Number Of Acetylcholine Receptors Research Articles

Advances in Understanding and Managing Myasthenia Gravis: Current Trends and Future Directions.

Myasthenia gravis (MG) is an autoimmune illness characterized by autoantibodies against the acetylcholine receptor (AChR), muscle-specific tyrosine kinase (MuSK), and an increasing number of extra postsynaptic proteins. Pathogenic autoantibodies reduce the number of functional AChRs in the neuromuscular junction's (NMJ)muscle end plate. The cause of the autoimmune response is unknown, but thymic abnormalities and immune regulatory deficiencies are significant. The disease's incidence is likely influenced by genetic predisposition, with sex hormones and exercise playing a role. MGcan affect any age, race, or gender and can be caused by any stressor, with infections being the most frequent cause. Treatment focuses on airway support and the triggering incident. MG is a rare autoimmune disease causing fatigue-inducing weakness in the axial, respiratory, leg, and bulbar muscles. Initially affecting the eyes, most MGpatients experience at least one worsening symptom during their illness. The disease is mainly caused by antibodies against the AChR, dependence on the immune system within cells, and engagement of the complement system. The complement system plays a significant role in MG, and complement inhibition can both prevent the onset and slow its development. Ocular MG affects around 15% of people, with most patients having blocking antibodies against the cholinergic receptor. There may be correlations between thymoma and other autoimmune conditions, especially thyroid illness. Treatment and management for MGinvolve removing autoantibodies from circulation or blocking effector mechanisms using techniques such as complement inhibition, plasmapheresis, and B-cell elimination.

Development of abnormalities at the neuromuscular junction in the SOD1-G93A mouse model of ALS: dysfunction then disruption of postsynaptic structure precede overt motor symptoms.

The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS. We employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages. Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint. Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.

Lack of Sod1 induces disruption of innervation accompanied by Schwann cell proliferation in skeletal muscle

The neuromuscular junction (NMJ) is an excitatory synapse that constitutes the primary site of communication between the nervous system and skeletal muscle and therefore any degenerative changes at the NMJ have the potential to impair muscle function. The primary cellular components of the NMJ are the motor neuron, the muscle fiber and terminal Schwann cells (tSC) that surround the NMJ. The importance of redox homeostasis for the maintenance of NMJ integrity is supported by work from our group showing degenerative changes at NMJs in mice lacking copper zinc superoxide dismutase (CuZnSOD; Sod1 -/- ) as early as 4 months of age. Prior work from others suggests that tSCs contribute trophic support for the NMJ and facilitate motor unit remodeling, but changes in tSC structure and function under conditions of elevated oxidative stress have not been thoroughly explored. Using in vitro assays, we previously showed that primary Schwann cells treated with a sublethal dose of the reactive oxygen species inducing agent Paraquat (PQ) resulted in increased Schwann cell number, ki67+ staining, and gene expression of trophic factors and the critical NMJ organizing protein Agrin. Furthermore, differentiated C2C12 myotubes treated with conditioned media from PQ treated Schwann cell cultures showed increased number of acetylcholine receptor (AChR) plaques. The goal of the current study was to characterize NMJs in young Sod1 -/- mice (2-months) to determine the early effects of elevated oxidative stress on NMJ structure in vivo with a specific focus on tSCs. We hypothesized that loss of Sod1 would lead to aberrant tSC and NMJ structure associated with decreased muscle function. We assessed maximum isometric force, NMJ morphology, and number of Schwann cells in gastrocnemius muscles of WT (n = 3) and Sod1 -/- (n = 3) mice. In Sod1 -/- mice, muscle force was reduced by 26% ( p = 2e-4) with nerve stimulation compared to direct muscle stimulation, and overlap between motor nerve terminals and AChRs was reduced by nearly 60% compared to WT controls. Post-synaptic AChR area was increased by 37% in Sod1 -/- mice, and tSC area and numbers per NMJ were increased by 60% and 155%, respectively in Sod1 -/- mice. Finally, Schwann cells proximal to NMJs showed increased Ki67+ labeling in Sod1 -/- mice compared to WT mice. This analysis demonstrates that early changes in both pre- and post-synaptic NMJ components and reduced neurotransmission due to loss of Sod1 are associated with marked increases in tSC proliferation. Our data implicate a protective role of muscle-resident Schwann cells in preserving NMJ integrity in response to alterations in redox homeostasis that may be mediated in part through activation and proliferation of these cells. These findings indicate that further investigation of the dynamics between Schwann cells and NMJ function is important to increase understanding of neuromuscular degenerativeconditions that involve altered redox homeostasis such as sarcopenia. Supported by the University of Michigan Medical School Office of Research, the American Physiological Society, and NIH AR069620. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Anesthetic considerations in Hirayama disease: Primum non noncere.

