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Nature Cell Biology Mar 2024The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux...
The endoplasmic reticulum (ER) employs a diverse proteome landscape to orchestrate many cellular functions, ranging from protein and lipid synthesis to calcium ion flux and inter-organelle communication. A case in point concerns the process of neurogenesis, where a refined tubular ER network is assembled via ER shaping proteins into the newly formed neuronal projections to create highly polarized dendrites and axons. Previous studies have suggested a role for autophagy in ER remodelling, as autophagy-deficient neurons in vivo display axonal ER accumulation within synaptic boutons, and the membrane-embedded ER-phagy receptor FAM134B has been genetically linked with human sensory and autonomic neuropathy. However, our understanding of the mechanisms underlying selective removal of the ER and the role of individual ER-phagy receptors is limited. Here we combine a genetically tractable induced neuron (iNeuron) system for monitoring ER remodelling during in vitro differentiation with proteomic and computational tools to create a quantitative landscape of ER proteome remodelling via selective autophagy. Through analysis of single and combinatorial ER-phagy receptor mutants, we delineate the extent to which each receptor contributes to both the magnitude and selectivity of ER protein clearance. We define specific subsets of ER membrane or lumenal proteins as preferred clients for distinct receptors. Using spatial sensors and flux reporters, we demonstrate receptor-specific autophagic capture of ER in axons, and directly visualize tubular ER membranes within autophagosomes in neuronal projections by cryo-electron tomography. This molecular inventory of ER proteome remodelling and versatile genetic toolkit provide a quantitative framework for understanding the contributions of individual ER-phagy receptors for reshaping ER during cell state transitions.
Topics: Humans; Proteome; Proteomics; Endoplasmic Reticulum; Autophagy; Endoplasmic Reticulum Stress; Carrier Proteins; Neurogenesis
PubMed: 38429475
DOI: 10.1038/s41556-024-01356-4 -
JPMA. the Journal of the Pakistan... Feb 2024Diabetes gastroparesis is a common manifestation of autonomic neuropathy in persons with long-standing, uncontrolled diabetes. Most discussion about its management...
Diabetes gastroparesis is a common manifestation of autonomic neuropathy in persons with long-standing, uncontrolled diabetes. Most discussion about its management revolves around the mitigation of symptoms. Here, we share tips on choosing the right glucose-lowering medication, based upon predominant symptomatology of gastroparesis. We highlight about insulin preparations, and their timing of administration, can be tailored according to need. We also emphasize the need to choose oral glucose lowering drugs with care.
Topics: Humans; Gastroparesis; Diabetic Neuropathies; Glucose; Insulin; Diabetes Mellitus
PubMed: 38419246
DOI: 10.47391/JPMA.24-08 -
Diabetes & Metabolism Journal Feb 2024The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic...
BACKGROUND
The aim was to investigate if autonomic symptoms questionnaire Composite Autonomic Symptom Score (COMPASS) 31 has different association with cardiovascular autonomic neuropathy (CAN) and diagnostic performance between type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM).
METHODS
Seventy-nine participants with T1DM and 140 with T2DM completed COMPASS 31 before cardiovascular reflex tests (CARTs) for CAN, and assessment of symptoms, signs, vibration, and thermal perception thresholds for diabetic polyneuropathy (DPN) diagnosis.
RESULTS
COMPASS 31 total weighted score (TWS) was similar in the two groups, but significantly associated with confirmed CAN only in T1DM (P=0.0056) and not T2DM group (P=0.1768) and correlated with CARTs score more strongly in T1DM (rho=0.356, P=0.0016) than in T2DM group (rho=0.084, P=0.3218) (P=0.016). Only in T1DM and not T2DM group, the area under the receiver operating characteristic curve (AUC) reached a fair diagnostic accuracy (>0.7) for confirmed CAN (0.73±0.07 vs. 0.61±0.08) and DPN (0.75±0.06 vs. 0.68±0.05), although without a significant difference. COMPASS 31 TWS (cut-off 16.44) reached acceptable diagnostic performance in T1DM, with sensitivity for confirmed CAN 81.2% and sensitivity and specificity for DPN 76.3% and 78%, compared to T2DM group (all <70%). AUC for DPN of orthostatic intolerance domain was higher in T1DM compared to T2DM group (0.73±0.05 vs. 0.58±0.04, P=0.027).
