www.orpha.net), the total number of the patients is considerable. In China, a country with the largest population in the world, rare diseases are not uncommon, and the number of the patients affected by rare diseases is great. Therefore, we should pay much more attention to rare diseases, and more focuses on basic and clinical researches on these diseases are needed in China.

Among patients with Charcot–Marie–Tooth disease (CMT), the X-linked variant (CMTX) caused by gap junction protein beta 1 (GJB1) gene mutation is the second most frequent type, accounting for approximately 90% of all CMTX. More than 400 mutations have been identified in the GJB1 gene that encodes connexin 32 (CX32). CX32 is thought to form gap junctions that promote the diffusion pathway between cells. GJB1 mutations interfere with the formation of the functional channel and impair the maintenance of peripheral myelin, and novel mutations are continually discovered.

We included 79 unrelated patients clinically diagnosed with CMT at the Department of Neurology of the Chinese People’s Liberation Army General Hospital from December 20, 2012, to December 31, 2015. Clinical examination, nerve conduction studies, and molecular and bioinformatics analyses were performed to identify patients with CMTX1.

Nine GJB1 mutations (c.283G>A, c.77C>T, c.643C>T, c.515C>T, c.191G>A, c.610C>T, c.490C>T, c.491G>A, and c.44G>A) were discovered in nine patients. Median motor nerve conduction velocities of all nine patients were < 38 m/s, resembling CMT Type 1. Three novel mutations, c.643C>T, c.191G>A, and c.610C>T, were revealed and bioinformatics analyses indicated high pathogenicity.

The three novel missense mutations within the GJB1 gene broaden the mutational diversity of CMT1X. Molecular analysis of family members and bioinformatics analyses of the afflicted patients confirmed the pathogenicity of these mutations.

Paroxysmal kinesigenic dyskinesia (PKD) is the most common subtype of paroxysmal dyskinesias and is caused by mutations in PRRT2 gene. The majority of familial PKD was identified to harbor PRRT2 mutations. However, over two-third of sporadic PKD patients did not carry anyPRRT2 mutation, suggesting an existence of additional genetic mutations or possible misdiagnosis due to clinical overlap.

A cohort of 28 Chinese patients clinically diagnosed with sporadic PKD and excluded PRRT2 mutations were recruited. Clinical features were evaluated, and all subjects were screened for MR-1, SLC2A1, and CLCN1 genes, which are the causative genes of paroxysmal nonkinesigenic dyskinesia (PNKD), paroxysmal exertion-induced dyskinesia, and myotonia congenita (MC), respectively. In addition, 200 genetically matched healthy individuals were recruited as controls.

A total of 16 genetic variants including 4 in MR-1 gene, 8 in SLC2A1 gene, and 4 in CLCN1 gene were detected. Among them, SLC2A1 c.363G>A mutation was detected in one case, and CLCN1 c.1205C>T mutation was detected in other two cases. Neither of them was found in 200 controls as well as 1000 Genomes database and ExAC database. Both mutations were predicted to be pathogenic by SIFT and PolyPhen2. The SLC2A1 c.363G>A mutation was novel.

The phenotypic overlap may lead to the difficulty in distinguishing PKD from PNKD and MC. For those PRRT2-negative PKD cases, screening of SLC2A1 and CLCN1 genes are useful in confirming the diagnosis.

Deep brain stimulation (DBS) has been a promising treatment for patients with refractory Tourette syndrome (TS) for more than a decade. Despite successful DBS treatment of TS in more than 100 patients worldwide, studies with a large patient sample and long-term follow-up assessments are still scarce. Accordingly, we investigated the clinical efficacy and safety of globus pallidus internus (GPi) DBS in the treatment of intractable TS in 24 patients with a 1-year follow-up assessment.

