Therapeutic role of plasma exchange in the management of stiff person syndrome: experience from a tertiary care centre.

INTRODUCTION: The stiff person syndrome (SPS) is a rare and disabling neurological disorder characterized by muscle stiffness, painful spasms and rigidity involving the proximal and axial limb muscles, with an estimated incidence of 1 case per million per year. The first line of treatment for symptomatic management includes gamma-aminobutyric acid (GABA)ergic agonists, benzodiazepines and baclofen. The therapeutic plasma exchange (TPE), alone or as an adjuvant to other forms of immunomodulation, has been used as a therapeutic option, particularly in refractory cases. METHODS: An observational study was performed to review SPS patient symptoms, comorbidities, electromyography (EMG) studies and treatment, identifying autoantibodies, therapeutic plasma exchange (TPE) procedural details and clinical response. MAIN RESULTS: Five patients (4 male and one female) were treated with TPE during the study period as adjuvant therapy. The average age was 47 years (range 34 - 61 years), and anti-glutamic acid decarboxylase 65-kilodalton isoform (anti-GAD65) antibodies were positive in 80 % (4/5) of the patient population. All patients received immunosuppressive drugs along with TPE. Four patients received TPE during the first admission and one received it during the third hospital admission. All patients showed good improvement immediately after TPE, but it was not a sustainable effect. CONCLUSION: TPE may be helpful as adjuvant therapy for SPS patients to provide relief from clinical symptoms.

Use of Two Novel Dyes to Enhance Visualization of Cut Ends of the Vessel in Microvascular Anastomosis-An Experimental Study of 45 Rats.

BACKGROUND: Good visualization is a prerequisite for performing microvascular anastomosis. The most commonly used dye, methylene blue, has several limitations: it is washed off quickly and stains all the vessel layers. The objective of our study is to use 2 new novel dyes for improving visualization. METHODS: After ethical committee approval, 2 Dyes (2% cresyl violet, 1% eosin) were studied in 3 groups, 20 rats in each group and 5 rats in the combined group. End-to-side anastomosis was performed in the classic fashion in 45 rats. After venotomy, the dye was applied to the raw surface of the vessels and subsequently, anastomosis was performed. The improvement in visualization was judged by 3 blinded experts and nonexperts in 4 groups on a scale of 1-10. Scores were statistically analyzed. After 2 weeks, animals were re-explored to check the delayed patency, and segments were harvested for histopathologic analysis. RESULTS: The immediate and delayed patency rates were 100% (45/45) and 97% (33/34), respectively. In statistical analysis, the combined group (P = 0.005)was judged statistically significant because of the contrast in color. All the layers were stained by both dyes, staining lasted until the end of the surgery. Visibility of the cut ends was better in cresyl violet. All histopathologic findings suggested normal changes at the anastomotic site. CONCLUSIONS: This study showed that the use of these 2 dyes was not only feasible but highly efficacious. Even though all the layers were stained by both the dyes, the visibility of the cut ends was better. In both dyes, staining lasted until the end of surgery. To the best of our knowledge, this is the first study that has used these 2 novel dyes to improve visualization in microvascular anastomosis in an experimental setting.

Epilepsia Partialis Continua as a Sequelae of Measles Infection in Children With Hematolymphoid Malignancies.

PURPOSE: To share our clinical experience with the diagnosis and management of children with hematolymphoid malignancies presenting with epilepsia partialis continua (EPC) as a sequelae of measles infection. MATERIALS AND METHODS: In December 2022, a series of children in our hemato-oncology unit presented with focal status epilepticus with no conclusive evidence pointing toward any underlying etiology. One such child had a typical measles rash a few weeks before the onset of this focal status epilepticus. After a series of cases with a similar presentation, a clinical pattern suspicious for measles became evident. cerebrospinal fluid polymerase chain reaction was positive for measles virus with measles immunoglobin M detected in the serum. This led to the diagnosis of measles inclusion-body encephalitis in a series of children who presented with EPC over a period of 3 months. EPC is a rare manifestation of measles that is seen only in immunocompromised patients. RESULTS: Among the 18 children reported in this series, only 10 had a history of rashes. The rash was mostly transient and elicited only on retrospective history taking. Five of the 18 children who did not lose consciousness during the prolonged seizure episode survived the disease but had residual neurologic sequelae. Among the 18 children, two were unimmunized and immunization status could not be confirmed in three other children. CONCLUSION: This case series highlights the threats posed by measles infection in children with cancer who are immunosuppressed because of the underlying disease and ongoing chemotherapy. Loss of herd immunity because of declining measles immunization rates secondary to vaccine hesitancy and COVID-19 lockdown pose a greater risk of measles infection and its complications for patients with deficient immune systems.

