Effect of Follicular T Helper and T Helper 17 Cells-Related Molecules on Disease Severity in Patients with Myasthenia Gravis.

INTRODUCTION: Contribution of T helper 1 and 2 cells-related cytokines to pathogenesis of myasthenia gravis (MG) is well known. Recently, the contribution of follicular T helper (Tfh) and T helper 17 cells-related molecules to the pathogenesis has gained importance. In this study, we aimed to evaluate the changes in Tfh- and Th17-related molecules before and after rescue therapy in patients with myasthenic crisis (cMG) and to reveal the molecular differences between stable MG and cMG patients. METHODS: Patients with stable generalized MG (gMG) and cMG were classified according to Myasthenia Gravis Foundation of America (MGFA) classification. Serum samples were collected from cMG patients both before and after rescue therapy (plasmapheresis or intravenous immunoglobulin [IVIg]). Serum levels of Tfh- and selected Th17-related molecules (IL-22, IL-17A, CXCL13, sPD-L1, sICOSLG, and sCD40L) were analyzed by commercial ELISA kits. RESULTS: Twelve cMG (6 for IVIg, 6 for plasmapheresis) and 10 gMG patients were included in the study. A decrease in serum sPD-L1 and CXCL13 levels was observed in cMG patients after treatment, regardless of the treatment modality (p < 0.05). In contrast, serum sICOSLG levels decreased only in patients treated with IVIg (p < 0.05) and serum IL-22 levels increased in patients receiving plasmapheresis (p < 0.05). cMG patients had higher serum IL-17A levels compared to stable patients (p < 0.001) and its level was positively correlated with disease severity (r = 0.678, p = 0.001). CONCLUSION: Our results confirm the contribution of Tfh- and Th17-related cell pathways to MG pathogenesis. Both IVIg and plasmapheresis appear to be effective in reducing Tfh- and Th17-related cytokine/molecule levels in cMG patients. Increased serum IL-17A levels may contribute to disease severity.

The evaluation of small fibers in multiple sclerosis.

BACKGROUND: Dysesthetic or ongoing extremity pain is a common symptom in all multiple sclerosis (MS) types. Although the pathology of the disease is the demyelination of central neurons, the patients may also complain of neuropathic pain in distal extremities that is generally related to A-delta and C fiber dysfunction. It is not known whether thinly myelinated and unmyelinated fibers are affected in MS patients. We aim to investigate the small fiber loss and its length dependency. METHODS: We evaluated the skin biopsy taken from proximal and distal leg of MS patients with neuropathic pain. Six patients with primary progressive MS (PPMS), seven with relapsing-remitting MS (RRMS), seven with secondary progressive MS (SPMS) and as a control group ten age and sex-matched healthy controls were included. Neurological examination, electrophysiological evaluation and DN4 questionnaire were performed. Subsequently, skin punch biopsy from 10 cm above the lateral malleolus and proximal thigh were done. The biopsy samples were stained with PGP9.5 antibody and intraepidermal nerve fiber density (IENFD) was determined. RESULTS: The mean proximal IENFD was 8.58±3.58 fibers/mm among MS patients and 14.72±2.89 fiber/mm among healthy controls (p=0.001). However, the mean distal IENFD did not differ between MS patients and healthy controls (9.26±3.24 and 9.75±1.6 fiber/mm respectively. Although proximal and distal IENFD tends to be lower in MS patients with neuropathic pain, there was no statistically significant difference between MS patients with and without neuropathic pain CONCLUSION: Although MS is a demyelinating disease, unmyelinated fibers can also be affected. Our findings suggest non-length dependent small fiber neuropathy in MS patients.

Multimodal assessment of intensive care unit-acquired weakness in severe stroke patients.