Dear Editor, Hirayama disease is a sporadic, self-limiting juvenile muscular atrophy which affects the muscles of the arm of people of the Asian population in the third decade of life.[1] In the past 35 years, only 279 cases have been reported in India.[2] A 40-year-old male presented with complaints of weakness and pain in the right upper limb with grade 2/5 power and wasting of thenar, hypothenar, interossei muscles, wrist flexors, and extensors with the sparing of the brachioradialis muscle. It is called oblique amyotrophy.[3] The Babinski sign was positive. There was no history of involuntary movements, trauma, exaggeration of symptoms in winter, allergy to peanuts, and sulpha-containing drugs. There was no cranial nerve, sensory, bulbar, bladder, or bowel involvement. The Magnetic Resonance Imaging (MRI) [Figure 1] showed forward displacement of the posterior subdural sac on the flexion of the neck with prominent epidural space. Electromyographic nerve conduction velocity (EMG-NCV) findings showed partial denervation in the upper limb muscles. The thyroid function tests, creatinine kinase, and serum potassium levels were normal.Figure 1: MRI Hirayama diseaseAnticholinergic intravenous glycopyrrolate 0.2 mg was given as an anti-sialagogue. Following an intravenous propofol 1.5 mg/kg induction, we preferred rocuronium bromide 0.9 mg/kg for the neuromuscular blockade, for its rapid onset of action. Injection atracurium was avoided as it has a propensity to raise the ImmunoglobulinE (IGE) levels which precipitate atopic myelitis in the Hirayama disease.[4] Also, in patients with denervation because of spinal cord lesions, an increased number of peri-junctional nicotinic acetylcholine receptors on skeletal muscle can cause hyperkalemia after suxamethonium chloride. Laryngoscopy was performed with manual inline stabilization of the spine (MILS) and a LaerdalR Philadelphia hard cervical collar on, using a McCoy laryngoscope blade and the patient was intubated with a size 8.0 cuffed flexo-metallic tube. The immobilization aims to protect patients with an unstable cervical spine from secondary cervical spine injury induced by accidental movement of the spine.[5] Proning was done by proper precautions, adequate eye care, and padding of pressure points were done. Auto-compression stockings were applied on the lower limbs for deep venous thrombosis (DVT) prophylaxis. Sevoflurane was given to maintain Bispectral Index (BIS)-guided adequate depth of anesthesia. These patients may have a less physiological reserve to tolerate hypotension-induced ischemia and require higher arterial pressures to maintain spinal autoregulation.[5] Injection phenylephrine infusion 1 mg/cc was kept ready. Train Of Four (TOF) monitoring was done intraoperatively and readings were taken before reversal and extubation. Hirayama disease is a sporadic focal degenerative motor neuron disease affecting the cervical cord when the neck is in flexion. Repeated compression changes make the anterior horn cells prone to arterial or venous ischemic injury which causes increased intramedullary pressure and micro-circulatory disturbance.[3] This is in line with the Poisson effect which dictates that if a column of fixed volume is compressed, its cross-sectional area will increase. Conversely, if it is stretched, the cross-sectional area will decrease, which is based on the Chinese finger trap model [Figure 2]. The basic principle is to keep the neck in extension.Figure 2: The Chinese finger trap modelRational airway management, appropriate choice of muscle relaxants in motor neuron diseases, and the use of intraoperative neuromuscular monitoring helped in the optimal, safe, and effective anesthetic management. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient has given hid consent for his images and other clinical information to be reported in the journal. The patients should understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

