Palmitoylation-dependent control of JAK1 kinase signaling governs responses to neuropoietic cytokines and survival in DRG neurons.

Janus Kinase-1 (JAK1) plays key roles during neurodevelopment and following neuronal injury, while activatory JAK1 mutations are linked to leukemia. In mice, Jak1 genetic deletion results in perinatal lethality, suggesting non-redundant roles and/or regulation of JAK1 for which other JAKs cannot compensate. Proteomic studies reveal that JAK1 is more likely palmitoylated compared to other JAKs, implicating palmitoylation as a possible JAK1-specific regulatory mechanism. However, the importance of palmitoylation for JAK1 signaling has not been addressed. Here, we report that JAK1 is palmitoylated in transfected HEK293T cells and endogenously in cultured Dorsal Root Ganglion (DRG) neurons. We further use comprehensive screening in transfected non-neuronal cells and shRNA-mediated knockdown in DRG neurons to identify the related enzymes ZDHHC3 and ZDHHC7 as dominant protein acyltransferases (PATs) for JAK1. Surprisingly, we found palmitoylation minimally affects JAK1 localization in neurons, but is critical for JAK1's kinase activity in cells and even in vitro. We propose this requirement is likely because palmitoylation facilitates transphosphorylation of key sites in JAK1's activation loop, a possibility consistent with structural models of JAK1. Importantly, we demonstrate a leukemia-associated JAK1 mutation overrides the palmitoylation-dependence of JAK1 activity, potentially explaining why this mutation is oncogenic. Finally, we show that JAK1 palmitoylation is important for neuropoietic cytokine-dependent signaling and neuronal survival and that combined Zdhhc3/7 loss phenocopies loss of palmitoyl-JAK1. These findings provide new insights into the control of JAK signaling in both physiological and pathological contexts.

Comorbidity of Myasthenia gravis and Graves' disease as immune reconstitution-associated autoimmune disease in HIV infection: A case report and literature review.

BACKGROUND: Comorbidity of Myasthenia gravis (MG) and Graves' disease (GD) in treated HIV-infected individuals has rarely been described and little study has been done on the link between HIV-related immune reconstitution and autoimmune diseases occurring post antiretroviral therapy. CASE PRESENTATION: Here we report on a 33-year-old Chinese man with HIV infection who had been virologically suppressed since 2018. The patient was diagnosed with GD and was treated in 2020. Early in 2022, he developed fluctuating weakness and fatigue involving the bilateral extraocular muscles and limbs. With a positive neostigmine test, he was considered to have MG, but showed a poor response to oral medication. After multiple failed medication attempts, a thymectomy was finally performed to resolve his symptoms. The consecutive onset of immunological events may have partially resulted from immune reconstitution after viral control. CONCLUSIONS: This is a rare case of HIV-related immune reconstitution-associated autoimmune disease (IRAD) with comorbidity of MG and GD which was reported initially. Cooperation with multidisciplinary teams is essential to avoid misdiagnosis and to promote the overall health of HIV-infected patients.

The difference in nerve ultrasound and motor nerve conduction studies between autoimmune nodopathy and chronic inflammatory demyelinating polyneuropathy.

INTRODUCTION/AIMS: Nerve enlargement has been described in autoimmune nodopathy and chronic inflammatory demyelinating polyneuropathy (CIDP). However, comparisons of the distribution of enlargement between autoimmune nodopathy and CIDP have not been well characterized. To fill this gap, we explored differences in the ultrasonographic and electrophysiological features between autoimmune nodopathy and CIDP. METHODS: Between March 2015 and June 2023, patients fulfilling diagnostic criteria for CIDP were enrolled; among them, those with positive antibodies against nodal-paranodal cell-adhesion molecules were distinguished as autoimmune nodopathy. Nerve ultrasound and nerve conduction studies (NCS) were performed. RESULTS: Overall, 114 CIDP patients and 13 patients with autoimmune nodopathy were recruited. Cross-sectional areas (CSA) at all sites were larger in patients with CIDP and autoimmune nodopathy than in healthy controls. CSAs at the roots and trunks of the brachial plexus were significantly larger in patients with anti-neurofascin-155 (NF155), anti-contactin-1 (CNTN1), and anti-contactin-associated protein 1 (CASPR1) antibodies than in CIDP patients. The patients with anti-NF186 antibody did not have enlargement in the brachial plexus. NCS showed more frequent probable conduction block at Erb's point in autoimmune nodopathy than in CIDP (61.9% vs. 36.6% for median nerve, 52.4% vs. 39.5% for ulnar nerve). Markedly prolonged distal motor latencies were also present in autoimmune nodopathy. DISCUSSION: Patients with autoimmune nodopathies had distinct distributions of peripheral nerve enlargement revealed by ultrasound, as well as distinct NCS patterns, which were different from CIDP. This suggests the potential utility of nerve ultrasound and NCS to supplement clinical characteristics for distinguishing nodopathies from CIDP.

