Positive association between urinary albumin-creatinine ratio and lower extremity peripheral arterial disease in Chinese diabetes patients: A cross-section study with propensity score matching analysis.

BACKGROUND AND AIMS: Elevated urinary albumin-creatinine ratio (ACR) is an established risk factor for lower extremity peripheral arterial disease (PAD) in non-diabetes individual. This study aimed to determine the relationship between urinary ACR level and PAD in diabetes population. METHODS AND RESULTS: A cross-section study with 1396 hospitalized diabetes participants from department of endocrinology and neurology were performed and the propensity score matching method was applied to reduce the effects of confounding factors between the matched PAD and Non-PAD groups. The relationship between urinary ACR and ankle-brachial index (ABI) was analyzed by linear curve fitting analyses and multiple logistic regression models. Our study showed that the prevalence of PAD (low ABI, ABI<0.9) was 7.09% in our diabetes patients. The ABI level was significantly lower in high ACR group compared with those in normal urinary ACR group (1.11 ± 0.17 vs 1.13 ± 0.15, p = 0.010). The prevalence of PAD was increased with the increased tertile's of log2-transformed ACR in total patients before and after propensity score matching (p < 0.001 and p = 0.007, respectively). The OR (95% CI) between log2-transformed ACR and PAD was 1.0 and 1.70 (1.08-2.69, p = 0.022) respectively in normal and high ACR levels in diabetes patients after adjusting for potential confounders. After propensity score matching, the OR (95% CI) between log2-transformed ACR and PAD was 1.0 and 1.85 (1.05-3.23, p = 0.031) respectively in normal and high ACR levels in diabetes patients after adjusting for potential confounders. CONCLUSION: The elevated urinary ACR level was associated with PAD in Chinese diabetes patients.

Rate-dependent depression is impaired in amyotrophic lateral sclerosis.

OBJECTIVE: We investigated rate-dependent depression (RDD) of the Hoffman reflex (H-reflex) in patients with amyotrophic lateral sclerosis (ALS), a degenerative disease with ventral horn involvement. PATIENTS AND METHODS: In this case-control study, we enrolled 27 patients with ALS and 30 matched healthy control subjects. Clinical and electrophysiological assessments, as well as RDD in response to various stimulation frequencies (0.5 Hz, 1 Hz, 3 Hz and 5 Hz), were compared between groups. Multiple clinical and electrophysiological factors were also explored to determine any underlying associations with RDD. RESULTS: The ALS group showed a significant loss of RDD across all frequencies compared to the control group, most notably following 1 Hz stimulation (19.1 ± 20.3 vs. 34.0 ± 13.7%, p = 0.003). Among factors that might influence RDD, the enlargement of the motor unit potential (MUP) showed a significant relationship with RDD following multifactor analysis of variance (p = 0.007) and Pearson correlation analysis (ρ = - 0.70, p < 0.001), while various upper motor neuron manifestations were not correlated with RDD values (p > 0.05). CONCLUSION: We report a loss of RDD in patients with ALS. The strong correlation detected between the RDD deficit and increased MUP suggests that RDD is a sensitive indicator of underlying spinal disinhibition in ALS. TRIAL REGISTRATION: ChiCTR2000038848, 10/7/2020 (retrospectively registered), http://www.chictr.org.cn/ .

Tau associated peripheral and central neurodegeneration: Identification of an early imaging marker for tauopathy.

Pathological hyperphosphorylated tau is a key feature of Alzheimer's disease (AD) and Frontotemporal dementia (FTD). Using transgenic mice overexpressing human non-mutated tau (htau mice), we assessed the contribution of tau to peripheral and central neurodegeneration. Indices of peripheral small and large fiber neuropathy and learning and memory performances were assessed at 3 and 6 months of age. Overexpression of human tau is associated with peripheral neuropathy at 6 months of age. Our study also provides evidence that non-mutated tau hyperphosphorylation plays a critical role in memory deficits. In addition, htau mice had reduced stromal corneal nerve length with preservation of sub-basal corneal nerves, consistent with a somatofugal degeneration. Corneal nerve degeneration occurred prior to any cognitive deficits and peripheral neuropathy. Stromal corneal nerve loss was observed in patients with FTD but not AD. Corneal confocal microscopy may be used to identify early neurodegeneration and differentiate FTD from AD.

