Di-lysine motif-like sequences formed by deleting the C-terminal domain of aquaporin-4 prevent its trafficking to the plasma membrane.

Aquaporin-4 is a transmembrane water channel protein, the C-terminal domain of which is facing the cytosol. In the process of investigating the role of the C-terminal domain of aquaporin-4 with regard to intracellular trafficking, we observed that a derivative of aquaporin-4, in which the C-terminal 53 amino acids had been removed (Δ271-323), was localized to intracellular compartments, including the endoplasmic reticulum, but was not expressed on the plasma membranes. This was determined by immunofluorescence staining and labeling of the cells with monoclonal antibody specifically recognizing the extracellular domain of aquaporin-4, followed by confocal microscopy and flow cytometry. Deletion of additional amino acids in the C-terminal domain of aquaporin-4 led to its redistribution to the plasma membrane. This suggests that the effect of the 53-amino acid deletion on the subcellular localization of aquaporin-4 could be attributed to the formation of a signal at the C terminus that retained aquaporin-4 in intracellular compartments, rather than the loss of a signal required for plasma membrane targeting. Substitution of the lysine at position 268 with alanine could rescue the Δ271-323-associated retention in the cytosol, suggesting that the C-terminal sequence of the mutant served as a signal similar to a di-lysine motif.

Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke.

Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.

Alteration of global protein SUMOylation in neurons and astrocytes in response to Alzheimer's disease-associated insults.

SUMOylation, a post-translational modification of lysine residues by small ubiquitin-like modifier (SUMO) proteins, has been implicated in the pathogenesis of neurodegenerative disorders including Alzheimer's disease (AD), and in neuron- and astrocyte-specific physiological functions. Global SUMOylation is increased in the AD mouse brain in the pre-plaque-forming stage but returns to wild-type levels in the plaque-bearing stage. To clarify the reason for the transient change in SUMOylation, we analyzed the alteration of global SUMOylation induced by AD-associated cytotoxic stimuli in neurons and astrocytes individually. In neurons, amyloid ß42 oligomers induced some but not significant increase in levels of SUMO1-modified proteins. Both hydrogen peroxide and glutamate significantly reduced SUMO1-modified protein levels. These changes were more prominent in neurons than in astrocytes. The opposite effect of Aß and oxidative/excitotoxic stimuli on SUMO1 modification may cause the pathological stage-associated change in the level of SUMO-modified proteins in the AD mouse brain.

Sustained down-regulation of ß-dystroglycan and associated dysfunctions of astrocytic endfeet in epileptic cerebral cortex.

Epilepsy is characterized by the abnormal activation of neurons in the cerebral cortex, but the molecular and cellular mechanisms contributing to the development of recurrent seizures are largely unknown. Recently, the critical involvement of astrocytes in the pathophysiology of epilepsy has been proposed. However, the nature of plastic modulations of astrocytic proteins in the epileptic cortex remains poorly understood. In this study, we utilized the zero magnesium in vitro model of epilepsy and examined the potential molecular changes of cortical astrocytes, focusing specifically on endfeet, where specialized biochemical compartments exist. We find that the continuous epileptic activation of neurons for 1 h decreases the expression level of ß-dystroglycan (ßDG) in acute cortical brain slices prepared from mice. This change is completely abolished by the pharmacological blockade of NMDA-type glutamate receptors as well as by matrix metalloproteinase inhibitors. Consistent with the highly specialized localization of ßDG at astrocytic endfeet, where it plays a pivotal role in anchoring endfeet-enriched proteins in astrocytes, the down-regulation of ßDG is accompanied by a decrease in the expression of AQP4 but not laminin. Importantly, this down-regulation of ßDG persists for at least 1 h, even after the apparent recovery of neuronal activation. Finally, we show that the down-regulation of ßDG is associated with the dysfunction of the endfeet at the blood-brain interface as a diffusion barrier. These results suggest that the sustained down-regulation of ßDG leads to dysfunctions of astrocytic endfeet in the epileptic cerebral cortex and may contribute to the pathogenesis of epilepsy.

Aquaporin 4-dependent expression of glial fibrillary acidic protein and tenascin-C in activated astrocytes in stab wound mouse brain and in primary culture.