ROLE OF AYURVEDA IN THE MANAGEMENT OF MYASTHENIA GRAVIS: A CASE STUDY

Myasthenia Gravis (MG) is a neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness with fatigue. The underlying defect in diseases is a decrease in the number of available acetylcholine receptors (AChRs) at postsynaptic neuromuscular junctions due to the binding of autoantibody at acetylcholine receptors. The most commonly and firstly affected muscles are those of the eyes, i.e., ocular muscles leading to drooping of eyelids because of more availability of receptors in less surface area of muscle, later leads to symptoms like difficulty in swallowing leading to (dysphagia), Difficulty to speak (dysarthria), other skeletal muscles fatigability etc. In Ayurveda, we cannot correlate to any particular diseases, but it can be understood in view of upahata dhatu ushma, srotas and marutha, respectively, leading to avarana to the normal functioning of vata. The present study was conducted to determine the efficacy of Ayurvedic management in Myasthenia gravis. In this paper, a case of 47 years old female who was diagnosed with myasthenia gravis (MG) with autoimmune hypothyroidism for 13 years was reported to complain of drooping of eyelids, pain and stiffness at the nape of the neck and bilateral shoulder joints, disturbed sleep, reduced appetite, with occasional diplopia, dysphagia, which got aggravated for six months, hence she approached OPD of SKAMCH&RC, Bengaluru. Considering the signs and symptoms patient was treated on the line of kaphavruta vata, and by considering urdwajatrugata lakshana shirodhara, greevabasti along with nasya line of treatment was adopted, and when a patient got relief in her symptoms, and she was wanted to continue her treatment hence virechana was adopted for sroto shodhanartha. Treatment shows significant improvement in her symptoms without any side effects.

Different responses of skeletal muscles to femoral artery ligation-induced ischemia identified in BABL/c and C57BL/6 mice.

Peripheral arterial disease (PAD) is a common circulatory problem in lower extremities, and the murine ischemic model is used to reproduce human PAD. To compare strain differences of skeletal muscle responses to ischemia, the left femoral artery was blocked by ligation to reduce blood flow to the limb of BALB/c and C57BL/6 mice. After 6 weeks of the femoral artery ligation, the functional and morphological changes of the gastrocnemius muscle were evaluated. BALB/c mice displayed serious muscular dystrophy, including smaller myofibers (524.3 ± 66 µM2), accumulation of adipose-liked tissue (17.8 ± 0.9%), and fibrosis (6.0 ± 0.5%), compared to C57BL/6 mice (1,328.3 ± 76.3 µM2, 0.27 ± 0.09%, and 1.56 ± 0.06%, respectively; p < 0.05). About neuromuscular junctions (NMJs) in the gastrocnemius muscle, 6 weeks of the femoral artery ligation induced more damage in BALB/c mice than that in C57BL/6 mice, demonstrated by the fragment number of nicotinic acetylcholine receptor (nAChR) clusters (8.8 ± 1.3 in BALB/c vs. 2.5 ± 0.7 in C57BL/6 mice, p < 0.05) and amplitude of sciatic nerve stimulated-endplate potentials (EPPs) (9.29 ± 1.34 mV in BALB/c vs. 20.28 ± 1.42 mV in C57BL/6 mice, p < 0.05). More importantly, 6 weeks of the femoral artery ligation significantly weakened sciatic nerve-stimulated skeletal muscle contraction in BALB/c mice, whereas it didn’t alter the skeletal muscle contraction in C57BL/6 mice. These results suggest that the femoral artery ligation in BALB/c mice is a useful animal model to develop new therapeutic approaches to improve limb structure and function in PAD, although the mechanisms about strain differences of skeletal muscle responses to ischemia are unclear.

Therapeutic efficacy of 3,4-Diaminopyridine phosphate on neuromuscular junction in Pompe disease

3,4-Diaminopyridine (3,4-DAP) and its phosphate form, 3,4-DAPP have been used efficiently in the past years to treat muscular weakness in myasthenic syndromes with neuromuscular junctions (NMJs) impairment. Pompe disease (PD), an autosomal recessive metabolic disorder due to a defect of the lysosomal enzyme α-glucosidase (GAA), presents some secondary symptoms that are related to neuromuscular transmission dysfunction, resulting in endurance and strength failure. In order to evaluate whether 3,4-DAPP could have a beneficial effect on this pathology, we took advantage of a transient zebrafish PD model that we previously generated and characterized. We investigated presynaptic and postsynaptic structures, NMJs at the electron microscopy level, and zebrafish behavior, before and after treatment with 3,4-DAPP. After drug administration, we observed an increase in the number of acetylcholine receptors an increment in the percentage of NMJs with normal structure and amelioration in embryo behavior, with recovery of typical movements that were lost in the embryo PD model. Our results revealed early NMJ impairment in Pompe zebrafish model with improvement after administration of 3,4-DAPP, suggesting its potential use as symptomatic drug in patients with Pompe disease.