Neurofascin antibodies in chronic inflammatory demyelinating polyradiculoneuropathy: from intrinsic genetic background to clinical manifestations.

There are bunch of autoantibodies, particularly autoantibodies against proteins located at the node of Ranvier, have been discovered and transformed the clinical management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurofascin (NF) plays an important role in both the nodal and paranodal regions of the node of Ranvier. In this review, we focus on the two characteristic forms of neurofascin: NF186 and NF155, comparing the similarities and differences between them, reviewing the current knowledge on genetic backgrounds, pathogenesis, clinical manifestations, and management of patients with anti-neurofascin positive CIDP. Autoantibodies against neurofascin were mainly IgG4 isotype. Mutation of NFASC gene in human causes severe neurodevelopment disorders, and HLA DRB1*15 may be a strong risk factor for the development of anti-NF155 antibodies. Motor impairment, sensory ataxia, and tremor were the typical presentations of patients with anti-NF155+ CIDP, while tetraplegia and cranial nerve involvement were more common in patients with anti-NF186+ CIDP. Recent studies have depicted a relatively clear picture of anti-NF155+ CIDP, and the strong clinical correlation of NF186 with CIDP remains unclear. The genetic background of neurofascin will assist in future explorations.

From PNS to CNS: characteristics of anti-neurofascin 186 neuropathy in 16 cases.

INTRODUCTION: Neurofascin (NF) is critical for the formation and maintenance of Ranvier nodes. NF186, the neuronal form of NF, localizes in the initial segment of axon and Ranvier node. NF186 antibody has been detected in demyelinating diseases of both central nervous system (CNS) and peripheral nervous system (PNS). AIMS: To evaluate the clinical features of patients with anti-NF186 IgG neuropathy. METHODS: Sixteen patients (16/138) with serum-positive anti-NF186 IgG were included and divided into groups of either CNS or PNS-involved according to their clinical manifestations. Anti-NF186 IgG was detected by cell-based assays. RESULTS: In 7 patients who were confirmed to have CNS involvement, the most frequent symptoms were dizziness (57%) and vision impairment (43%); lesions in centrum semiovale, cerebellum, and meninges were shown by magnetic resonance imaging (MRI). In comparison, limb weakness (78%) and numbness (78%) were the most common symptoms in PNS-involved patients; axonal loss and demyelination were confirmed by nerve conduction examinations. Elevated level of cerebrospinal fluid (CSF) protein was found in 12 cases without statistically significant difference between the CNS and PNS groups. Meanwhile, CSF white blood cell counts were found significantly elevated in CNS-involved patients compared with patients of PNS group. Thirteen patients received immunomodulating treatments, and patients with chronic onset and progressive course showed poor response to the therapies. CONCLUSIONS: Patients with anti-NF186 IgG neuropathy showed no specific symptoms or signs. It is worth noting that quite a few patients show CNS-impaired signs only, and cranial MRI is essential for the screening of CNS involvement.

TGFß1 transduction enhances immunomodulatory capacity of neural stem cells in experimental autoimmune encephalomyelitis.

Bone marrow-derived neural stem cells (BM-NSCs) have therapeutic effect on EAE, an animal model of multiple sclerosis. However, the beneficial effect is suboptimal due to the limited immunomodulatory capacity of these cells. In this study, we engineered BM-NSCs with inducible TGFß1, a potent immunosuppressive cytokine, to enhance their anti-inflammatory capacity. We found that i.v. injected TGFß1-BM-NSCs more effectively suppressed clinical severity, inflammation and demyelination of the central nervous system of EAE mice. Transduction of TGFß1 resulted in a higher percentage of Tregs and lower percentage of Th1 and Th17 cells in the periphery, with increased production of IL-10, and reduced production of IFN-γ, IL-17 and GM-CSF. Moreover, myelin-specific splenic proliferation was also inhibited more profoundly by TGFß1-BM-NSCs. We also found that TGFß1-BM-NSCs have the capacity to switch microglia from M1 to M2 phenotype. On the other hand, transduction of TGFß1 did not affect proliferative ability and differentiating potential of BM-NSCs in vitro and in vivo. Together, these findings demonstrate that transduction of TGFß1 significantly enhanced the immunomodulatory capacity of BM-NSCs for EAE treatment, through inducing Tregs and an M2 phenotype of macrophages/microglia, while retaining their capacity for neural cell differentiation. Thus, our study provides an easily accessible, inducible and effective therapy for CNS inflammatory demyelination.