Neuromuscular ultrasound in combination with nerve conduction studies helps identify inflammatory motor neuropathies from lower motor neuron syndromes.

BACKGROUND AND PURPOSE: Identifying patients with inflammatory motor neuropathies (IMNs) is warranted since effective treatments are available and the prognosis of these patients differs from that of amyotrophic lateral sclerosis patients. METHODS: Between January 2019 and May 2022, 102 consecutive treatment-naïve lower motor neuron syndrome (LMNS) patients were recruited; these patients were suspected of having multifocal motor neuropathy, pure motor chronic inflammatory demyelinating polyneuropathy or amyotrophic lateral sclerosis with initial lower motor neuron presentation. Neuromuscular ultrasound (US) and nerve conduction studies (NCSs) were conducted at baseline. Relevant diagnostic investigations were performed if clinically warranted. The proposed US evidence of IMN was as follows: (i) nerve enlargement at ≥1 of the predetermined sites or (ii) absence of high intensity fasciculations in predefined muscle groups. Final diagnoses were made by experienced physicians after a prolonged follow-up period (≥12 months). IMN patients were defined as LMNS patients who experienced convincing improvements in response to immunotherapies. IMN patients without electrodiagnostic demyelinating features were diagnosed with treatment-responsive LMNS (TR-LMNS). RESULTS: In total, 16 patients were classified as IMN, including nine chronic inflammatory demyelinating polyneuropathy/multifocal motor neuropathy patients and seven TR-LMNS patients. Six TR-LMNS patients were identified by neuromuscular US. The sensitivity and specificity of NCSs, nerve US and muscle US were 56.3% and 100%, 43.8% and 90.7% and 68.8% and 97.7%, respectively. When these three modalities were combined, the sensitivity and specificity were 93.8% and 88.4%, respectively. CONCLUSION: Neuromuscular US studies are supplementary modalities to NCSs, and the combined use of these techniques might improve the identification of IMNs in LMNS patients.

Pembrolizumab for the treatment of progressive multifocal leukoencephalopathy in China.

The aim of this study is to analyze the clinical characteristics and outcomes of Chinese patients with progressive multifocal leukoencephalopathy (PML) who were treated with programmed cell death protein 1 (PD1) blockade therapies. We retrospectively analyzed patients who were admitted to our hospital between October 1, 2020, and October 1, 2022, diagnosed with PML and treated with PD1 blockade therapies. Four patients with PML who were treated with PD1 blockade therapies were identified. All patients were male, and their ages ranged from 19 to 54 years old. One patient (Case 2) exhibited mild pleocytosis, while three patients (Cases 2-4) had markedly reduced T lymphocyte cell counts prior to treatment. The time interval between symptom onset and treatment initiation ranged from six to 54 weeks. All patients received pembrolizumab treatment, with a total of two to four doses administered. Three patients who responded to pembrolizumab treatment showed clinical improvement starting around 8 weeks after the initiation of therapy. Although one patient did not show clinical improvement, they ultimately survived until the last follow-up. None of the patients in this study exhibited immune-related adverse events or immune reconstitution inflammatory syndrome. PD1 blockade appears to be a promising novel therapeutic option for PML; additional prospective studies are necessary to confirm its efficacy.