The Impact of Electronic Nicotine Delivery System (ENDS) Flavors on Nicotinic Acetylcholine Receptors and Nicotine Addiction-Related Behaviors.

Over the past two decades, combustible cigarette smoking has slowly declined by nearly 11% in America; however, the use of electronic cigarettes has increased tremendously, including among adolescents. While nicotine is the main addictive component of tobacco products and a primary concern in electronic cigarettes, this is not the only constituent of concern. There is a growing market of flavored products and a growing use of zero-nicotine e-liquids among electronic cigarette users. Accordingly, there are few studies that examine the impact of flavors on health and behavior. Menthol has been studied most extensively due to its lone exception in combustible cigarettes. Thus, there is a broad understanding of the neurobiological effects that menthol plus nicotine has on the brain including enhancing nicotine reward, altering nicotinic acetylcholine receptor number and function, and altering midbrain neuron excitability. Although flavors other than menthol were banned from combustible cigarettes, over 15,000 flavorants are available for use in electronic cigarettes. This review seeks to summarize the current knowledge on nicotine addiction and the various brain regions and nicotinic acetylcholine receptor subtypes involved, as well as describe the most recent findings regarding menthol and green apple flavorants, and their roles in nicotine addiction and vaping-related behaviors.

EFFECT OF PANCHKARMA IN MYASTHENIA GRAVIS: A CASE REPORT

Myasthenia Gravis (MG) is a long-term neuromuscular disease that leads to varying degrees of skeletal muscle weakness. The condition is caused by breakdown in communication between nerves and muscles. The underlying defect is a decrease in the number of available acetylcholine receptors (AChRs) at neuro-muscular junctions due to an antibody mediated autoimmune attack.1 The most commonly affected mus-cles are those of the eyes, face and swallowing. The cause of this disease can be understood in view of Dhatavgnimaandhya, Vyana Vayu Vikriti. The present observation was conducted with an objective to find out the efficacy of Ayurvedic management in Myasthenia Gravis. Here is a case of 60 years old Hindu male who was diagnosed as Myasthenia Gravis (MG) reported with complaint of slurred speech, low pitch of voice, difficulty to open the mouth and to swallow food and difficulty in elevating right eyebrow since 6 months was registered in OPD of Panchakarma, IPGT &amp; RA, Jamnagar. Considering the signs and symp-toms patient was treated on the line of Aavrita Vata Chikitsa, Sthanika Abhyanga with Bala Taila, Nasya with Anu Taila, Jihwa Pratisarana with Vacha Churna and Ghritapana before meal with Go Ghrita was administered. Treatment shows significant improvement in the symptoms without any side effects.

The disassembly of the neuromuscular synapse in high-fat diet-induced obese male mice

ObjectiveA sustained high fat diet in mice mimics many features of human obesity. We used male and female Non-Swiss albino mice to investigate the impact of short and long-term high-fat diet-(HFD)-induced obesity on the peripheral neuromuscular junction (NMJ) and whether obesity-related synaptic structural alterations were reversible after switching obese mice from HFD to a standard fat diet (SD). MethodsHFD-induced obese and age-matched control mice fed SD were used. We carried out in vivo time lapse imaging to monitor changes of synapses over time, quantitative fluorescence imaging to study the regulation of acetylcholine receptor number and density at neuromuscular junctions, and high resolution confocal microscope to study structural alterations in both the pre- and postsynaptic apparatus. ResultsTime-lapse imaging in vivo over a 9 month period revealed that NMJs of HFD obese male mice display a variety of obesity-related structural alterations, including the disappearance of large synaptic areas, significant reduction in the density/number of nicotinic acetylcholine receptor (AChRs), abnormal distribution of AChRs, high turnover rate of AChRs, retraction of axons from lost postsynaptic sites, and partially denervated synapses. The severity of these synaptic alterations is associated with the duration of obesity. However, no substantial alterations were observed at NMJs of age-matched HFD obese female mice or male mice fed with a standard or low fat diet. Intriguingly, when obese male mice were switched from HFD to a standard diet, receptor density and the abnormal pattern of AChR distribution were completely reversed to normal, whereas lost synaptic structures were not restored. ConclusionsThese results show that the obese male mice are more vulnerable than female mice to the impacts of long-term HFD on the NMJ damage and provide evidence that diet restriction can partially reverse obesity-related synaptic changes.