Bilateral/unilateral GPi-DBS was performed in 24 patients with TS. We evaluated symptoms of tics and obsessive-compulsive disorder (OCD) through the Yale Global Tic Severity Scale (YGTSS) and Yale-Brown Obsessive-compulsive Scale (Y-BOCS). We used the Wechsler Adult Intelligence Scale-Revised in China (WAIS-RC) to evaluate the safety of the treatment. We conducted follow-up assessments of all patients for at least 12 months (12–99 months).

Symptoms of tics and OCD were significantly relieved at a 12-month follow-up assessment. The mean YGTSS score was 74.04 ± 11.52, 49.83 ± 10.91, 32.58 ± 7.97, and 31.21 ± 8.87 at baseline, 3, 6, and 12 months, respectively. The mean YGTSS scores obtained at the follow-up assessments were significantly different from the baseline (P < 0.05). The improvement in motor tics was superior to that in phonic tics. The mean Y-BOCS scores were 21.61 ± 4.97, 18 ± 4.58, 14.39 ± 3.99, and 13.78 ± 4.56 at baseline, 3, 6, and 12 months, respectively (P < 0.05). We observed a remarkable improvement in psychiatric comorbidities, such as OCD and attention-deficit hyperactivity disorder, after the procedure. WAIS-RC scores were comparable before and after the operation. There were no severe postoperative complications.

GPi-DBS appears to comprehensively alleviate tic symptoms and psychiatric comorbidities in patients with TS, thus significantly improving patients’ quality of life.

The appropriate elbow position of short-segment nerve conduction study (SSNCS) to diagnose cubital tunnel syndrome (CubTS) is still controversial. The goal of this study was to determine the effect of different elbow positions at full extension and 70° flexion on SSNCS in CubTS.

In this cross-sectional study, the clinical data of seventy elbows from 59 CubTS patients between September, 2011 and December, 2014 in the Peking University First Hospital were included as CubTS group. Moreover, thirty healthy volunteers were included as the healthy group. SSNCS were conducted in all subjects at elbow full extension and 70° elbow flexion. Paired nonparametric test, bivariate correlation, Bland–Altman, and Chi-squared test analysis were used to compare the effectiveness of elbow full extension and 70° flexion elbow positions on SSNCS in CubTS patients.

Data of upper limit was calculated from healthy group, and abnormal latency was judged accordingly. CubTS group’s latency and compound muscle action potential (CMAP) of each segment at 70° elbow flexion by SSNCS was compared with full extension position, no statistically significant difference were found (all P > 0.05). Latency and CMAP of each segment at elbow full extension and 70° flexion were correlated (all P < 0.01), except the latency of segment of 4 cm to 6 cm above elbow (P = 0.43), and the latency (P = 0.15) and the CMAP (P = 0.06) of segment of 2 cm to 4 cm below elbow. Bivariate correlation and Bland–Altman analysis proved the correlation between elbow full extension and 70° flexion. Especially in segments across the elbow (2 cm above the elbow and 2 cm below it), latency at elbow full extension and 70° flexion were strong direct associated (r = 0.83, P < 0.01; r = 0.55, P < 0.01), and so did the CMAP (r = 0.49, P < 0.01; r = 0.72, P < 0.01). There was no statistically significant difference in abnormality of each segment at full extension as measured by SSNCS compared with that at 70° flexion (P > 0.05, respectively).

There was no statistically significant difference in the diagnosis of CubTS with the elbow at full extension compared with that at 70° flexion during SSNCS. We suggest that elbow positon at full extension can also be used during SSNCS.

Single-fiber electromyography (SFEMG) has been suggested as a quantitative method for supporting chronic partial denervation in amyotrophic lateral sclerosis (ALS) by the revised EI Escorial criteria. Although concentric needle (CN) electrodes have been used to assess jitter in myasthenia gravis patients and healthy controls, there are few reports using CN electrodes to assess motor unit instability and denervation in neurogenic diseases. The aim of this study was to determine whether quantitative changes in jitter and spike number using CN electrodes could be used for ALS studies.