Differentiation Between Amyotrophic Lateral Sclerosis and Mimics Using Quantitative Analysis of Fsciculation with Muscle Ultrasound.

Objective To determine the diagnostic accuracy of the intensity of fasciculation evaluated by muscle ultrasound in the differential diagnosis of amyotrophic lateral sclerosis (ALS). Methods We prospectively recruited patients who had ALS and neuropathy-radiculopathy attending Peking Union Medical College Hospital from 2017 to 2020. Healthy adults from a community were recruited as healthy controls. Muscle strength was assessed using the Medical Research Council (MRC) scale. At the first visit to the hospital, patients were assessed for maximal grade of fasciculations, total fasciculation score, and fasciculation grade in 16 muscle groups of bilateral upper and lower limbs using ultrasonography. The sensitivity and specificity of maximal grade of fasciculations, total fasciculation score, and fasciculation grade for the diagnosis of ALS were assessed by receiver operating characteristic analyses. Results The percentage of limb muscles with a maximal fasciculation grade higher than grade 2 in ALS patients and neuropathy-radiculopathy patients was 84.9% and 9.8%, respectively (χ2 = 172.436, P < 0.01). Of the 16 limb muscles detected, the total fasciculation score [median (interquartile range)] was 29 (15, 41) in ALS patients and 3 (0, 8) in neuropathy-radiculopathy patients (Z = 9.642, P < 0.001). Remarkable fasciculations were seen in ALS patients whose muscles with a MRC score ranging from 2 to 4, followed by patients with MRC score 5, and then in those with MRC score 0 and 1. The sensitivity and specificity of total fasciculation score for diagnosis of ALS were 80.6% and 93.4%, respectively (cut-off value 14). In patients with ALS, for muscles with MRC score 4 and 5, the percentage of muscles with fasciculation grades ≥ 3 was 42.3% and 24.1% respectively, while in neuropathy-radiculopathy patients, the percentage for muscles with MRC score 4 and 5 was only 1.7% and 0, respectively. Conclusion A combined analysis of fasciculation intensity and MRC score of the limb muscles may be helpful for differential diagnosis of ALS.

Chronic inflammatory demyelinating polyradiculoneuropathy concomitant with nephropathy.

BACKGROUND: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of the most common autoimmune peripheral neuropathies in adults. Membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), and other nephropathy have been reported in CIDP patients and are possibly correlated to CIDP pathogenesis. This study reviewed the previously described cases of patients with CIDP and nephropathy in order to provide comprehensive evidence on the diagnosis and treatment regarding CIDP patients in the context of renal diseases. METHOD: We reviewed our database to identify patients with CIDP and nephropathy. Online database including PubMed, EMBASE, and OVID were searched for relevant cases. RESULTS: We identified a total of 18 cases with CIDP and nephropathy, including 2 cases from our database and 16 ones from online searching. A predominance of male was observed [14 (77.8%)] with the mean age of 53.3 (standard deviation, SD: 16.6) years old. Almost all patients complained paresthesia in distal limbs (94.4%), except one only presented weakness of four extremities. Corticosteroids were prescribed for 14 (77.8%) patients, and 10 showed responsiveness. Three patients experienced relapses during the gradual tapering of steroids. CONCLUSION: The same immune-mediated pathogenesis may be involved in CIDP and concomitant nephropathy. Male and sensory-predominant CIDP are red flags for complications of renal diseases in CIDP patients. Corticosteroids remain the first-line treatment for CIDP when complicated with renal diseases. Slower tapering or long-term maintenance of steroids may be beneficial for the prognosis of patients with CIDP and nephropathy.

Nerve ultrasound may help predicting response to immune treatment in chronic inflammatory demyelinating polyradiculoneuropathy.