Hermite-scan imaging for differentiating glioblastoma from normal brain: Simulations and ex vivo studies for applications in intra-operative tumor identificationa).

Hermite-scan (H-scan) imaging is a tissue characterization technique based on the analysis of raw ultrasound radio frequency (RF) echoes. It matches the RF echoes to Gaussian-weighted Hermite polynomials of various orders to extract information related to scatterer diameter. It provides a color map of large and small scatterers in the red and blue H-scan image channels, respectively. H-scan has been previously reported for characterizing breast, pancreatic, and thyroid tumors. The present work evaluated H-scan imaging to differentiate glioblastoma tumors from normal brain tissue ex vivo. First, we conducted 2-D numerical simulations using the k-wave toolbox to assess the performance of parameters derived from H-scan images of acoustic scatterers (15-150 µm diameters) and concentrations (0.2%-1% w/v). We found that the parameter intensity-weighted percentage of red (IWPR) was sensitive to changes in scatterer diameters independent of concentration. Next, we assessed the feasibility of using the IWPR parameter for differentiating glioblastoma and normal brain tissues (n = 11 samples per group). The IWPR parameter estimates for normal tissue (44.1% ± 1.4%) were significantly different (p < 0.0001) from those for glioblastoma (36.2% ± 0.65%). These findings advance the development of H-scan imaging for potential use in differentiating glioblastoma tumors from normal brain tissue during resection surgery.

Role of magnetoencephalography in predicting the epileptogenic zone and post-operative seizure outcome - A retrospective study.

PURPOSE: Study assessed the role of MSI in predicting the post-operative seizure outcome. METHODS: This retrospective study included patients who underwent MEG and epilepsy surgery and had a minimum 6 months of postoperative follow-up. Concordance of MEG cluster with post-surgical resection cavity was classified as follows Class I) Concordant and region-specific, Class II) Concordant and region non-specific, Class III) Concordant lateralization only and Class IV) Discordant lateralization. The relationship between MSI concordance and post-operative seizure outcome was assessed. RESULTS: A total of 183 patients (M: F = 109:74) were included. The mean age at onset of seizures: 8.0 ± 6.4 years. The dipoles were frequent in 123(67.2 %). The primary cluster orientation was regular in 59 (32.2 %) and mixed in 124 (67.8 %) patients. Concordance between MEG and resection cavity: Class I - 124 (67.8 %), class II- 30 (16.4 %), class III- 23 (12.6 %), and class IV- 6 (3.3 %). The post-surgically mean duration of follow-up was 19.52 ± 11.27 months. At 6-month follow-up period, 144 (78.7 %) patients had complete seizure freedom out of which 106 (73.6 %) had class I concordance. Concordance of MEG with resection cavity was associated with a good outcome at 6 months (p = 0.001), 1 year (p = 0.001), 2 years (p = 0.0005) and 5 years (p = 0.04). MEG cluster characteristics had no association with seizure outcome except the strength of the cluster and outcome at 3 years (p = 0.02) follow-up. CONCLUSION: The study supports that the complete resection of the MEG cluster had high chance of seizure-freedom and can be used as a complementary noninvasive presurgical evaluation tool.

Localisation of eloquent cortex using magnetoencephalography and its clinical implications.