CONCLUSION
COMPASS 31 is more weakly related to CAN in T2DM than in T1DM, with a fair diagnostic accuracy for confirmed CAN only in T1DM. This difference supports a multifactorial origin of symptoms and should be considered when using COMPASS 31.
PubMed: 38408489
DOI: 10.4093/dmj.2023.0301 -
International Journal of Molecular... Feb 2024Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of... (Review)
Review
Autoimmune autonomic ganglionopathy (AAG) is a disease of autonomic failure caused by ganglionic acetylcholine receptor (gAChR) autoantibodies. Although the detection of autoantibodies is important for distinguishing the disease from other neuropathies that present with autonomic dysfunction, other factors are important for accurate diagnosis. Here, we provide a comprehensive review of the clinical features of AAG, highlighting differences in clinical course, clinical presentation, and laboratory findings from other neuropathies presenting with autonomic symptoms. The first step in diagnosing AAG is careful history taking, which should reveal whether the mode of onset is acute or chronic, followed by an examination of the time course of disease progression, including the presentation of autonomic and extra-autonomic symptoms. AAG is a neuropathy that should be differentiated from other neuropathies when the patient presents with autonomic dysfunction. Immune-mediated neuropathies, such as acute autonomic sensory neuropathy, are sometimes difficult to differentiate, and therefore, differences in clinical and laboratory findings should be well understood. Other non-neuropathic conditions, such as postural orthostatic tachycardia syndrome, chronic fatigue syndrome, and long COVID, also present with symptoms similar to those of AAG. Although often challenging, efforts should be made to differentiate among the disease candidates.
Topics: Humans; Ganglia, Autonomic; Post-Acute COVID-19 Syndrome; Autoimmune Diseases of the Nervous System; Autonomic Nervous System; Autonomic Nervous System Diseases; Autoimmune Diseases; Peripheral Nervous System Diseases; Autoantibodies
PubMed: 38396973
DOI: 10.3390/ijms25042296 -
Frontiers in Neurology 2024A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN...
A few cases of small fiber neuropathy (SFN) and tinnitus (TN) associated with coronavirus disease 2019 have been reported. However, the relationship between SFN and TN has not been studied. This study investigated a possible relationship between SFN and patients with TN (PwTNs) using autonomic function tests (AFTs) including quantitative sudomotor axon reflex tests (QSART). We performed QSARTs and other AFTs such as the Sympathetic skin response (SSR), Valsalva ratio (VR), and heart rate variability (HRV). The QSART results, obtained at seven hospitals using same protocols, were compared between PwTNs and healthy controls. We confirmed the abnormalities in SSR, VR, and HRV in PwTNs, although those parasympathetic AFTs were not performed in healthy controls. Additionally, we checked Tinnitus handicap inventory (THI) scores for PwTNs and ~50% of PwTNs had low-grade disability, whereas 9.3% had high-grade disability. Data from 57 PwTNs and 122 healthy controls were analyzed. The sweat volumes of QSART in the older age group tended to be higher in the PwTNs than in age-matched healthy controls, and significant differences between the PwTN and control groups were observed in the feet in both sexes ( < 0.001) and in the arms in women ( = 0.013). In the younger age group, the sweat volumes in the feet of men were higher in PwTNs than in healthy controls ( = 0.017). No association was observed between THI and QSART scores. In this study, the sweat volumes in QSARTs were higher in PwTNs than in healthy controls. However, abnormal SSR, HRV, and VR results were not commonly observed in PwTNs. Although the results should be interpreted with caution because of limitations in study, PwTNs might also have SFN apart from dysautonomia. This is the first study to perform QSART with other parasympathetic AFTs in PwTNs. However, larger and more rigorously controlled studies will be needed to reveal the relationship between SFN and TN in the future.
PubMed: 38375462
DOI: 10.3389/fneur.2024.1297371 -
Journal of Medical Case Reports Feb 2024Cardiac autonomic neuropathy is a highly prevalent pathology in the diabetic population, and is the leading cause of death in this population. Orthostatic hypotension is...
BACKGROUND
Cardiac autonomic neuropathy is a highly prevalent pathology in the diabetic population, and is the leading cause of death in this population. Orthostatic hypotension is the main clinical manifestation of the disease. In some patients, this orthostatic hypotension is associated with supine hypertension, posing a therapeutic challenge since treatment of one entity may aggravate the other. The challenge is to manage each of these two hemodynamic opposites without exposing the patient to a life-threatening risk of severe hypotension or hypertension.