Twenty-seven healthy controls and 23 ALS patients were studied using both CN and single-fiber needle (SFN) electrodes on the extensor digitorum communis muscle with an SFEMG program. The SFN-jitter and SFN-fiber density data were measured using SFN electrodes. The CN-jitter and spike number were measured using CN electrodes.

The mean CN-jitter was significantly increased in ALS patients (47.3 ± 17.0 μs) than in healthy controls (27.4 ± 3.3 μs) (P < 0.001). Besides, the mean spike number was significantly increased in ALS patients (2.5 ± 0.5) than in healthy controls (1.7 ± 0.3) (P < 0.001). The sensitivity and specificity in the diagnosis of ALS were 82.6% and 92.6% for CN-jitter (cut-off value: 32 μs), and 91.3% and 96.3% for the spike number (cut-off value: 2.0), respectively. There was no significant difference between the SFN-jitter and CN-jitter in ALS patients; meanwhile, there was no significant difference between the SFN-jitter and CN-jitter in healthy controls.

CN-jitter and spike number could be used to quantitatively evaluate changes due to denervation-reinnervation in ALS.

Differentiating intracerebral hemorrhage (ICH) from cerebral infarction as early as possible is vital for the timely initiation of different treatments. This study developed an applicable model for the ambulance system to differentiate stroke subtypes.

From 26,163 patients initially screened over 4 years, this study comprised 1989 consecutive patients with potential first-ever acute stroke with sudden onset of the focal neurological deficit, conscious or not, and given ambulance transport for admission to two county hospitals in Yutian County of Hebei Province. All the patients underwent cranial computed tomography (CT) or magnetic resonance imaging to confirm the final diagnosis based on stroke criteria. Correlation with stroke subtype clinical features was calculated and Bayes’ discriminant model was applied to discriminate stroke subtypes.

Among the 1989 patients, 797, 689, 109, and 394 received diagnoses of cerebral infarction, ICH, subarachnoid hemorrhage, and other forms of nonstroke, respectively. A history of atrial fibrillation, vomiting, and diabetes mellitus were associated with cerebral infarction, while vomiting, systolic blood pressure ≥180 mmHg, and age <65 years were more typical of ICH. For noncomatose stroke patients, Bayes’ discriminant model for stroke subtype yielded a combination of multiple items that provided 72.3% agreement in the test model and 79.3% in the validation model; for comatose patients, corresponding agreement rates were 75.4% and 73.5%.

The model herein presented, with multiple parameters, can predict stroke subtypes with acceptable sensitivity and specificity before CT scanning, either in alert or comatose patients. This may facilitate prehospital management for patients with stroke.

Dermatomyositis (DM) and polymyositis (PM) are common inflammatory myopathies whose immunopathogenic mechanisms remain poorly understood. The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is a type of cytoplasmic multiprotein inflammasome and is responsible for the activation of inflammatory reactivations. Responding to a wide range of exogenous and endogenous microbial or sterile stimuli, NLRP3 inflammasomes can cleave pro-caspase-1 into active caspase-1, which processes the pro-inflammatory cytokines pro-interleukin (IL)-1β and pro-IL-18 into active and secreted IL-1β and IL-18. The NLRP3 inflammasome is implicated in infectious and sterile inflammatory diseases. However, it remains unclear whether it is involved in the pathogenesis of DM/PM, which we aim to address in our research.

In this study, 22 DM/PM patients and 24 controls were recruited. The protein and RNA expression of IL-1β, IL-18, NLRP3, and caspase-1 in serum and muscle samples were tested and compared between the two groups.