We previously reported that aquaporin 4 (AQP4) has a neuroimmunological function via astrocytes and microglial cells involving osteopontin. AQP4 is a water channel localized in the endofoot of astrocytes in the brain, and its expression is upregulated after a stab wound to the mouse brain or the injection of methylmercury in common marmosets. In this study, the correlation between the expression of AQP4 and the expression of glial fibrillary acidic protein (GFAP) or tenascin-C (TN-C) in reactive astrocytes was examined in primary cultures and brain tissues of AQP4-deficient mice (AQP4/KO). In the absence of a stab wound to the brain or of any stimulation of the cells, the expressions of both GFAP and TN-C were lower in astrocytes from AQP4/KO mice than in those from wild-type (WT) mice. High levels of GFAP and TN-C expression were observed in activated astrocytes after a stab wound to the brain in WT mice; however, the expressions of GFAP and TN-C were insignificant in AQP4/KO mice. Furthermore, lipopolysaccharide (LPS) stimulation activated primary culture of astrocytes and upregulated GFAP and TN-C expression in cells from WT mice, whereas the expressions of GFAP and TN-C were slightly upregulated in cells from AQP4/KO mice. Moreover, the stimulation of primary culture of astrocytes with LPS also upregulated inflammatory cytokines in cells from WT mice, whereas modest increases were observed in cells from AQP4/KO mice. These results suggest that AQP4 expression accelerates GFAP and TN-C expression in activated astrocytes induced by a stab wound in the mouse brain and LPS-stimulated primary culture of astrocytes.

Sympathotomy for palmar hyperhidrosis: the cutting versus clamping methods.

PURPOSE: Endoscopic thoracic sympathectomy/sympathotomy for the treatment of palmar hyperhidrosis is generally performed by either cutting or clamping the sympathetic chain. However, it remains unclear as to which of these methods is more effective and has fewer side effects. This study was conducted to compare the effects of sympathotomy by cutting or clamping at T3 on two outcomes--postoperative palmar sweating and compensatory sweating; it also evaluated postoperative patient satisfaction. METHODS: The participants were among 289 patients who underwent bilateral sympathotomy at T3 for palmar hyperhidrosis. These patients were sent questionnaires by mail to assess their self-reported degree of postoperative palmar sweating and compensatory sweating, as well as their level of satisfaction. Of the 92 patients who responded to the questionnaire, 54 had undergone sympathotomy by cutting (cutting group) and 38 by clamping (clamping group). RESULTS: The degree of postoperative palmar sweating was significantly lower in the cutting group than in the clamping group. However, compensatory sweating was significantly more severe in the cutting group than in the clamping group. No significant difference was observed in the degree of patient satisfaction between the groups. CONCLUSIONS: Sympathotomy by clamping at T3 was less effective in reducing the primary symptom of postoperative palmar sweating, but induced less compensatory sweating than did sympathotomy by cutting at T3. However, both methods were similar with regard to patient satisfaction. The degree of postoperative palmar sweating and the severity of compensatory sweating were inversely correlated with the degree of patient satisfaction.

Expression and localization of aquaporin-4 in sensory ganglia.

Aquaporin-4 (AQP4) is a water channel protein that is predominantly expressed in astrocytes in the CNS. The rapid water flux through AQP4 may contribute to electrolyte/water homeostasis and may support neuronal activities in the CNS. On the other hand, little is known about the expression of AQP4 in the peripheral nervous system (PNS). Using AQP4(-/-) mice as a negative control, we demonstrated that AQP4 is also expressed in sensory ganglia, such as trigeminal ganglia and dorsal root ganglia in the PNS. Immunohistochemistry revealed that AQP4 is exclusively localized to satellite glial cells (SGCs) surrounding the cell bodies of the primary afferent sensory neurons in the sensory ganglia. Biochemical analyses revealed that the expression levels of AQP4 in sensory ganglia were considerably lower than those in astrocytes in the CNS. Consistently, behavioral analyses did not show any significant difference in terms of mechanical and cold sensitivity between wild type and AQP4(-/-) mice. Overall, although the pathophysiological relevance of AQP4 in somatosensory perception remains unclear, our findings provide new insight into the involvement of water homeostasis in the peripheral sensory system.

Immunological function of aquaporin-4 in stab-wounded mouse brain in concert with a pro-inflammatory cytokine inducer, osteopontin.