BACKGROUNDS: Nerve ultrasound has been proven to be an accurate tool in diagnosing chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, its value in guiding treatment has not been well evaluated. The aim of this study was to explore whether nerve ultrasound and its changing trend could predict the response to immune treatment in CIDP. METHODS: Eighty-nine therapy-naive CIDP patients were recruited prospectively and treated with steroids and/or intravenous immunoglobulin (IVIG). Ultrasonographic and electrophysiological studies were performed on the median and ulnar nerves before treatment in all patients and followed up in 45 patients. The cross-sectional area (CSA) was measured at ten sites on both the median and ulnar nerves. RESULTS: The response rate to steroids (95%) was significantly higher than that to IVIG (70%) (P = 0.001) in patients with normal or moderately enlarged CSA, while there was no significant difference in the response rate between steroid therapy (84%) and IVIG (75%) (P = 0.653) in patients with markedly enlarged CSA. CSAs decreased in 15 patients during follow-up, most of whom had good IVIG and steroid responses (83%) and no need for immune suppressant treatment (82%). CONCLUSIONS: Nerve ultrasonography could help guide treatment strategies in patients with CIDP. Patients with normal or moderately enlarged CSA may respond better to steroids than to IVIG. The decrease in CSA after treatment may also indicate better prognosis.

The palmitoyl acyltransferases ZDHHC5 and ZDHHC8 are uniquely present in DRG axons and control retrograde signaling via the Gp130/JAK/STAT3 pathway.

Palmitoylation, the modification of proteins with the lipid palmitate, is a key regulator of protein targeting and trafficking. However, knowledge of the roles of specific palmitoyl acyltransferases (PATs), which catalyze palmitoylation, is incomplete. For example, little is known about which PATs are present in neuronal axons, although long-distance trafficking of palmitoyl-proteins is important for axon integrity and for axon-to-soma retrograde signaling, a process critical for axon development and for responses to injury. Identifying axonally targeted PATs might thus provide insights into multiple aspects of axonal biology. We therefore comprehensively determined the subcellular distribution of mammalian PATs in dorsal root ganglion (DRG) neurons and, strikingly, found that only two PATs, ZDHHC5 and ZDHHC8, were enriched in DRG axons. Signals via the Gp130/JAK/STAT3 and DLK/JNK pathways are important for axonal injury responses, and we found that ZDHHC5 and ZDHHC8 were required for Gp130/JAK/STAT3, but not DLK/JNK, axon-to-soma signaling. ZDHHC5 and ZDHHC8 robustly palmitoylated Gp130 in cotransfected nonneuronal cells, supporting the possibility that Gp130 is a direct ZDHHC5/8 substrate. In DRG neurons, Zdhhc5/8 shRNA knockdown reduced Gp130 palmitoylation and even more markedly reduced Gp130 surface expression, potentially explaining the importance of these PATs for Gp130-dependent signaling. Together, these findings provide new insights into the subcellular distribution and roles of specific PATs and reveal a novel mechanism by which palmitoylation controls axonal retrograde signaling.

Nerve ultrasound studies in POEMS syndrome.

INTRODUCTION: The aim of our study was to assess the ultrasonographic features of peripheral nerves in patients with POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome. METHOD: 34 POEMS syndrome patients and 26 healthy control (HC) participants were recruited prospectively. Cross-sectional area (CSA) was measured in nerves of limbs, trunks of brachial plexus, and cervical nerve roots RESULTS: The CSAs were mildly enlarged at the arm segment of median nerve, elbow segment of ulnar nerve and upper trunk, moderately enlarged at the forearm segment of both median and ulnar nerve, upper trunk of brachial plexus, and C6, C7 cervical nerve roots, and markedly enlarged at the arm segment of ulnar nerve, middle and lower trunk of brachial plexus, as well as C5 cervical root. DISCUSSION: The CSAs of upper limb nerves were larger in POEMS syndrome patients than in HCs, and the enlargements were most prominent proximally.

Fasciculation differences between ALS and non-ALS patients: an ultrasound study.