The serum IL-1β and IL-18 levels were significantly higher in DM/PM patients than those in the controls by enzyme linked immunosorbent assay (ELISA, DM vs. control, 25.02 ± 8.29 ng/ml vs. 16.49 ± 3.30 ng/ml, P < 0.001; PM vs. control, 26.49 ± 7.79 ng/ml vs. 16.49 ± 3.30 ng/ml, P < 0.001). Moreover, the real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) showed that DM/PM patients exhibited higher RNA expression of IL-1β, IL-18, and NLRP3 in the muscle (for IL-1β, DM vs. control, P = 0.0012, PM vs. control, P = 0.0021; for IL-18, DM vs. control, P = 0.0045, PM vs. control, P = 0.0031; for NLRP3, DM vs. control, P = 0.0017, PM vs. control, P = 0.0006). Moreover, the protein expression of NLRP3 and caspase-1 in muscle samples of DM/PM patients were also significantly elevated compared to that in the muscles of the controls.

Our findings demonstrate that the NLRP3 inflammasome is implicated in the pathogenesis of DM/PM. High NLRP3 expression led to elevated levels of IL-1β and IL-18 and could be one of the factors promoting disease progress.

Proteasome subunits (PSMB) and transporter associated with antigen processing (TAP) loci are located in the human leukocyte antigen (HLA) Class II region play important roles in immune response and protein degradation in neurodegenerative diseases. This study aimed to explore the association between single nucleotide polymorphisms (SNPs) of PSMB and TAP and Parkinson’s disease (PD).

A case–control study was conducted by genotyping SNPs in PSMB8, PSMB9, TAP1, and TAP2 genes in the Chinese population. Subjects included 542 sporadic patients with PD and 674 healthy controls. Nine identified SNPs in PSMB8, PSMB9, TAP1, and TAP2 were genotyped through SNaPshot testing.

The stratified analysis of rs17587 was specially performed on gender. Data revealed that female patients carry a higher frequency of rs17587-G/G versus (A/A + G/A) compared with controls. But there was no significant difference with respect to the genotypic frequencies of the SNPs in PSMB8, TAP1, and TAP2 loci in PD patients.

Chinese females carrying the rs17587-G/G genotype in PSMB9 may increase a higher risk for PD, but no linkage was found between other SNPs in HLA Class II region and PD.

Talaromyces (Penicillium) marneffei (TM) is an emerging dimorphic human pathogenic fungus that is endemic to SoutheastAsia. TM mostly occurs as an opportunistic infection in patients with human immunodeficiency virus (HIV). The objective of this study was to compare the clinical and laboratory parameters of patients with TM infections who were HIV-positive and HIV-negative and to assess therapies and outcomes.

This was a retrospective analysis of 26 patients diagnosed with disseminated TM infection from September 2005 to April 2014 at Fujian Provincial Hospital, China.

Patients with TM infection tend to present with fever, weight loss, and anemia. The time from symptom onset to confirmed diagnosis was greater for HIV-negative patients (n = 7; median: 60 days, range: 14–365 days) than for HIV-positive patients (n = 19; median: 30 days, range: 3–90 days, Mann–Whitney U = 31.50, P = 0.041). HIV-negative patients were more likely to have dyspnea (57.1% vs. 5.3%, χ² = 8.86, P = 0.010), low neutrophil count (Mann–Whitney U = 27.00, P = 0.029), high CD4 count (Mann–Whitney U = 0.00, P = 0.009), and high lymphocyte count (Mann–Whitney U = 21.00, P = 0.009). There were no significant differences in other demographic, clinical, or biochemical characteristics. Among all the patients, 12 HIV-positive patient and 1 HIV-negative patient received amphotericin and fluconazole treatment, 9 of whom improved, 1 died, 2 had kidney damage, 1 had hypokalemia due to exceeded doses.

HIV-negative patients with TM infections tend to have a longer diagnostic interval, a higher percentage of dyspnea, higher levels of CD4 and lymphocytes, and lower neutrophil counts than TM infection in HIV-positive patients. Treatment programs with amphotericin and fluconazole are mostly effective.