Antibody-induced crosslinking and cholesterol-sensitive, anomalous diffusion of nicotinic acetylcholine receptors.

Synaptic strength depends on the number of cell-surface neurotransmitter receptors in dynamic equilibrium with intracellular pools. Dysregulation of this homeostatic balance occurs, for example in myasthenia gravis, an autoimmune disease characterized by a decrease in the number of postsynaptic nicotinic acetylcholine receptors (nAChRs). Monoclonal antibody mAb35 mimics this effect. Here we use STORM nanoscopy to characterize the individual and ensemble dynamics of monoclonal antibody-crosslinked receptors in the clonal cell line CHO-K1/A5, which robustly expresses adult muscle-type nAChRs. Antibody labeling of live cells results in 80% receptor immobilization. The remaining mobile fraction exhibits a heterogeneous combination of Brownian and anomalous diffusion. Single-molecule trajectories exhibit a two-state switching behavior between free Brownian walks and anticorrelated walks within confinement areas. The latter act as permeable fences (~34nm radius, ~400ms lifetime). Dynamic clustering, trapping, and immobilization also occur in larger nanocluster zones (120-180nm radius) with longer lifetimes (11±1s), in a strongly cholesterol-sensitive manner. Cholesterol depletion increases the size of the clustering phenomenon; cholesterol enrichment has the opposite effect. The disclosed high proportion of monoclonal antibody-crosslinked immobile receptors, together with their anomalous, cholesterol-sensitive diffusion and clustering, provides new insights into the antibody-enhanced antigenic modulation that leads to physiopathological internalization and degradation of receptors in myasthenia.

Modulation of the Acetylcholine-Induced Input Current by Noopept in Helix Lucorum Neurons

Abstract—Possible causes of the positive modulating effect of noopept (in a concentration range of 0.1 to 10 nM) on the amplitude of the acetylcholine-induced input current are analyzed using a developed mathematical model. The results revealed that the calculated and experimental current curves coincide when the number of nicotinic acetylcholine receptors on the neuron membrane is increased or the efficiency of muscarinic acetylcholine receptors is changed.

Epidural anesthesia for open gastrostomy in a patient with amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis is characterized by the progressive degeneration of motor neurons, causing a constellation of symptoms that include muscle weakness, atrophy, fasciculations, spasticity, and hyperreflexia. Currently, Rulizol is the only treatment that has been shown to delay its progression, though to a very small extent. Disease prognosis is grim, with death caused mainly by respiratory failure secondary to muscle weakness, making anesthetic management of these patients a true challenge. The use of muscle relaxants must be avoided as much as possible because of the high risk of ventilatory depression, considering that these patients have an abnormal unpredictable response as a result of heightened sensitivity related to the lower number of acetylcholine receptors. If muscle relaxants are required during the surgery, rocuronium, among nondepolarizing muscle relaxants, is the drug of choice because of its short half-life, while depolarizing relaxants such as succinylcholine are contraindicated because of the risk of lethal hyperkalemia. In terms of intraoperative hypnotics and analgesics, propofol and remifentanil are ideal because of their short half-life. Regarding neuroaxial anesthesia, despite widespread reluctancy to use it, its benefits and rather uncommon adverse effects lead many anesthetists to consider it as an important alternative when it comes to deciding between general or neuroaxial anesthesia, because it reduces airway manipulation significantly, thus reducing respiratory complications as described in this clinical case.

Hypothalamic Sirt1 protects terminal Schwann cells and neuromuscular junctions from age-related morphological changes.