CNS involvement in CMTX1 caused by a novel connexin 32 mutation: a 6-year follow-up in neuroimaging and nerve conduction.

X-linked Charcot-Marie-Tooth disease, type 1 (CMTX1) is one of the most common inherited neurological disorders. Obvious CNS involvement is relatively rare in CMTX1 patients. A 24-year-old male with CMTX1 presented with three transient stroke-like attacks, and was followed up regularly for 6 years with brain MRI and electrophysiological examination. Transient symmetrical high signals on T2 imaging and restricted diffusion were found in bilateral deep white matter. Electrophysiological measurement revealed a sensorimotor peripheral neuropathy with slightly reduced nerve conduction velocities. A novel thymine to cytosine mutation at nucleotide position 445 in the connexin 32 allele of the GJB1 gene was identified. During the 6-year longitudinal study, patient's motor and sensory function did not worsen; radiological abnormalities correlated with episodes of CNS dysfunction and resolved after clinical recovery; electrophysiological records showed no obvious change. Little change in the patient's clinical, radiological and electrophysiological results over the follow-up reflected a slow disease progression.

Fibrinogen deposition promotes neuroinflammation and fibrin-derived γ377-395 peptide ameliorates neurological deficits after ischemic stroke.

BACKGROUND: Fibrin(ogen) deposition in the central nervous system (CNS) contributes to neuropathological injury; however, its role in ischemic stroke is unknown. In this study, we identified fibrinogen as a novel proinflammatory regulator of post-stroke neuroinflammation and revealed the neuro-protection effect of fibrin-derived γ377-395peptide in stroke. METHODS: Fibrinogen depletion and fibrinogen-derived γ377-395peptide treatment were performed 2 h after establishing a permanent middle cerebral artery occlusion (pMCAO) model. The infarction volume, neurological score, fibrin(ogen) deposition, and inflammatory response were evaluated 24 h after occlusion. Both in vivo and in vitro studies were conducted to assess the therapeutic potential of the γ377-395peptide in blocking the interactions between fibrin(ogen) and neutrophils. RESULTS: Fibrin(ogen) deposited in the infarct core promoted post-stroke inflammation and exacerbated neurological deficits in the acute phase after stroke onset. Reducing fibrinogen deposition resulted in a decrease in infarction volume, improved neurological scores, and reduced inflammation in the brain. Additionally, the presence of neutrophil accumulation near fibrin(ogen) deposits was observed in ischemic lesions, and the engagement of fibrin(ogen) by integrin receptor αMß2 promoted neutrophil activation and post-stroke inflammation. Finally, inhibiting fibrin(ogen)-mediated neutrophil activation using a fibrinogen-derived γ377-395peptide significantly attenuated neurological deficits. CONCLUSIONS: Fibrin(ogen) is a crucial regulator of post-stroke inflammation and contributes to secondary brain injury. The inflammation induced by fibrin(ogen) is primarily driven by neutrophils during acute ischemic stroke and can be ameliorated using the fibrin-derived γ377-395peptide. Targeting the fibrin(ogen)-mediated neuropathological process represents a promising approach for neuroprotective therapy after stroke while preserving its beneficial coagulation function.

Risk Factors for Subclinical Diabetic Peripheral Neuropathy in Type 2 Diabetes Mellitus.