BACKGROUND: Fasciculation is an important sign for the diagnosis of amyotrophic lateral sclerosis (ALS). Our study aimed to analyze the difference in fasciculation detected with muscle ultrasonography (MUS) between ALS patients and non-ALS patients with symptoms resembling ALS. METHODS: Eighty-eight ALS patients and fifty-four non-ALS (eight multifocal motor neuropathy, 32 chronic inflammatory demyelinating polyneuropathy/Charcot-Marie-Tooth, and 14 cervical spondylopathy or lumbar spondylopathy) patients were recruited. MUS was performed on 19 muscle groups in cervical, lumbosacral, bulbar, and thoracic regions for each patient. The intensity of fasciculation was divided into five grades based on firing frequency and number in the involved muscle groups. RESULTS: The overall detection rates were 72.8% in ALS and 18% in non-ALS patients. The fasciculation grades (median [IQR]) were 2 (0-3) in ALS and 0 (0-0) in non-ALS patients (P < 0.001). Fasciculations were observed in four regions for ALS patients and primarily distributed in proximal limbs. Fasciculations in non-ALS patients were primarily low-grade and mostly distributed in distal limbs. DISCUSSION: The fasciculation grade was higher in ALS than non-ALS patients. The distribution pattern of fasciculation was different between ALS and non-ALS patients. CONCLUSIONS: The fasciculation grade and distribution pattern detected with MUS could help distinguish ALS from non-ALS patients.

BAG3-Related Myofibrillar Myopathy Presenting as Hypercapnia: A Case Report and Literature Review.

Objective BAG3-related myopathy is a rare condition so far reported in twenty patients worldwide. The purpose of this study was to draw attention to this rare disease and to the fact that BAG3-related myopathy should be considered as a rare differential diagnosis of hypercapnia. Methods We report a sporadic case of a 14-year-old Chinese girl with a de novo p.Pro209Leu mutation in BAG3 and reviewed the literatures for reported cases related to this mutation. Results We described a 14-year-old Chinese girl who presented with gradually appearing symptoms of hypercapnia that required assisted ventilation. The muscle biopsy and the blood whole-exome sequencing results confirmed the diagnosis of myofibrillar myopathy with a de novo p.Pro209Leu mutation in BAG3. Totally twenty-one patients from twenty families with a confirmed diagnosis of BAG3-related myopathy were reported to date, including this patient and literature review. The male to female ratio was 11:10 and most showed initial symptoms in the first decade of life. Most patients presented toe/clumsy walking or running as the onset symptom, followed by muscle weakness or atrophy. Creatine kinase levels were elevated in fourteen patients and were normal in three. Eighteen patients developed respiratory insufficiency during the disease course and thirteen (one could not tolerate non-invasive assisted ventilation) required non-invasive assisted ventilation for treatment. Except for one not reported, heart involvement was found in seventeen patients during the disease course and seven underwent heart transplantation. Z-disk streaming and aggregation could be observed in most of the patients' muscle histology. In the long-term follow-up, five patients died of cardiac or respiratory failure. Conclusion BAG3-associated myopathy is a rare type of myofibrillar myopathy. It should be considered as a rare differential diagnosis of hypercapnia.

Abduction range: A potential parameter for the long exercise test in hypokalemic periodic paralysis during inter-attack periods.

BACKGROUND: The abduction range of the little finger in the long exercise test (ET) has rarely been reported in patients with hypokalemic periodic paralysis (HypoPP) during inter-attack periods, and the diagnostic value requires clarification. METHODS: The long ET was performed in 43 HypoPP patients during inter-attack periods and in 20 healthy controls (HCs). The compound muscle action potential (CMAP) and the abduction range of the little finger were recorded concurrently. RESULTS: There were significant differences in the percent changes of the CMAP amplitudes and the abduction ranges after exercise between HypoPP patients and the HCs. The curve of percent changes in abduction ranges overlapped substantially with that of the CMAP amplitudes, and the sensitivity, specificity, and cutoff values were 0.860, 0.900, and 22.6%, respectively. CONCLUSIONS: The abduction range of the little finger can serve as a novel parameter in the long ET for the diagnosis of HypoPP during inter-attack periods.

Cross-sectional area reference values for sonography of nerves in the upper extremities.