SummaryNeuromuscular decline occurs with aging. The neuromuscular junction (NMJ), the interface between motor nerve and muscle, also undergoes age‐related changes. Aging effects on the NMJ components—motor nerve terminal, acetylcholine receptors (AChRs), and nonmyelinating terminal Schwann cells (tSCs)—have not been comprehensively evaluated. Sirtuins delay mammalian aging and increase longevity. Increased hypothalamic Sirt1 expression results in more youthful physiology, but the relationship between NMJ morphology and hypothalamic Sirt1 was previously unknown. In wild‐type mice, all NMJ components showed age‐associated morphological changes with ~80% of NMJs displaying abnormalities by 17 months of age. Aged mice with brain‐specific Sirt1 overexpression (BRASTO) had more youthful NMJ morphologic features compared to controls with increased tSC numbers, increased NMJ innervation, and increased numbers of normal AChRs. Sympathetic NMJ innervation was increased in BRASTO mice. In contrast, hypothalamic‐specific Sirt1 knockdown led to tSC abnormalities, decreased tSC numbers, and more denervated endplates compared to controls. Our data suggest that hypothalamic Sirt1 functions to protect NMJs in skeletal muscle from age‐related changes via sympathetic innervation.

English

Myasthenia gravis is a neuro-muscular junction disorder characterized by skeletal muscle weakness and fatiguability. It is due to a decrease in the number of available acetylcholine receptors at the neuromuscular junction as a result of antibody mediated autoimmune attack. Weakness of muscles may involve cranial and somatic musculatures. Weakness resembling myasthenia gravis may occur in other conditions as a result of drug, endocrine disease of thyroid, certain malignancies, bacterial toxins and also by non-autoimmune mechanisms involving the neuromuscular junction. The weakness may involve all the skeletal muscles of the body but the distribution of weakness has a characteristic pattern and there is a diurnal variation of symptoms. If the weakness of respiratory muscles becomes so severe as to require respiratory assistance, then it is called myasthenic crisis. The myasthenia may be generalized one involving all the groups of muscles or it may involve the extra ocular muscles and facial muscles. Sometimes the bulbar muscles alone may be involved and the condition is called bulbar myasthenia gravis. In some of the patients, (anti-AchR) Acetyl choline receptor antibodies may be positive and in some it will be negative. In some of the patients, anti-muscle specific tyrosine kinase antibodies will be positive and negative in some of the patients. CONCLUSION : 1. In our study, the commonest age group of presentation of myasthenic crisis is the fourth decade (36%). 2. Male predominance (56%) was noted in our study. 3. The most common predisposing factor is the respiratory infection (28%). 4. In three patients, the presenting symptoms of myasthenia gravis was crisis itself. 5. The mean duration of onset of myasthenia gravis to the onset of crisis was 439.36 days. 6. The duration of myasthenia gravis does not influence the occurrence of myasthenic crisis. 7. Our patients presented with predominant bulbar symptoms with respiratory distress. 8. Ventilator associated pneumonia and other respiratory complications influenced the outcome of treatment of myasthenic crisis. 9. 32% of thymectomised patients had myasthenic crisis. 10. Higher age is a risk factor and younger age is a favourable factor for good outcome. 11. Duration of myasthenia gravis have no role on the outcome of crisis. 12. The better survival rate in ventilated patients outweigh the preventable ventilator related complications.

Modulation of the Neuregulin 1/ErbB system after skeletal muscle denervation and reinnervation

Neuregulin 1 (NRG1) is a growth factor produced by both peripheral nerves and skeletal muscle. In muscle, it regulates neuromuscular junction gene expression, acetylcholine receptor number, muscle homeostasis and satellite cell survival. NRG1 signalling is mediated by the tyrosine kinase receptors ErbB3 and ErbB4 and their co-receptors ErbB1 and ErbB2. The NRG1/ErbB system is well studied in nerve tissue after injury, but little is known about this system in skeletal muscle after denervation/reinnervation processes. Here, we performed a detailed time-course expression analysis of several NRG1 isoforms and ErbB receptors in the rat superficial digitorum flexor muscle after three types of median nerve injuries of different severities. We found that ErbB receptor expression was correlated with the innervated state of the muscle, with upregulation of ErbB2 clearly associated with the denervation state. Interestingly, the NRG1 isoforms were differently regulated depending on the nerve injury type, leading to the hypothesis that both the NRG1α and NRG1β isoforms play a key role in the muscle reaction to injury. Indeed, in vitro experiments with C2C12 atrophic myotubes revealed that both NRG1α and NRG1β treatment influences the best-known atrophic pathways, suggesting that NRG1 might play an anti-atrophic role.