Purpose: To investigate the risk factors associated with subclinical diabetic peripheral neuropathy (sDPN) in patients with type 2 diabetes mellitus (T2DM). Patients and Methods: This cross-sectional, retrospective study involved 311 patients with T2DM who were successively admitted from January 2018 to December 2021 without any neurological symptoms. All participants underwent a nerve conduction study (NCS), and those asymptomatic patients with abnormal nerve conduction were diagnosed with sDPN. Differences between groups were evaluated by the chi-squared, Wilcoxon, or Fisher's exact test. Binary logistic regression analysis was performed to determine the independent risk factors for sDPN. Receiver operating characteristic (ROC) curves were constructed, and the areas under curves (AUCs) were detected. Results: Among 311 asymptomatic patients with T2DM, 142 (45.7%) with abnormal nerve conduction were diagnosed with sDPN. Patients with sDPN significantly differed from those without diabetic peripheral neuropathy (DPN) in age, history of hypertension, duration of diabetes, anemia, neutrophil-to-lymphocyte ratio, fasting C-peptide level, serum creatinine level, and albuminuria (all p<0.05). Furthermore, the duration of diabetes (odds ratio [OR]: 1.062, 95% confidence interval [CI]: 1.016-1.110), fasting C-peptide level (OR: 2.427, 95% CI: 1.126-5.231), and presence of albuminuria (OR: 2.481, 95% CI: 1.406-4.380) were independently associated with the development of sDPN (all p<0.05). The AUCs for fasting C-peptide level, duration of diabetes, and the two factors combined were 0.6229 (95% CI: 0.5603-0.6855, p=0.0002), 0.6738 (95% CI: 0.6142-0.7333, p<0.0001), and 0.6808 (95% CI: 0.6212-0.7404, p<0.0001), respectively. Conclusion: For patients with T2DM and longer duration of diabetes, lower fasting C-peptide levels, and presence with albuminuria, the risk for developing DPN is higher even if they have no clinical signs or symptoms. Identifying potential risk factors for the development of sDPN and effectively controlling them early are critical for the successful management of DPN.

Imaging of microglia in post-stroke inflammation.

Microglia constantly survey the central nervous system microenvironment and maintain brain homeostasis. Microglia activation, polarization and inflammatory response are of great importance in the pathophysiology of ischemic stroke. For exploring biochemical processes in vivo, positron emission tomography (PET) is a superior imaging tool. Translocator protein 18 kDa (TSPO), is a validated neuroinflammatory biomarker which is widely used to evaluate various central nervous system (CNS) pathologies in both preclinical and clinical studies. TSPO level can be elevated due to peripheral inflammatory cells infiltration and glial cells activation. Therefore, a clear understanding of the dynamic changes between microglia and TSPO is critical for interpreting PET studies and understanding the pathophysiology after ischemic stroke. Our review discusses alternative biological targets that have attracted considerable interest for the imaging of microglia activation in recent years, and the potential value of imaging of microglia in the assessment of stroke therapies.

Rate-Dependent Depression: A Predictor of the Therapeutic Efficacy in Treating Painful Diabetic Peripheral Neuropathy.

We investigated the application of rate-dependent depression (RDD) of the Hoffmann (H) wave as a predictor of treatment efficacy in patients with painful diabetic peripheral neuropathy (DPN). General medical information, scales, and nerve conduction data were collected from 73 healthy subjects, 50 subjects with type 2 diabetes and painless DPN, and 71 subjects with type 2 diabetes and painful DPN. The left tibial nerve was stimulated, and RDD was calculated by the decline in amplitude of the third H wave relative to the first one. Gabapentin treatment was initiated after baseline evaluation, and the RDD and visual analog scale (VAS) score were both evaluated regularly during the 2-week study period. At baseline, the painful DPN group exhibited significant RDD impairment across all stimulation frequencies. Gabapentin treatment significantly reduced the VAS score and restored RDD during the 2-week observation period. RDD was found to be an independent factor of minimal VAS score improvement, such that the benefit increased by 1.27 times per 1% decrease in the RDD value. In conclusion, this study demonstrates that diabetes-induced loss of RDD can be modified by gabapentin and suggests that RDD may be valuable for predicting the initial efficacy of gabapentin therapy in patients with painful DPN.

Pharmacological Modulation of Rate-Dependent Depression of the Spinal H-Reflex Predicts Therapeutic Efficacy against Painful Diabetic Neuropathy.

Impaired rate-dependent depression (RDD) of the spinal H-reflex occurs in diabetic rodents and a sub-set of patients with painful diabetic neuropathy. RDD is unaffected in animal models of painful neuropathy associated with peripheral pain mechanisms and diabetic patients with painless neuropathy, suggesting RDD could serve as a biomarker for individuals in whom spinal disinhibition contributes to painful neuropathy and help identify therapies that target impaired spinal inhibitory function. The spinal pharmacology of RDD was investigated in normal rats and rats after 4 and 8 weeks of streptozotocin-induced diabetes. In normal rats, dependence of RDD on spinal GABAergic inhibitory function encompassed both GABAA and GABAB receptor sub-types. The time-dependent emergence of impaired RDD in diabetic rats was preceded by depletion of potassium-chloride co-transporter 2 (KCC2) protein in the dorsal, but not ventral, spinal cord and by dysfunction of GABAA receptor-mediated inhibition. GABAB receptor-mediated spinal inhibition remained functional and initially compensated for loss of GABAA receptor-mediated inhibition. Administration of the GABAB receptor agonist baclofen restored RDD and alleviated indices of neuropathic pain in diabetic rats, as did spinal delivery of the carbonic anhydrase inhibitor acetazolamide. Pharmacological manipulation of RDD can be used to identify potential therapies that act against neuropathic pain arising from spinal disinhibition.