OBJECTIVES: This study aimed to localise the eloquent cortex and measure evoked field (EF) parameters using magnetoencephalography in patients with epilepsy and tumours near the eloquent cortex. METHODS: A total of 41 patients (26 with drug-refractory epilepsy and 15 with tumours), with a mean age of 33 years, were recruited. Visual evoked field (VEF), auditory evoked field (AEF), sensory evoked field (SSEF), and motor-evoked field (MEF) latencies, amplitudes, and localisation were compared with those of a control population. Subgroup analyses were performed based on lobar involvement. Evoked Field parameters on the affected side were compared with those on the opposite side. The effect of distance from the lesion on nearby and distant evoked fields was evaluated. RESULTS: AEF and VEF amplitudes and latencies were reduced bilaterally (p < 0.05). Amplitude in the ipsilateral SSEF was reduced by 29.27% and 2.16% in the AEF group compared to the contralateral side (p = 0.02). In patients with temporal lobe lesions, the SSEF amplitude was reduced bilaterally (p < 0.02), and latency was prolonged compared with controls. The MEF amplitude was reduced and latency was prolonged in patients with frontal lobe lesions (p = 0.01). EF displacement was 32%, 57%, 21%, and 16% for AEF, MEF, VEF, and SSEF respectively. Patients in the epilepsy group had distant EF abnormalities. CONCLUSIONS: EF amplitude was reduced and latency was prolonged in the involved hemisphere. Distant EF amplitudes were more affected than latencies in epilepsy. Amplitude and distance from the lesion had negative correlation for all EF. EF changes indicated eloquent cortical displacement which may not be apparent on MRI.

Neuroanatomical zones of human traumatic brain injury reveal significant differences in protein profile and protein oxidation: Implications for secondary injury events.

Traumatic brain injury (TBI) causes significant neurological deficits and long-term degenerative changes. Primary injury in TBI entails distinct neuroanatomical zones, i.e., contusion (Ct) and pericontusion (PC). Their dynamic expansion could contribute to unpredictable neurological deterioration in patients. Molecular characterization of these zones compared with away from contusion (AC) zone is invaluable for TBI management. Using proteomics-based approach, we were able to distinguish Ct, PC and AC zones in human TBI brains. Ct was associated with structural changes (blood-brain barrier (BBB) disruption, neuroinflammation, axonal injury, demyelination and ferroptosis), while PC was associated with initial events of secondary injury (glutamate excitotoxicity, glial activation, accumulation of cytoskeleton proteins, oxidative stress, endocytosis) and AC displayed mitochondrial dysfunction that could contribute to secondary injury events and trigger long-term degenerative changes. Phosphoproteome analysis in these zones revealed that certain differentially phosphorylated proteins synergistically contribute to the injury events along with the differentially expressed proteins. Non-synaptic mitochondria (ns-mito) was associated with relatively more differentially expressed proteins (DEPs) compared to synaptosomes (Syn), while the latter displayed increased protein oxidation including tryptophan (Trp) oxidation. Proteomic analysis of immunocaptured complex I (CI) from Syn revealed increased Trp oxidation in Ct > PC > AC (vs. control). Oxidized W272 in the ND1 subunit of CI, revealed local conformational changes in ND1 and the neighboring subunits, as indicated by molecular dynamics simulation (MDS). Taken together, neuroanatomical zones in TBI show distinct protein profile and protein oxidation representing different primary and secondary injury events with potential implications for TBI pathology and neurological status of the patients.

Evaluation of a rapid, chip-based, micro-PCR assay for detection of rabies virus in human and canine specimens.

Rabies, a lethal zoonotic encephalitis, remains a significant global health concern, causing an estimated 60 000 annual fatalities worldwide. Dogs serve as the primary reservoirs and vectors for transmitting this infection to humans. Definitive diagnosis of rabies in both human and animal cases necessitates laboratory testing involving various clinical specimens. However, the complexity of laboratory infrastructure and the need for skilled personnel, along with the challenge of maintaining cold-chain integrity during sample referral, hinder the decentralization of diagnostic facilities. This study aimed to assess the efficacy of the Truenat rabies assay, a rapid, portable, semiautomated, and closed PCR-based system, for the diagnosis of rabies in both humans and animals. The Truenat assay demonstrated a sensitivity of 100% and a specificity of 86.96% when compared with the fluorescent antibody test (FAT), as the reference standard, on 147 canine brain samples tested. Notably, the Truenat assay exhibited a sensitivity and specificity of 100% when tested on 48 human brain specimens. Furthermore, an examination of 148 human antemortem samples (cerebrospinal fluid, saliva, and skin biopsy) using both the Truenat assay and a validated real-time reverse transcriptase PCR assay revealed a κ value of 0.505, indicative of a moderate level of agreement between the two tests. Thus, the Truenat assay offers a robust, reliable, and affordable point-of-care solution to enhance rabies diagnostic capacity in endemic areas.