INTRODUCTION: Detailed morphological features of the peripheral nerves could improve the diagnostic sensitivity in some polyneuropathies. In this study we aimed to establish multiple-site, cross-sectional area (CSA) reference values for peripheral nerves of upper extremities in a healthy Chinese population. METHODS: One hundred eleven healthy subjects, 15 to 70 years of age, were prospectively recruited. CSA at predetermined sites of the median, ulnar, radial nerves, and brachial plexus was measured bilaterally. Ten consecutive sites were studied along the median/ulnar nerves. RESULTS: The CSA at ten sites of the median nerve ranged from 5.59 ± 0.89 to 8.43 ± 1.30 mm2 , and for the ulnar nerve from 2.94 ± 0.57 to 5.63 ± 1.08 mm2 . Both age and gender correlated with nerve CSA at most sites. DISCUSSION: CSA was not uniform along the length of the median and ulnar nerves. The multiple-site reference values could be helpful for investigating polyneuropathies in the Asian population.

Biopsy histopathology in the diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP).

AIM: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is an inherited rare disease affecting young adults. We present the clinical, imaging, and neuropathological results of our case series, emphasizing biopsy histology combined with clinical information will increase the accuracy of early diagnosis. METHODS: In total, 4 females and 2 male ALSP patients with onset at ages 24-45 years were enrolled. Clinical manifestations, neuroimaging, and histopathology as well as gene mutation were analyzed and compared with literature. RESULTS: Clinical manifestations include cognitive decline with/without psycho-behavior problems and movement disorders including paralysis, hemiplegia, parkinsonism, and pyramidal tract injury, as well as dysarthria, dysphagia, and sensory disturbances. MRI showed multiple periventricular and subcortical white matter lesions, involving the corpus callosum, with no enhancement, but with persistent hyperintensity on diffuse-weighted imaging. Histology showed widespread white matter damage and pale stain, especially destroyed axons with spheroids and funicular axons which were stained with neurofilament and ubiquitin. Foamy and pigmented macrophages were another typical change. CSF1R mutation was found in 4 of them. All of the patients were misdiagnosed and treated for a long time for multiple sclerosis, cerebral infarction, normal pressure hydrocephalus, etc. CONCLUSION: ALSP will cause rapidly progressing dementia with/without movement disorders in young adults. The definite diagnosis should be based on a comprehensive analysis of clinical manifestations, and neuroimaging, histology, and genetic results. Early biopsy will add to the accuracy of the diagnosis.

Serial nerve ultrasound and motor nerve conduction studies in chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION: The objective of this study was to evaluate the correlation between cross-sectional area (CSA) and nerve conduction studies (NCS) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to determine how CSA changes over time after standard treatment. METHODS: Fifty-four patients with CIDP were recruited prospectively, and 21 patients were followed for more than 6 months. Ultrasonography and motor NCS were performed in the median and ulnar nerves. RESULTS: No or weak correlation was observed between the maximum CSA and motor conduction velocity. There were segmental nerve enlargements at 61% of sites with conduction block or temporal dispersion. Among 19 patients with clinical improvement after immunotherapy, CSA decreased to normal in 5, increased in 10, and were unchanged in 4. DISCUSSION: Different patterns of CSA and motor NCS changes after immune treatment may indicate different CIDP pathologic mechanisms. Exploration of these pathologic mechanisms could guide treatment choices in the future. Muscle Nerve, 2019.

Single-fiber EMG with concentric electrodes in lambert-eaton myasthenia.

INTRODUCTION: We analyzed jitter recordings made with concentric needle electrode (CNE) single-fiber electromyography (SFEMG) in Lambert-Eaton myasthenia (LEM). METHODS: Fifteen subjects diagnosed with LEM were studied using CNE-SFEMG in the extensor digitorum (ED) and tibialis anterior (TA) muscles. CNE-SFEMG in the ED and TA was also used to evaluate 12 and 10 healthy controls (HCs), respectively. RESULTS: Ten men and 5 women were diagnosed with LEM based on an increase of 100% in compound muscle action potential amplitude during 50 Hz repetitive nerve stimulation. All patients exhibited markedly greater jitter in the ED (88.8 ± 23.2 µs) and TA (92.2 ± 30.2 µs) than HCs (28.3 ± 3.4 µs and 30.9 ± 5.1 µs, respectively). CONCLUSIONS: CNE-SFEMG is sensitive for discovering abnormalities in neuromuscular transmission in LEM. Muscle Nerve 56: 253-257, 2017.