A Stable Cell Line Expressing Clustered AChR: A Novel Cell-Based Assay for Anti-AChR Antibody Detection in Myasthenia Gravis.

Cell-based assays (CBAs) and radioimmunoprecipitation assay (RIPA) are the most sensitive methods for identifying anti-acetylcholine receptor (AChR) antibody in myasthenia gravis (MG). But CBAs are limited in clinical practice by transient transfection. We established a stable cell line (KL525) expressing clustered AChR by infecting HEK 293T cells with dual lentiviral vectors expressing the genes encoding the human AChR α1, ß1, δ, ϵ and the clustering protein rapsyn. We verified the stable expression of human clustered AChR by immunofluorescence, immunoblotting, and real-time PCR. Fluorescence-activated cell sorting (FACS) was used to detect anti-AChR antibodies in 103 MG patients and 58 healthy individuals. The positive results of MG patients reported by the KL525 was 80.6% (83/103), 29.1% higher than the 51.4% (53/103) of RIPA. 58 healthy individuals tested by both the KL525 CBA and RIPA were all negative. In summary, the stable expression of clustered AChR in our cell line makes it highly sensitive and advantageous for broad clinical application in CBAs.

Association Between Low-Density Lipoprotein Cholesterol and Platelet Distribution Width in Acute Ischemic Stroke.

Objective: Elevated low-density lipoprotein cholesterol (LDL-C) is an established risk factor for ischemic stroke; however, whether LDL-C affects the platelet deformation function in the peripheral blood circulation in patients with acute ischemic stroke (AIS) is unknown. The present study aimed to investigate the relationship between LDL-C and platelet distribution width (PDW) in AIS patients. Methods: We conducted a cross-sectional hospitalized-based study of consecutive 438 patients with AIS within 24 h. Blood samples were collected upon admission and prior to drug administration, and LDL-C and PDW (a parameter that reflects the heterogeneity of platelet volume) were assessed. The relationship between LDL-C and PDW were analyzed by linear curve fitting analyses. Crude and adjusted beta coefficients of LDL-C for PDW with 95% confidence intervals were analyzed using multivariate-adjusted linear regression models. Results: The PDW was significantly higher in the high LDL-C group compared with those in the normal LDL-C group (16.28 ± 0.37 fl vs. 16.08 ± 0.37 fl, p < 0.001). Adjusted smoothed plots suggested that there are linear relationships between LDL-C and PDW, and the Pearson's correlation coefficient (95%) was 0.387 (0.304-0.464, p < 0.001). The beta coefficients (95% CI) between LDL-C and PDW were 0.15 (0.12-0.18, p < 0.001) and 0.14 (0.11-0.18, p < 0.001), respectively, in AIS patients before and after adjusting for potential confounders. Conclusion: Our study suggested that the elevated LDL-C level was related to increased PDW among AIS patients.

Lambert-Eaton myasthenia syndrome: specified description of a response pattern to low-frequency repetitive nerve stimulation.

OBJECTIVE: We aimed to specify and quantify the characteristics of the decrement in low-frequency repetitive nerve stimulation response in Lambert-Eaton myasthenia syndrome (LEMS) and compare it to those of myasthenia gravis (MG). PATIENTS AND METHODS: We retrospectively reviewed 18 patients with LEMS and 24 patients with MG. Ten consecutive stimulations were applied at 3 Hz to the abductor pollicis brevis. We determined the position of the smallest wave in the stimulation sequence, and we calculated the decrement and recovery. RESULTS: The median sequential order of the minimum wave was 8 in the LEMS group and 5 in the MG group (p < 0.001). The median decrement in the LEMS group was 36.7%, while that in the MG group was 21.0% (p = 0.047). The recovery percentage was 1.4% in the LEMS group and 3.5% in the MG group (p = 0.001). The area under the curve for the sequential order of the minimum wave was 0.90, and the reciprocal optimum cut-off point was 6.5. CONCLUSIONS: We elucidated a pattern with a delayed nadir and subsequent poor recovery, featuring a low-frequency decrement; furthermore, we determined the most likely sequential order of the minimum wave in patients with LEMS, and the indicator was useful for differentiation.