NIMHANS Neuropsychological Battery for Elderly in Parkinson's Disease Patients: Validation and Diagnosis using MDS PD-MCI Task Force Criteria in Indian Population.

Introduction: Cognitive impairment is a common non-motor feature of Parkinson's Disease (PD). Diagnosis of mild cognitive impairment is challenging and routinely missed in clinical practice. Our study aimed to study the efficacy of NIMHANS Neuropsychological Battery for Elderly (NNB-E) in diagnosing subtle cognitive deficits in PD patients. Objective: The aim of this study is to validate NNB-E and evaluate cognitive impairment in PD patients in comparison with healthy controls. Methods: We recruited 31 PD patients and 31 healthy controls in the current study. We validated NNB-E using receiver operating characteristic (ROC) curve analysis, Crohnbach's alpha, principal component analysis, and Pearson product-moment correlation, and studied the cognitive impairments using NNB-E in the non-demented PD patients and controls who scored ≥24 on HMSE. Results: Cognitive performance of PD patients was poor compared to controls. NNB-E showed good internal consistency and construct validity with Crohnbach's alpha of 0.861 and area under the curve (AUC) of 0.878. The battery was able to detect mild cognitive impairment in 74.1% of patients and 6.4% of controls. The ROC curve showed that the overall sensitivity of the battery was 73.2% and specificity was 92.6% at an optimal cutoff score. Different cutoff values set for defining PD-MCI as per MDS task force criteria resulted in varying frequencies of MCI ranging from 25.8% to 71%. Conclusion: Our study established the validity of NNB-E in PD patients, and this tool was suitable for diagnosing PD-MCI and discriminating PD patients from normal controls in the Indian population. This study also showed PD-MCI at various cutoff scores with greater impairment in executive and attention domains.

Repeat intramuscular transplantation of human dental pulp stromal cells is more effective in sustaining Schwann cell survival and myelination for functional recovery after onset of diabetic neuropathy.

BACKGROUND AIMS: Mesenchymal stromal cell (MSC) therapy for diabetic neuropathy (DN) has been extensively researched in vitro and in pre-clinical studies; however, the clinical scenario thus far has been disappointing. Temporary recovery, a common feature of these studies, indicates that either the retention of transplanted cells deteriorates with time or recovery of supportive endogenous cells, such as bone marrow-derived MSCs (BM-MSCs), does not occur, requiring further replenishment. In DN, BM-MSCs are recognized mediators of Schwann cell regeneration, and we have earlier shown that they suffer impairment in the pre-neuropathy stage. In this study, we attempted to further elucidate the mechanisms of functional recovery by focusing on changes occurring at the cellular level in the sciatic nerve, in conjunction with the biodistribution and movement patterns of the transplanted cells, to define the interval between doses. METHOD & RESULTS: We found that two doses of 1 × 106 dental pulp stromal cells (DPSCs) transplanted intramuscularly at an interval of 4 weeks effectively improved nerve conduction velocity (NCV) and restored motor coordination through improving sciatic nerve architecture, Schwann cell survival and myelination. Despite very minimal recovery of endogenous BM-MSCs, a temporary restoration of NCV and motor function was achieved with the first dose of DPSC transplantation. However, this did not persist, and a repeat dose was needed to consolidate functional improvement and rehabilitate the sciatic nerve architecture. CONCLUSION: Thus, repeat intramuscular transplantation of DPSCs is more effective for maintenance of Schwann cell survival and myelination for functional recovery after onset of DN.

Resting-State Functional MRI/PET Profile as a Potential Alternative to Tri-Modality EEG-MR/PET Imaging: An Exploratory Study in Drug-Refractory Epilepsy.