During injury to the central nervous system (CNS), astrocytes and microglia proliferate and migrate around the lesion sites. Recently, it has been reported that one of the water channels, aquaporin-4 (AQP4) is seemed to have a role in astroglial migration and glial scar formation caused by brain injury, although its molecular mechanism is largely unknown. In the present study, we examined the expression profiles in wild-type (WT) and AQP4-deficient (AQP4/KO) mice after a stab wound to the cerebral cortex. Three days after the stab wound, AQP4 expression was observed in activated microglia around the lesion site as well as in astrocytes. A microarray analysis revealed that 444 genes around the lesion site were upregulated 3 days after the wounding in WT mice. Surprisingly, most of these up-regulations were significantly attenuated in AQP4/KO mice. Real-time RT-PCR and immunofluorescence showed that osteopontin (OPN) expression around the lesion site was much lower in AQP4/KO mice than in WT mice. Moreover, the up-regulation of pro-inflammatory cytokines was significantly attenuated in AQP4/KO mice. Taken together, these results suggest that AQP4 plays an important role in immunological function in concert with OPN under pathological conditions in the CNS.

Efficacy and safety of intravenous fosphenytoin for patients with acute herpes zoster-associated pain: A placebo-controlled randomized trial.

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 µg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330.

Successful neurolytic thoracic sympathetic ganglion block using C-arm fluoroscopic cone-beam computed tomography in patients with postmastectomy pain syndrome: a report of 3 cases.

BACKGROUND: Postmastectomy pain syndrome involves persistent neuropathic and sympathetically maintained neuropathic pain that can be improved using a thoracic sympathetic ganglion block. However, conventional fluoroscopic procedures pose technical difficulties and are associated with potential severe complications. We report the use of C-arm fluoroscopic cone-beam computed tomography to enhance procedural success and treatment safety. CASE PRESENTATION: Three women diagnosed with postmastectomy pain syndrome and experiencing persistent pain underwent C-arm fluoroscopic cone-beam computed tomography-assisted ethanol neurolytic thoracic sympathetic ganglion block. Pain severity decreased substantially after the procedure. The therapeutic effects were sustained for 12 months in cases 1 and 2 and for 5 months in case 3. All patients experienced a remarkable decrease in allodynia and hyperalgesia intensities. CONCLUSION: C-arm fluoroscopic cone-beam computed tomography-assisted neurolytic thoracic sympathetic ganglion block offers a valuable alternative for managing otherwise intractable postmastectomy pain syndrome before considering more invasive techniques.

A tyrosine-based YXXΦ motif regulates the degradation of aquaporin-4 via both lysosomal and proteasomal pathways and is functionally inhibited by a 10-amino-acid sequence within its C-terminus.

Aquaporin-4 (AQP4) is a dominant water channel in the brain and is expressed on astrocytic end-feet, mediating water homeostasis in the brain. AQP4 is a target of an inflammatory autoimmune disease, neuromyelitis optica spectrum disorders (NMOSD), that causes demyelination. An autoantibody recognizing the extracellular domains of AQP4, called NMO-IgG, is critically implicated in the pathogenesis of the disease. Complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) in astrocytes are the primary causes of the disease, preceding demyelination and neuronal damage. Additionally, some cytotoxic effects of binding of NMO-IgG to AQP4, independent of CDC/ADCC, have been proposed. Antibody-induced endocytosis of AQP4 is thought to be involved in CDC/ADCC-independent cytotoxicity induced by the binding of NMO-IgG to AQP4. To clarify the mechanism responsible for antibody-induced endocytosis of AQP4, we investigated the subcellular localization and trafficking of AQP4, focusing on its C-terminal domain, by making a variety of deletion and substitution mutants of mouse AQP4. We found that a tyrosine-based YXXΦ motif in the C-terminal domain of AQP4 plays a critical role in the steady-state subcellular localization/turnover and antibody-induced endocytosis/lysosomal degradation of AQP4. Our results indicate that the YXXΦ motif has to escape the inhibitory effect of the C-terminal 10-amino-acid sequence and be located at an appropriate distance from the plasma membrane to act as a signal for lysosomal degradation of AQP4. In addition to lysosomal degradation, we demonstrated that the YXXΦ motif also functions as a signal to degrade AQP4 using proteasomes under specific conditions.