Central nervous system impairment detected by somatosensory evoked potentials in patients with Charcot-Marie-Tooth disease type 1A.

Diseases related to peripheral myelin protein 22 (PMP22) have been implicated to involve the central nervous system (CNS). This study aimed to detect central nerve impairment using somatosensory evoked potentials (SSEPs) in patients with Charcot-Marie-Tooth disease (CMT) 1A. A total of 30 CMT1A patients and 26 healthy volunteers were included. Baseline characteristics, brain MRI and segmental SSEPs were collected from the participants. The peak latencies of N9, N13 and N20 were recorded, and central conduction velocity (CCT) was calculated and compared between groups. Significant differences were found in the peak latencies and amplitudes of N9, N13 and N20 between the two groups. CCT was significantly prolonged in the CMT group (7.05 ± 2.09 ms) compared to the control group (5.40 ± 1.79 ms) (p = 0.003). Six of 30 CMT patients had abnormal MRI signals, but no correlation with CCT was found. The central somatosensory pathway that carries SSEPs was impaired in CMT1A patients, which implies an important underlying role of PMP22 in the CNS.

The differential expression of natural killer cells in NMOSD and MS.

Natural killer (NK) cells are involved in the pathogenesis of inflammatory demyelinating diseases of the central nervous system. However, the differential expressions of NK cells in the peripheral blood of patients with neuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) are unknown. This study aimed to explore the differential expressions of NK cells in NMOSD and MS and evaluate the clinical implications of this difference. We performed a cross-sectional study to investigate the expression of NK cells in the peripheral blood of patients with NMOSD (n = 78) and MS (n = 24) and of healthy controls (HC, n = 27). Furthermore, we investigated the relationship between NK cell level and disease phase in 102 patients with NMOSD and MS through Spearman correlation analysis and receiver operating characteristic (ROC) analysis. Our results showed that the median (interquartile range) NK cell levels in acute-phase NMOSD patients, remission-phase NMOSD patients, acute-phase MS patients, and HC subjects were 114.10 (64.75-153.38) cells/µL, 167.60 (116.35-266.15) cells/µL, 282.55 (140.57-368.20) cells/µL, and 221.00 (170.40-269.55) cells/µL, respectively (p < 0.001). The Spearman correlation coefficient (95%) for the relationship between NK level and disease phase in NMOSD patients was 0.366 (0.150-0.550) (p < 0.001). Furthermore, ROC analysis revealed that patients with NK cell values lower than 172.200 cells/µL were more prone to have acute-phase NMOSD than MS. In conclusion, the expression of NK cells in peripheral blood was lower in patients with NMOSD than in patients with MS in the acute phase, and a low expression of NK cells may suggest having acute-phase NMOSD rather than MS.

Different distributions of nerve demyelination in chronic acquired multifocal polyneuropathies.

BACKGROUND: Multifocal motor neuropathy (MMN), Lewis-Sumner syndrome (LSS), and many chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs) are representative of acquired multifocal polyneuropathy and are characterized by conduction block (CB). This retrospective study aimed to investigate the demyelinating distribution and the selective vulnerability of MMN, LSS, and CIDP with CB (CIDP-CB) in nerves. METHODS: Fifteen LSS subjects (107 nerves), 24 MMN subjects (176 nerves), and 17 CIDP-CB subjects (110 nerves) were included. Their clinical information was recorded, blood and cerebrospinal fluid tests were conducted, and nerve conductions of the median, ulnar, radial, peroneal, and tibial nerves were evaluated. CB, temporal dispersion, distal motor latency (DML), and F-wave latency were recorded, and nerve conduction velocity, terminal latency index, and modified F-wave ratio were calculated. RESULTS: CB was more likely to occur around the elbow in CIDP-CB than in MMN (78.6% vs. 6.8%, P < 0.01) but less likely to occur between the wrist and the elbow than in LSS (10.7% vs. 39.3%, P < 0.05). Tibial nerve CB was most frequently observed in MMN (47.4%, P < 0.05). CIDP-CB was characterized by a prolonged DML in all nerves, and slow motor nerve velocity of the upper limb was significant when CB nerves were excluded (P < 0.05). CONCLUSIONS: We report the different distributions of segmental and diffuse demyelination of the ulnar and tibial nerves in LSS, MMN, and CIDP-CB. These distinct distributions could help in differentiating among these conditions.