CASE PRESENTATION
We report a case of a 62-year-old ethnic Moroccan woman who has cardiovascular risk factors such as type 2 diabetes, arterial hypertension, and dyslipidemia. The patient's symptoms included dizziness, tremors, morning sickness, palpitations, and intolerance to exertion. Given her symptomatology, the patient benefited from an exploration of the autonomic nervous system through cardiovascular reactivity tests (Ewing tests), which confirmed the diagnosis of cardiac autonomic neuropathy. In addition to orthostatic hypotension, our patient had supine arterial hypertension, complicating management. To treat orthostatic hypotension, we advised the patient to avoid the supine position during the day, to raise the head of the bed during the night, and to have a sufficient fluid intake, with a gradual transition from decubitus to orthostatism and venous restraint of the lower limbs. Supine hypertension was treated with transdermal nitrates placed at bedtime and removed 1 hour before getting up. One week after the introduction of treatment, the patient reported a clear regression of functional symptoms, with an improvement in her quality of life. Improvement in symptomatology was maintained during quarterly follow-up consultations.
CONCLUSIONS
Cardiac autonomic neuropathy is a very common pathology in diabetic patients. It is a serious condition with a life-threatening prognosis. Its management must be individualized according to the symptomatology and profile of each patient. The treatment of patients with orthostatic hypotension and supine hypertension requires special attention to ensure that each entity is treated without aggravating the other.
Topics: Female; Humans; Middle Aged; Hypotension, Orthostatic; Diabetes Mellitus, Type 2; Quality of Life; Hypertension; Autonomic Nervous System Diseases; Autonomic Nervous System
PubMed: 38374205
DOI: 10.1186/s13256-024-04346-0 -
Malawi Medical Journal : the Journal of... Sep 2023Guillain-Barré syndrome (GBS), the most common cause of acute paralytic neuropathy, covers a number of recognizably different variants. We aimed to evaluate the...
BACKGROUND
Guillain-Barré syndrome (GBS), the most common cause of acute paralytic neuropathy, covers a number of recognizably different variants. We aimed to evaluate the clinical characteristics of the patients with GBS and the outcome results of the patients after rehabilitation.
METHODS
We enrolled 24 adult patients with GBS and evaluated their demographic characteristics, signs, complications, functional levels, and residual symptoms at admission, discharge, and during the 1st and 3rd-year follow-up visits. Functional Independence Scale (FIM), Functional Ambulation Scale (FAS), Hughes functional grading scale, Six-Minute Walking Test (6MWT), and Fatigue Severity Scale (FSS) were used for patient evaluation.
RESULTS
In this study, patients with a mean age of 47.29 ± 16.2 years (40% female) were hospitalized for an average of 28.91 ± 25.6 days. The predominant symptoms experienced by these patients were fatigue (100%), neuropathic pain (70.8%), joint pain (54.2%), and autonomic dysfunction (50%). Significant changes were observed in FIM, Hughes functional grading scale, FAS, 6MWT, and MRC score at admission, discharge, and 1st/3rd-year follow-ups (p=0.000, p=0.000, p=0.000, p=0.001, p=0.000, respectively). Fatigue and Hughes score increased significantly with age (p=0.019, r=0.475; p=0.041, r=0.419, respectively). Negative correlations were found between age and FAS, 6MWT, and MRC score at 1st-year follow-up (p=0.025, r=-0.456; p=0.027, r=-0.450; p=0.008, r=-0.528). FSS was above 4 before admission and in 53.1% at 3rd-year follow-up, correlating negatively with 6MWT and MRC sum score. GBS clinical types showed no significant differences.
CONCLUSION
Rehabilitation improves functional improvement in GBS patients, with long-term benefits observed. However, residual symptoms such as fatigue and neuropathic pain may persist despite functional improvement. These findings highlight the importance of incorporating rehabilitation into the management of GBS and addressing residual symptoms to improve patient outcomes.
Topics: Adult; Humans; Female; Middle Aged; Male; Guillain-Barre Syndrome; Follow-Up Studies; Neuralgia; Fatigue
PubMed: 38362288
DOI: 10.4314/mmj.v35i3.4