Prolonged Light Exposure Induces Circadian Impairment in Aquaporin-4-Knockout Mice.

Astrocytes are densely present in the suprachiasmatic nucleus (SCN), which is the master circadian oscillator in mammals, and are presumed to play a key role in circadian oscillation. However, specific astrocytic molecules that regulate the circadian clock are not yet well understood. In our study, we found that the water channel aquaporin-4 (AQP4) was abundantly expressed in SCN astrocytes, and we further examined its circadian role using AQP4-knockout mice. There was no prominent difference in circadian behavioral rhythms between Aqp4-/- and Aqp4+/+ mice subjected to light-dark cycles and constant dark conditions. However, exposure to constant light induced a greater decrease in the Aqp4-/- mice rhythmicity. Although the damped rhythm in long-term constant light recovered after transfer to constant dark conditions in both genotypes, the period until the reappearance of original rhythmicity was severely prolonged in Aqp4-/- mice. In conclusion, AQP4 absence exacerbates the prolonged light-induced impairment of circadian oscillations and delays their recovery to normal rhythmicity.

Long-Term Analgesic Efficacy of Neurolytic Splanchnic Nerve Block via the Transintervertebral Disc Approach to Retrocrural Space: A Multicenter Retrospective Study.

INTRODUCTION: The celiac plexus block is effective for treating intractable cancer pain and has been the focus of many studies. At our affiliated institution, fluoroscopy-guided splanchnic nerve block with a single needle via the transintervertebral disc approach was the first choice of treatment. The short-term efficacy of this technique has been reported, but the long-term efficacy is not clear. In the present study, we investigated the long-term analgesic efficacy of this technique. METHODS: This multicenter, retrospective, observational study reviewed the medical records of patients who underwent neurolytic splanchnic nerve block (NSNB) via the transintervertebral disc approach for intractable cancer pain at five tertiary hospitals in Japan from April 2005 to October 2020. The primary outcome was the long-term analgesic efficacy of a one-time NSNB via the transintervertebral disc approach. RESULTS: In total, 76 patients were included in the analysis. The median lowest numerical rating scale (NRS) score was 1 within 14 days. At 1, 2, 3, and 6 months after the nerve block, the median NRS score was also ≤ 2, while the median equivalent oral morphine dose did not show any clinically noticeable increase at those times. CONCLUSION: The long-term analgesic efficacy of NSNB via the transintervertebral disc approach in patients with intractable cancer pain has been demonstrated.

The celiac plexus block is effective for treating intractable cancer pain and has been the focus of many studies. The celiac plexus nerve block relieves intractable cancer pain arising from the pancreas or other organs in close proximity, and the splanchnic nerve block is considered clinically equivalent to the celiac plexus block for analgesia. At our affiliated institution, fluoroscopy-guided neurolytic splanchnic nerve block with a single needle via the transintervertebral disc approach is the first choice of treatment because it is technically simpler and less invasive than other approaches. While the short-term efficacy of this technique is known, its long-term efficacy remains unclear. Thus, this multicenter, retrospective, observational study aimed to investigate the long-term analgesic efficacy of a neurolytic splanchnic nerve block via the transintervertebral disc approach. The medical records of patients in whom intractable cancer pain was managed using this technique at five tertiary hospitals in Japan were analyzed. The primary outcome was the long-term analgesic efficacy of a one-time neurolytic splanchnic nerve block via the transintervertebral disc approach. The median lowest numerical rating scale score was 1 within 14 days. At 1, 2, 3, and 6 months after the nerve block, the median numerical rating scale score was also ≤ 2, while the median equivalent oral morphine dose did not show any clinically noticeable increase at those times. This technique may reduce opioid dose and associated side effects compared with long-term conventional pharmacotherapy alone.

An astrocyte-specific enhancer of the aquaporin-4 gene functions through a consensus sequence of POU transcription factors in concert with multiple upstream elements.