Insulin-like growth factor-1 activates AMPK to augment mitochondrial function and correct neuronal metabolism in sensory neurons in type 1 diabetes.

OBJECTIVE: Diabetic sensorimotor polyneuropathy (DSPN) affects approximately half of diabetic patients leading to significant morbidity. There is impaired neurotrophic growth factor signaling, AMP-activated protein kinase (AMPK) activity and mitochondrial function in dorsal root ganglia (DRG) of animal models of type 1 and type 2 diabetes. We hypothesized that sub-optimal insulin-like growth factor 1 (IGF-1) signaling in diabetes drives loss of AMPK activity and mitochondrial function, both contributing to development of DSPN. METHODS: Age-matched control Sprague-Dawley rats and streptozotocin (STZ)-induced type 1 diabetic rats with/without IGF-1 therapy were used for in vivo studies. For in vitro studies, DRG neurons from control and STZ-diabetic rats were cultured and treated with/without IGF-1 in the presence or absence of inhibitors or siRNAs. RESULTS: Dysregulation of mRNAs for IGF-1, AMPKα2, ATP5a1 (subunit of ATPase), and PGC-1ß occurred in DRG of diabetic vs. control rats. IGF-1 up-regulated mRNA levels of these genes in cultured DRGs from control or diabetic rats. IGF-1 treatment of DRG cultures significantly (P < 0.05) increased phosphorylation of Akt, P70S6K, AMPK and acetyl-CoA carboxylase (ACC). Mitochondrial gene expression and oxygen consumption rate (spare respiratory capacity), ATP production, mtDNA/nDNA ratio and neurite outgrowth were augmented (P < 0.05). AMPK inhibitor, Compound C, or AMPKα1-specific siRNA suppressed IGF-1 elevation of mitochondrial function, mtDNA and neurite outgrowth. Diabetic rats treated with IGF-1 exhibited reversal of thermal hypoalgesia and, in a separate study, reversed the deficit in corneal nerve profiles. In diabetic rats, IGF-1 elevated the levels of AMPK and P70S6K phosphorylation, raised Complex IV-MTCO1 and Complex V-ATP5a protein expression, and restored the enzyme activities of Complex IV and I in the DRG. IGF-1 prevented TCA metabolite build-up in nerve. CONCLUSIONS: In DRG neuron cultures IGF-1 signals via AMPK to elevate mitochondrial function and drive axonal outgrowth. We propose that this signaling axis mediates IGF-1-dependent protection from distal dying-back of fibers in diabetic neuropathy.

Successful treatment with risperidone increases 5-HT 3A receptor gene expression in patients with paranoid schizophrenia - data from a prospective study.

INTRODUCTION: The relationship between peripheral 5-HT3A receptor mRNA level and risperidone efficiency in paranoid schizophrenia patients is still unknown. METHODS: A total 52 first-episode and drug-naive paranoid schizophrenia patients who were treated with risperidone and 53 matched healthy controls were enrolled. Patients were naturalistically followed up for 8 weeks. Positive and Negative Syndrome Scale (PANSS) was applied to assess symptom severity of the patients at baseline and at the end of 8th week. RESULTS: There was no difference in 5-HT3A receptor mRNA level between paranoid schizophrenia patients and healthy controls at baseline (p = .24). Among 47 patients who completed 8-week naturalistic follow-up, 37 were responders to risperidone treatment. 5-HT3A receptor mRNA level of paranoid schizophrenia patients did not change in overall patients after 8-week treatment with risperidone (p = .29). However, 5-HT3A receptor mRNA level in responders increased significantly (p = .04), but not in nonresponders (p = .81). CONCLUSIONS: Successful treatment with risperidone increases 5-HT3A receptor gene expression in patients with paranoid schizophrenia, indicating that 5-HT3A receptor may be involved in the mechanism of risperidone effect.