Objective The study explores whether the epileptic networks associate with predetermined seizure onset zone (SOZ) identified from other modalities such as electroencephalogram/video electroencephalogram/structural MRI (EEG/VEEG/sMRI) and with the degree of resting-state functional MRI/positron emission tomography (RS-fMRI/PET) coupling. Here, we have analyzed the subgroup of patients who reported having a seizure on the day of scan as postictal cases and compared the findings with interictal cases (seizure-free interval). Methods We performed independent component analysis (ICA) on RS-fMRI and 20 ICA were hand-labeled as large scale, noise, downstream, and epilepsy networks (Epinets) based on their profile in spatial, time series, and power spectrum domains. We had a total of 43 cases, with 4 cases in the postictal group (100%). Of 39 cases, 14 cases did not yield any Epinet and 25 cases (61%) were analyzed for the final study. The analysis was done patient-wise and correlated with predetermined SOZ. Results The yield of finding Epinets on RS-fMRI is more during the postictal period than in the interictal period, although PET and RS-fMRI spatial, time series, and power spectral patterns were similar in both these subgroups. Overlaps between large-scale and downstream networks were noted, indicating that epilepsy propagation can involve large-scale cognition networks. Lateralization to SOZ was noted as blood oxygen level-dependent activation and correlated with sMRI/PET findings. Postoperative surgical failure cases showed residual Epinet profile. Conclusion RS-fMRI may be a viable option for trimodality imaging to obtain simultaneous physiological information at the functional network and metabolic level.

Inflammatory myofibroblastic tumors: A short series with an emphasis on the diagnostic and therapeutic challenges.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are a distinct entity of mesenchymal tumors. We present the challenges in their diagnosis and management. MATERIALS AND METHODS: A retrospective study with detailed clinical, radiological, and histopathological (HPE) features along with management and outcome of 10 biopsy-proven patients with IMT, between 2001 and 2020. RESULTS: The location included intracranial (5), orbital (4), and spinal (1) with M : F = 7 : 3. The mean age of onset was in the third decade. The commonest symptom was headache, while proptosis and blurred vision occurred in orbital IMTs. HPE revealed diffuse infiltration of mixed inflammatory cells over proliferating myofibroblasts. Smooth muscle antigen immunoreactivity was noted in fibroblastic spindle cells of all IMTs. However, we did not find anaplastic lymphoma kinase expression in any of our cases, as this is only found in ~ 50% of all IMTs. Tumor infiltration into adjacent tissue was noted in 4 patients. Surgical excision was limited to orbital IMTs, as most central nervous system (CNS) tumors were not amenable for resection. Steroid administration showed moderate improvement in the IMT-CNS patients but also required additional immunomodulation. Four patients had a median long-term follow-up of 7 years. Two patients had recurrent lesions demonstrated by imaging after 2 years of initial presentation. CONCLUSION: IMTs are rare and ambiguous tumors of unknown etiology that can occur anywhere in the body. Clinical and radiological features may not be specific to determine the diagnosis, but it should be considered as a differential diagnosis. Extensive thorough workup with histopathology along with the help of immunohistochemistry is conducive to better clinical outcomes. Surgical biopsy with extensive and total resection of these tumors along with steroid and radiotherapy may enhance the survival outcomes.

A network map of GDNF/RET signaling pathway in physiological and pathological conditions.

Glial cell line-derived neurotrophic factor (GDNF) signals through a multi-component receptor system predominantly consisting of glycosyl-phosphatidylinositol-anchored GDNF family receptor alpha-1 (GFRα1) and the Rearranged during transfection (RET) receptor tyrosine kinase. GDNF/RET signaling is vital to the central and peripheral nervous system, kidney morphogenesis, and spermatogenesis. In addition, the dysregulation of the GDNF/RET signaling has been implicated in the pathogenesis of cancers. Despite the extensive research on GDNF/RET signaling, a molecular network of reactions induced by GDNF reported across the published literature. However, a comprehensive GDNF/RET pathway resource is currently unavailable. We describe an integrated signaling pathway reaction map of GDNF/RET consisting of 1151 molecular reactions. These include information pertaining to 52 molecular association events, 70 enzyme catalysis events, 36 activation/inhibition events, 22 translocation events, 856 gene regulation events, and 115 protein-level expression events induced by GDNF in diverse cell types. We developed a comprehensive GDNF/RET signaling network map based on these molecular reactions. The pathway map was made accessible through WikiPathways database ( https://www.wikipathways.org/index.php/Pathway:WP5143 ). Biocuration and development of gene regulatory network map of GDNF/RET signaling pathway.

Corpus Callosotomy for Non-Localizing Drug Resistant Epilepsy with Drop Attacks.