The one-step method was routine practices in China, scientific evidence to support this intervention is scarce. The purpose of this study was to observe the natural process of head-to-body delivery interval by waiting for at least one contraction (two-step) after head delivered in normal birth.

From March 1 to March 30 in 2015 at Haikou Maternal and Child Hospital in China, normal vaginal birth with normal baby condition were recorded by video. Videotapes were transferred to computer then replayed and observed.

Ninety-two cases were enrolled in this study. The average head-to-body delivery interval by two-step delivery was 71.04 ± 61.02 s, (mean + 2 standard deviation = 193.07 s, 95% confidence interval [15.65–229.15] s). Fifty-one patients (51/92, 55.43%) were <60 s, 41 patients (41/92, 44.57%) were over 60 s. Shoulders delivered at the first contraction were 96.74% (89/92), 3.26% (3/92) had delivered by the second contraction. Shoulders emerged from perineum were 71.73% (66/92), 15.21% (14/92) transversely, and 13.04% (12/92) emerged from under pubic arch. Babies cried before the shoulder were 31.52% (29/92), cried after birth 52.17% (48/92), and 16.30% (15/92) did not cry after birth. Baby activities included as making faces, sucking, and bubbled from mouth and noses, and the lighter blue color of skin with good perfusion.

The average time of head-to-body delivery interval was longer than 60 s by two-step delivery. Majority shoulders were delivered at the first contraction. Majority shoulders emerged from perineum rather from under pubic arch. The routine one-step method of shoulder delivery where the downward force applied is not necessary and is not the right direction. Baby’s breath, making faces, sucking, bubble from noses and mouth, and the light blue color of the faces, all those signs during shoulder delivery indicated a normal live birth.

Gastrojejunostomy (GJJ) and endoscopic stenting (ES) are palliative treatments for gastric outlet obstruction (GOO) caused by gastric cancer. We compared the outcomes of GJJ with ES by performing a meta-analysis.

Clinical trials that compared GJJ with ES for the treatment of GOO in gastric cancer were included in the meta-analysis. Procedure time, time to resumption of oral intake, duration of hospital stay, patency duration, and overall survival days were compared using weighted mean differences (WMDs). Technical success, clinical success, procedure-related mortality, complications, the rate of re-obstruction, postoperative chemotherapy, and reintervention were compared using odds ratios (ORs).

Nine studies were included in the analysis. Technical success and clinical success were not significantly different between the ES and GJJ groups. The ES group had a shorter procedure time (WMD = −80.89 min, 95% confidence interval [CI] = −93.99 to −67.78, P < 0.001), faster resumption of oral intake (WMD = −3.45 days, 95% CI = –5.25 to −1.65, P < 0.001), and shorter duration of hospital stay (WMD = −7.67 days, 95% CI = −11.02 to −4.33, P < 0.001). The rate of minor complications was significantly higher in the GJJ group (OR = 0.13, 95% CI = 0.04–0.40, P < 0.001). However, the rates of major complications (OR = 6.91, 95% CI = 3.90–12.25, P < 0.001), re-obstruction (OR = 7.75, 95% CI = 4.06–14.78, P < 0.001), and reintervention (OR = 6.27, 95% CI = 3.36–11.68, P < 0.001) were significantly lower in the GJJ group than that in the ES group. Moreover, GJJ was significantly associated with a longer patency duration (WMD = −167.16 days, 95% CI = −254.01 to −89.31, P < 0.001) and overall survival (WMD = −103.20 days, 95% CI = −161.49 to −44.91, P = 0.001).

Both GJJ and ES are effective procedures for the treatment of GOO caused by gastric cancer. ES is associated with better short-term outcomes. GJJ is preferable to ES in terms of its lower rate of stent-related complications, re-obstruction, and reintervention. GJJ should be considered a treatment option for patients with a long life expectancy and good performance status.