Aquaporin-4, a predominant water channel in the brain, is specifically expressed in astrocyte endfeet and plays a central role in water homeostasis, neuronal activity, and cell migration in the brain. It has two dominant isoforms called M1 and M23, whose mRNA is driven by distinct promoters located upstream of exons 0 and 1 of the aquaporin-4 gene, respectively. To identify cis-acting elements responsible for the astrocyte-specific transcription of M1 mRNA, the promoter activity of the 5'-flanking region upstream of exon 0 in primary cultured mouse astrocytes was examined by luciferase assay, and sequences, where nuclear factors bind, were identified by electrophoretic mobility shift assay. An astrocyte-specific activity enhancing transcription from the M1 promoter was observed within ∼2 kb from the transcriptional start sites of M1 mRNA. At least five elements clustered within the 286-bp region were found to function as a novel astrocyte-specific enhancer. Among the five elements, a consensus sequence of Pit-1/Oct/Unc-86 (POU) transcription factors was indispensable to the astrocyte-specific enhancer since disruption of the POU motif completely abolished the enhancer activity in astrocytes. However, the POU motif alone had little activity, indicating the requirement for cooperation with other upstream elements to exert full enhancer activity.

[Percutaneous vertebroplasty for vertebral compression fractures in the patient with acute lymphoblastic leukemia].

Percutaneous vertebroplasty (PVP) is an interventional treatment for painful vertebral compression fractures caused by osteoporosis and malignant diseases such as multiple myeloma and metastatic bone tumors. We present the first case of PVP performed on a man in his thirties with vertebral compression fractures secondary to acute lymphoblastic leukemia. PVP at T11 and L1 levels resulted in a marked improvement in refractory pain although he developed delayed pyogenic spondylitis two months after the intervention. This case suggests that PVP could be one of the useful therapeutic procedures for intractable back pain associated with vertebral compression fractures in acute lymphoblastic leukemia if we are extremely vigilant for the risk of spondylitis.

Aquaporin-4 in Neuromyelitis Optica Spectrum Disorders: A Target of Autoimmunity in the Central Nervous System.

Since the discovery of a specific autoantibody in patients with neuromyelitis optica spectrum disorder (NMOSD) in 2004, the water channel aquaporin-4 (AQP4) has attracted attention as a target of autoimmune diseases of the central nervous system. In NMOSD, the autoantibody (NMO-IgG) binds to the extracellular loops of AQP4 as expressed in perivascular astrocytic end-feet and disrupts astrocytes in a complement-dependent manner. NMO-IgG is an excellent marker for distinguishing the disease from other inflammatory demyelinating diseases, such as multiple sclerosis. The unique higher-order structure of AQP4-called orthogonal arrays of particles (OAPs)-as well as its subcellular localization may play a crucial role in the pathogenesis of the disease. Recent studies have also demonstrated complement-independent cytotoxic effects of NMO-IgG. Antibody-induced endocytosis of AQP4 has been suggested to be involved in this mechanism. This review focuses on the binding properties of antibodies that recognize the extracellular region of AQP4 and the characteristics of AQP4 that are implicated in the pathogenesis of NMOSD.

Glymphatic system clears extracellular tau and protects from tau aggregation and neurodegeneration.

Accumulation of tau has been implicated in various neurodegenerative diseases termed tauopathies. Tau is a microtubule-associated protein but is also actively released into the extracellular fluids including brain interstitial fluid and cerebrospinal fluid (CSF). However, it remains elusive whether clearance of extracellular tau impacts tau-associated neurodegeneration. Here, we show that aquaporin-4 (AQP4), a major driver of the glymphatic clearance system, facilitates the elimination of extracellular tau from the brain to CSF and subsequently to deep cervical lymph nodes. Strikingly, deletion of AQP4 not only elevated tau in CSF but also markedly exacerbated phosphorylated tau deposition and the associated neurodegeneration in the brains of transgenic mice expressing P301S mutant tau. The current study identified the clearance pathway of extracellular tau in the central nervous system, suggesting that glymphatic clearance of extracellular tau is a novel regulatory mechanism whose impairment contributes to tau aggregation and neurodegeneration.

Successful annuloplasty using the cone-beam computed tomography-assisted radiofrequency thermocoagulation system in a patient with severe vertebral deformity: a case report.