The interactions of anthelmintic drugs with nicotinic receptors in parasitic nematodes.

Parasitic nematodes express a large number of distinct nicotinic acetylcholine receptors and these in turn are the targets of many classes of anthelmintic drug. This complexity poses many challenges to the field, including sorting the exact subunit composition of each of the receptor subtypes and how much they vary between species. It is clear that the model organism Caenorhabditis elegans does not recapitulate the complexity of nicotinic pharmacology of many parasite species and data using this system may be misleading when applied to them. The number of different receptors may allow nematodes some plasticity which they can exploit to evolve resistance to a specific cholinergic drug; however, this may mean that combinations of cholinergic agents may be effective at sustainably controlling them. Resistance may involve the expression of truncated receptor subunits that affect the expression levels of the receptors via mechanisms that remain to be deciphered.

B cells in the pathophysiology of myasthenia gravis.

Myasthenia gravis (MG) is an archetypal autoimmune disease. The pathology is characterized by autoantibodies to the acetylcholine receptor (AChR) in most patients or to muscle-specific tyrosine kinase (MuSK) in others and to a growing number of other postsynaptic proteins in smaller subsets. A decrease in the number of functional AChRs or functional interruption of the AChR within the muscle end plate of the neuromuscular junction is caused by pathogenic autoantibodies. Although the molecular immunology underpinning the pathology is well understood, much remains to be learned about the cellular immunology contributing to the production of autoantibodies. This Review documents research concerning the immunopathology of MG, bringing together evidence principally from human studies with an emphasis on the role of adaptive immunity and B cells in particular. Proposed mechanisms for autoimmunity, which take into account that different types of MG may incorporate divergent immunopathology, are offered. Muscle Nerve 57: 172-184, 2018.

Dietary Genistein Influences Number of Acetylcholine Receptors in Female Diabetic Jejunum.

Background Intestinal dysfunction in the ob/ob mouse model of diabetes mimics that seen clinically. Methods We determined the effects of a 4-week genistein diet (600 mg genistein/kg food) on intestinal function (contractility, morphology, AChR, and motility) in female ob/ob and lean mice. Results Contractility of the jejunum in response to incrementally increasing concentrations of KCl was comparable in ob/ob females and lean controls regardless of a genistein-diet. There were no changes in the wall thickness measured. We assessed the number of clusters of AChR in the jejunum wall; AChR were decreased by 48% in ob/ob mice versus leans, and the genistein diet reversed this. In utilizing a video-imaging system to evaluate gastrointestinal motility, we determined that the distance between consecutive contractile events was significantly increased by 1.87-fold in ob/ob mice versus leans, and the genistein diet was without effect. Conclusions These data suggest that slowed intestinal transit in the diabetic ob/ob mouse may be due in part to decreased AChR and decreased contraction events occurring per unit time. A genistein diet rescues the number of AChR to levels of leans yet did not change the number of contractile events. Feeding ob/ob mice a genistein-rich diet has potential therapeutic benefits towards improving the debilitating diabetes-related gastrointestinal dysfunction.

Electrical stimulation enhances the acetylcholine receptors available for neuromuscular junction formation.

The beneficial effects of electrical stimulation (ES) on human cells in vitro and in vivo have long been known. Although the effects of stimulation are clear and the therapeutic benefits are known, no uniform parameters exist with regard to the duration, frequency and amplitude of the ES. To this end, we are answering several important questions on the parameters for ES of nerve and muscle monocultures and co-cultures by probing the effects on the enhancement of acetylcholine receptors (AChR) clustering available for neuromuscular junction formation using a conductive platform. This work opens the possibility to combine electrical stimulus delivered via conductive polymer substrates, from which biomolecules could also be delivered, providing opportunities to further enhance the therapeutic effect.