BACKGROUND: Corpus callosotomy (CC) is a surgical palliative procedure done for a selected group of patients with drug resistant epilepsy (DRE) to stop drop attacks and prevent falls. METHODS: We performed a retrospective chart review of consecutive patients who underwent CC for DRE with drop attacks at our center between 2015 and 2019. Clinical, imaging details and surgical findings were noted. Clinical outcomes and functional status were evaluated. RESULTS: During the study period, 17 patients underwent corpus callosotomy (Male: Female 14:3). The mean age at surgery was 10.3 years (standard deviation - 5.85, interquartile range [IQR] = 6.5). The mean age at onset of seizure was 2.23 years (standard deviation - 3.42, IQR = 1.5). Preoperative seizure frequency ranged from 2 to 60 attacks per day (median: 20, IQR= 36). All patients had atonic seizures/drop attacks. One patient underwent anterior CC and 16 underwent complete CC. Three patients had complications in the postoperative period. The median follow-up was 26 months. All patients had cessation of drop attacks immediately following surgery. One patient with anterior CC had a recurrence of drop attacks for which she underwent completion CC. Another patient had recurrent drop attacks 3 years later and was found to have a residual callosal connection. Three patients had complete seizure freedom and 4 patients had a <50% reduction in seizure frequency. CONCLUSIONS: Our study lends additional support to the efficacy of CC in patients with DRE, with the cessation of drop attacks. It also provided a reasonable reduction in seizure frequency. Complete CC led to better control of drop attacks.

Pathological (Dis)Similarities in Neuronal Exosome-Derived Synaptic and Organellar Marker Levels Between Alzheimer's Disease and Frontotemporal Dementia.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are pathologically distinct neurodegenerative disorders with certain overlap in cognitive and behavioral symptoms. Both AD and FTD are characterized by synaptic loss and accumulation of misfolded proteins, albeit, in different regions of the brain. OBJECTIVE: To investigate the synaptic and organellar markers in AD and FTD through assessment of the levels of synaptic protein, neurogranin (Ng) and organellar proteins, mitofusin-2 (MFN-2), lysosomal associated membrane protein-2 (LAMP-2), and golgin A4 from neuronal exosomes. METHODS: Exosomes isolated from the plasma of healthy controls (HC), AD and FTD subjects were characterized using transmission electron microscopy. Neurodegenerative status was assessed by measurement of neurofilament light chain (NfL) using Simoa. The pooled exosomal extracts from each group were analyzed for Ng, MFN-2, LAMP-2, and golgin A4 by western blot analysis using enhanced chemiluminescence method of detection. RESULTS: The densitometric analysis of immunoreactive bands demonstrated a 65% reduction of Ng in AD and 53% in FTD. Mitochondrial protein MFN-2 showed a significant reduction by 32% in AD and 46% in FTD. Lysosomal LAMP-2 and Golgi complex associated golgin A4 were considerably increased in both AD and FTD. CONCLUSION: Changes in Ng may reflect the ongoing synaptic degeneration that are linked to cognitive disturbances in AD and FTD. Importantly, the rate of synaptic degeneration was more pronounced in AD. Changes to a similar extent in both the dementia groups in organellar proteins indicates shared mechanisms of protein accumulation/degradation common to both AD and FTD.

A molecular network map of orexin-orexin receptor signaling system.

Orexins are excitatory neuropeptides, which are predominantly associated with feeding behavior, sleep-wake cycle and energy homeostasis. The orexinergic system comprises of HCRTR1 and HCRTR2, G-protein-coupled receptors of rhodopsin family and the endogenous ligands processed from HCRT pro-hormone, Orexin A and Orexin B. These neuropeptides are biosynthesized by the orexin neurons present in the lateral hypothalamus area, with dense projections to other brain regions. The orexin-receptor signaling is implicated in various metabolic as well as neurological disorders, making it a promising target for pharmacological interventions. However, there is limited information available on the collective representation of the signal transduction pathways pertaining to the orexin-orexin receptor signaling system. Here, we depict a compendium of the Orexin A/B stimulated reactions in the form of a basic signaling pathway map. This map catalogs the reactions into five categories: molecular association, activation/inhibition, catalysis, transport, and gene regulation. A total of 318 downstream molecules were annotated adhering to the guidelines of NetPath curation. This pathway map can be utilized for further assessment of signaling events associated with orexin-mediated physiological functions and is freely available on WikiPathways, an open-source pathway database ( https://www.wikipathways.org/index.php/Pathway:WP5094 ).