BACKGROUND: Complex anatomical features are challenging for minimally invasive intradiscal therapy owing to insufficient visualization for accurate needle advancement. We report the case of a patient with dysraphic vertebral pathologies who presented with L5/S1 degeneration and was successfully treated with annuloplasty using the cone-beam computed tomography (CBCT)-assisted radiofrequency thermocoagulation system. CASE PRESENTATION: A 34-year-old woman presented with a lower back and left radicular pain of L5/S1 discogenic origin, accompanied by spina bifida occulta and lumbosacral transitional vertebra. Radiofrequency annuloplasty was performed to preserve disc height and spinal stability, with real-time CBCT guidance for the congenital and degenerative conditions. The procedure relieved her left lower-extremity pain and magnetic resonance imaging revealed that the L5/S1 disc bulging decreased while the disc height was preserved. CONCLUSION: Optimal accessibility of radiofrequency thermocoagulation and effective needle guidance using CBCT significantly improve the success rate of annuloplasty at the L5/S1 degenerative disc with severe vertebral deformity.

Quantitative measurement of diffusion-weighted imaging signal using expression-controlled aquaporin-4 cells: Comparative study of 2-compartment and diffusion kurtosis imaging models.

The purpose of this study was to compare parameter estimates for the 2-compartment and diffusion kurtosis imaging models obtained from diffusion-weighted imaging (DWI) of aquaporin-4 (AQP4) expression-controlled cells, and to look for biomarkers that indicate differences in the cell membrane water permeability. DWI was performed on AQP4-expressing and non-expressing cells and the signal was analyzed with the 2-compartment and diffusion kurtosis imaging models. For the 2-compartment model, the diffusion coefficients (Df, Ds) and volume fractions (Ff, Fs, Ff = 1-Fs) of the fast and slow compartments were estimated. For the diffusion kurtosis imaging model, estimates of the diffusion kurtosis (K) and corrected diffusion coefficient (D) were obtained. For the 2-compartment model, Ds and Fs showed clear differences between AQP4-expressing and non-expressing cells. Fs was also sensitive to cell density. There was no clear relationship with the cell type for the diffusion kurtosis imaging model parameters. Changes to cell membrane water permeability due to AQP4 expression affected DWI of cell suspensions. For the 2-compartment and diffusion kurtosis imaging models, Ds was the parameter most sensitive to differences in AQP4 expression.

Efficacy and Safety of Neurolytic Splanchnic Nerve Block via Transintervertebral Disc Approach to Retrocrural Space: A Multicenter Retrospective Study.

INTRODUCTION: Celiac plexus block is effective for treating intractable cancer pain and has been the focus of many studies. Several guiding techniques such as fluoroscopy, computed tomography, and endoscopy have been devised, and the target of the block has varied in previous studies as both the celiac plexus and splanchnic nerve, which is the main origin of the celiac plexus, have been targeted. At our affiliated institution, fluoroscopy-guided splanchnic nerve block with a single needle via transintervertebral disc approach is the first choice. However, there have been few reports on the use of this technique. This study investigated the efficacy and safety of this technique. METHODS: This multicenter retrospective observational study reviewed the medical records of patients who underwent neurolytic splanchnic nerve block (NSNB) via transintervertebral disc approach for intractable cancer pain at five tertiary hospitals in Japan from April 2005 to October 2020. The primary outcome was the clinical success ratio of NSNB, and the secondary outcome was the incidence ratio of NSNB-related adverse events. RESULTS: In total, 103 patients were included in the analysis. Of these, 77 patients met the definition of clinical success, with a ratio of 74.8%. The incidence ratio of NSNB-related adverse events was 40.8% (hypotension, 21.4%; alcohol intoxication, 13.6%; diarrhea, 11.7%; and vascular puncture, 3.9%; duplicates were present). All adverse events improved with observation and symptomatic treatment only. No patient had infection or serious adverse events such as organ or nerve damage. CONCLUSIONS: The clinical success ratio of this technique was 74.8%. Although the incidence of adverse events was 40.8%, all events were mild and no serious adverse events were observed. The findings demonstrate the efficacy and safety of our NSNB in patients with intractable cancer pain.

In patients with intractable pain from abdominal cancer, fluoroscopy-guided neurolytic splanchnic nerve block via transintervertebral disc approach is an effective and safe procedure. It can be completed with a single needle puncture, and is anatomically less likely to cause organ or nerve damage compared with other approaches. The analgesia produced by this technique, along with conventional pharmacotherapy for cancer pain, may reduce opioid dose and its side effects and improve patients' quality of life.