BACKGROUND: Intensive care unit-acquired weakness (ICUAW) defines generalized muscle weakness seen in critically ill patients in the absence of other causative factors. Herein, we aimed to evaluate ICUAW in stroke patients by electrodiagnostic testing, histopathology, and assessment of respiratory complex activities (RCA), to define the frequency of ICUAW in this patient group, and to reach new parameters for early prediction and diagnosis. METHODS: We prospectively recruited twenty-four severe acute stroke patients during a sixteen-month period. In addition to serial nerve conduction studies (NCS), we performed muscle biopsy and RCA analysis on the non-paretic side when ICUAW developed. Patients undergoing orthopedic surgery without metabolic and neuromuscular diseases constituted the control group for RCA. Survival and longitudinal data were analyzed by joint modeling to determine the relationship between electrophysiological parameters and ICUAW diagnosis. RESULTS: Eight patients (33%) developed ICUAW, and six of them within the first two weeks. Extensor digitorum brevis, abductor digiti minimi (ADM), rectus femoris and vastus medialis (VM) compound muscle action potential (CMAP) amplitudes showed a significant decrease in the ICUAW group. VM CMAP amplitude (BIC = 358.1574) and ADM CMAP duration (BIC = 361.1028) were the best-correlated parameters with ICUAW diagnosis. The most informative electrophysiological findings during the entire study were obtained within the first 11 days. Muscle biopsies revealed varying degrees of type 2 fiber atrophy. Complex I (p = 0.003) and IV (p = 0.018) activities decreased in patients with ICUAW compared to controls. CONCLUSION: VM CMAP amplitude and ADM CMAP duration correlate well with ICUAW diagnosis, and may aid in the early diagnosis.

The functional and structural evaluation of small fibers in asymptomatic carriers of TTR p.Val50Met (Val30Met) mutation.

Therapeutic advances in hereditary amyloid transthyretin (ATTRv) amyloidosis with polyneuropathy extended life expectancy and delayed symptom progression especially in patients with early disease. Thus, detection and monitoring of asymptomatic carriers gained importance. However, there is still limited consensus on genetic screening of ATTRv-polyneuropathy patients' family members and diagnostic tests that must be done in the follow-up. In this study, we followed prospectively five asymptomatic carriers of a family with ATTRV30M (p.Val50Met) mutation by different diagnostic tests for three years. The carriers were followed by neurological examination, nerve conduction studies, sympathetic skin response test, heart rate variability, SFN-SIQ and DN4 questionnaires, quantitative sensory testing (QST), skin biopsy and in vivo corneal confocal microscopy. Nerve conduction studies, sympathetic skin response test and heart rate variability were normal in all for three years. Baseline QST and SFN-SIQ were normal but became abnormal during follow-up of two individuals who developed small fiber neuropathy symptoms. Baseline intraepidermal nerve fiber density was low in three carriers and decreased to below normative values in all during follow-up, while corneal sub-basal nerve density was low in all carriers compared to controls during the entire follow-up. Thus, our study showed that SFN-SIQ and QST are useful diagnostic tools to detect the transition to symptomatic ATTRv-polyneuropathy.

Sealer penetration into dentinal tubules in the presence or absence of smear layer: a confocal laser scanning microscopic study.

INTRODUCTION: The aim of this study was to test the dentinal tubule penetration of AH26 (Dentsply DeTrey, Konstanz, Germany) and MTA Fillapex (Angelus, Londrina, PR, Brazil) in instrumented root canals obturated by using cold lateral compaction or warm vertical compaction techniques in either the presence or absence of the smear layer. METHODS: Forty-five extracted single-rooted human mandibular premolar teeth were used. The crowns were removed, and the root canals were instrumented by using the Self-Adjusting File (ReDent-Nova, Ra'anana, Israel) with continuous sodium hypochlorite (2.6%) irrigation. Final irrigation was either with 5% EDTA or with sodium hypochlorite. The canals were dried and obturated by using rhodamine B-labeled AH26 or MTA Fillapex in combination with the cold lateral compaction or the warm vertical compaction technique. After setting, the roots were sectioned horizontally at 4-, 8-, and 12-mm distances from the apical tip. On each section, sealer penetration in the dentinal tubules was measured by using confocal laser scanning microscopy. RESULTS: Regardless of the usage of EDTA, MTA Fillapex, compared with AH26, was associated with greater sealer penetration when used with the cold lateral compaction technique, and, conversely, AH26, compared with MTA Fillapex, was associated with greater sealer penetration when used with the warm vertical compaction technique (P < .05). Removal of the smear layer increased the penetration depth of MTA Fillapex used with the cold lateral compaction technique (P < .05); however, it had no significant effect on the penetration depth of AH26. CONCLUSIONS: Greater sealer penetration could be achieved with either the MTA Fillapex-cold lateral compaction combination or with the AH26-warm vertical compaction combination. Smear layer removal was critical for the penetration of MTA Fillapex; however, the same did not hold for AH26.