The effect of CCR5Δ32 on the risk of grade 3-4 acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: A systematic review and meta-analysis.

OBJECTIVE: Many studies have showed that CCR5 was involved in the pathological process of acute graft-versus-host disease (aGVHD). However, the relationship between CCR5Δ32, a frameshift mutation, and grade 3-4 acute GVHD risk has not been well established. We performed a meta-analysis to explore the effects of CCR5 gene polymorphisms on grade 3-4 aGVHD. METHODS: PubMed, Embase, Web of Science, and Cochrane Library were searched to collect relevant articles. Studies about association between CCR5 genotype in recipients or donors of allo-HSCT and aGVHD risk were included. All pooled analyses were based on fixed effects models. The effects were assessed from odd ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of three studies comprising 937 recipients and 914 donors of allo-HSCT met the inclusion criteria. Compared with the wild-type CCR5 homozygotes, the pooled odd ratios (ORs) for CCR5Δ32 mutation (both homozygous and heterozygous) was 0.71 (95% CI, 0.40-1.26; P = .24) for donors, and 0.79 (95% CI, 0.35-1.81; P = .58) for recipients. No relationship was found between the presence of the CCR5Δ32 mutation and grade 3-4 aGVHD. Larger clinical investigations and retrospective studies are needed to explore the association of CCR5 gene polymorphisms with aGVHD risk as well as the outcome of HSCT.

Modality-based organization of ascending somatosensory axons in the direct dorsal column pathway.

The long-standing doctrine regarding the functional organization of the direct dorsal column (DDC) pathway is the "somatotopic map" model, which suggests that somatosensory afferents are primarily organized by receptive field instead of modality. Using modality-specific genetic tracing, here we show that ascending mechanosensory and proprioceptive axons, two main types of the DDC afferents, are largely segregated into a medial-lateral pattern in the mouse dorsal column and medulla. In addition, we found that this modality-based organization is likely to be conserved in other mammalian species, including human. Furthermore, we identified key morphological differences between these two types of afferents, which explains how modality segregation is formed and why a rough "somatotopic map" was previously detected. Collectively, our results establish a new functional organization model for the mammalian direct dorsal column pathway and provide insight into how somatotopic and modality-based organization coexist in the central somatosensory pathway.

Intracranial atherosclerosis in Chinese young adult stroke patients.

BACKGROUND: Until now, intracranial atherosclerosis has been less well studied because of its rarity. We sought to investigate the prevalence and risk factors of intracranial atherosclerosis in Chinese young adult stroke patients. METHODS: We retrospectively reviewed the medical records of consecutive young adult patients with first-ever ischemic stroke at our institution from May 2007 to May 2012. The demographic features and risk factors of intracranial large-artery atherosclerotic (LAA) stroke were analyzed by comparison with other stroke subtypes. RESULTS: One hundred ninety-seven patients (age 39±9 years, 127 male) were recruited. There were 81 (41%) patients with LAA stroke, including 68 (35%) strokes because of intracranial stenosis. Male gender (P=.001), dyslipidemia (P=.015), smoking (P<.001), hypertension (P<.001), hyperhomocysteinemia (P=.003), and family history of stroke (P=.024) were more common in patients with intracranial LAA stroke than with non-LAA stroke. A high percentage of patients with intracranial LAA stroke had multiple modifiable risk factors (ie, at least 2 of dyslipidemia, hypertension, diabetes mellitus, smoking, and hyperhomocysteinemia), much more than the patients with non-LAA stroke (82% versus 42%, P<.001). Simultaneous multiple modifiable risk factor exposure was the strongest "risk factor" for intracranial LAA stroke, with the adjusted odds ratio of 4.99. CONCLUSIONS: Intracranial atherosclerosis is highly prevalent in Chinese young stroke patients. Our results suggest that simultaneous exposure to multiple risk factors may contribute to the early development of intracranial atherosclerosis.