Discovery of the spectrum of autoimmune encephalitis (AIE) is among the most attractive events of neurology in the past decade. AIE includes a heterogeneous group of encephalitic syndromes, which generally include two major categories: classic paraneoplastic limbic encephalitis (LE) associated with the so-called well-characterized onconeural autoantibodies against intracellular neuronal antigens (e.g., Hu, Ma2, etc.) and new-type AIE associated with autoantibodies to the neuronal surface or synaptic antigens.^[1]Paraneoplastic LE occurs in the context of malignant tumors and results from an immunological response to tumor antigens, which mimic intracellular antigens expressed in neurons. The autoantibodies in this situation might not be pathogenic but can serve as diagnostic markers for paraneoplastic LE. The new-type AIE occurs in association with pathogenic autoantibodies against synaptic receptors or membrane antigens, and the binding of autoantibodies to their targets causes neuronal dysfunction, usually irreversibly. Over a dozen new-type autoantibodies have been identified since the discovery of anti-N-methyl-D-aspartate receptor (NMDAR) antibody by Dalmauet al.in 2007.^[2]Most of these autoantibodies associated with specific and well-characterized symptoms and the detection of these autoantibodies confirm the diagnosis. Since the introduction and establishment of the diagnostic test for anti-NMDAR antibody in China in 2010,^[3]hundreds of cases of AIE have been diagnosed and treated, which has changed our clinical approach to encephalitis management. The following sections will focus on a few recent advances as well as related clinical research on AIE in China.

Severe acute pancreatitis (AP) remains a challenge in clinical practice, and there are no internationally agreed specific therapies.^[1]Severe AP typically presents with epigastric pain, abdominal distention, vomiting, and constipation at the early stage and is similar to the Yangming-Fushi syndrome of traditional Chinese medicine (TCM). The Chinese herbal ointment Liu-He-Dan (LHD) has been adapted for the treatment of AP with Yangming-Fushi syndrome externally on belly for many years in our hospital. However, the potential mechanism of LHD in the treatment of severe AP has not been elucidated. Therefore, the present study sought to evaluate the effect of LHD on AP patients and preliminarily investigate its anti-inflammatory mechanism.

Tibial plateau fractures represent approximately 1% of all fractures which have been reported to commonly accompany by soft tissue injuries.^[1]Neglect or missed diagnosis of such soft tissue injuries have negative effects on clinical outcome. In this article, we report a rare case of tibial plateau fracture combined with extensive soft tissue injuries, including bucket-handle tears (BHTs) of both the medial meniscus (MM) and the lateral meniscus (LM). The patient also had an anterior cruciate ligament (ACL) tibial avulsion fracture, which led to the formation of a loose body in the joint. If left untreated, all of these concomitant injuries could cause unpleasant residual symptoms, such as joint locking and loss of extension.

To the Editor: A 55-year-old homosexual man presented with complaints of right axillary redness for one week. He has been sexually active with a male partner during his travel to South China in hot weather about a month ago. Physical examination revealed redness in his right axillary area, which stained his white clothing [Figure 1a]. A lot of mobilePthirus pubisinsects were visible on his axillary hair in the affected area [Figure 1bandFigure 1c]. Dermatoscopy confirmed the presence ofP. pubison his right axillary hair [Figure 1d]. The patient was found with no other sexually transmitted diseases exceptP. pubiswith a detailed laboratory test and physical examination. Microbiological studies revealed no bacterial or fungal etiology. Cotton stained with axillary sweat was seen. No systemic illnesses, genital lesions, or pruritus outside the axilla area were observed. A diagnosis ofP. pubis-related pseudochromhidrosis of the axillary hairs was made. No lice or nits were detected in the beard, armpits, mustache, or eyelashes. No other sexually transmitted diseases were identified. The right axillary area was shaved and treated with 10% sulfur ointment once daily for 3 days. The patient was advised to wash all clothing and fomites with insecticide. The color vanished quickly. Two weeks later, the itching was resolved and the nits disappeared. No relapse or recurrence was observed over a 12-month follow-up.