Long-term effect of posterior nasal neurectomy for perennial allergic rhinitis.

BACKGROUND: Surgical treatment is recommended for patients with severe allergic rhinitis (AR) refractory to medical treatment. Endoscopic posterior nasal neurectomy (PNN) is primarily performed to improve rhinorrhea in severe perennial AR, however studies on its long-term prognosis are lacking. AIMS/OBJECTIVES: This study aimed to investigate the long-term prognosis of PNN. MATERIALS AND METHODS: A questionnaire survey was administered to 17 patients (12 men and 5 women) at least 1 year after PNN. Nasal symptoms and medications, as well as patient satisfaction with surgery at the time of survey, were scored. Furthermore, scores were compared between patients with postoperative periods of >5 years and <5 years. RESULTS: Nasal symptoms and medication scores significantly improved after surgery. There was no significant difference between patients with a postoperative period of >5 years and <5 years in both preoperative and postoperative nasal symptoms and medication scores. No correlation was found between patient satisfaction with surgery and postoperative period. CONCLUSIONS AND SIGNIFICANCE: PNN improved nasal symptoms and medication scores in patients with severe perennial AR. Furthermore, the study results suggest that the long-term effect of PNN for perennial AR lasts for >5 years. J. Med. Invest. 71 : 62-65, February, 2024.

Identification of compounds that cause axonal dieback without cytotoxicity in dorsal root ganglia explants and intervertebral disc cells with potential to treat pain via denervation.

Low back pain, knee osteoarthritis, and cancer patients suffer from chronic pain. Aberrant nerve growth into intervertebral disc, knee, and tumors, are common pathologies that lead to these chronic pain conditions. Axonal dieback induced by capsaicin (Caps) denervation has been FDA-approved to treat painful neuropathies and knee osteoarthritis but with short-term efficacy and discomfort. Herein, we propose to evaluate pyridoxine (Pyr), vincristine sulfate (Vcr) and ionomycin (Imy) as axonal dieback compounds for denervation with potential to alleviate pain. Previous literature suggests Pyr, Vcr, and Imy can cause undesired axonal degeneration, but no previous work has evaluated axonal dieback and cytotoxicity on adult rat dorsal root ganglia (DRG) explants. Thus, we performed axonal dieback screening using adult rat DRG explants in vitro with Caps as a positive control and assessed cytotoxicity. Imy inhibited axonal outgrowth and slowed axonal dieback, while Pyr and Vcr at high concentrations produced significant reduction in axon length and robust axonal dieback within three days. DRGs treated with Caps, Vcr, or Imy had increased DRG cytotoxicity compared to matched controls, but overall cytotoxicity was minimal and at least 88% lower compared to lysed DRGs. Pyr did not lead to any DRG cytotoxicity. Further, neither Pyr nor Vcr triggered intervertebral disc cell death or affected cellular metabolic activity after three days of incubation in vitro. Overall, our findings suggest Pyr and Vcr are not toxic to DRGs and intervertebral disc cells, and there is potential for repurposing these compounds for axonal dieback compounds to cause local denervation and alleviate pain.

Lesión electromiográfica del nervio axilar en fracturas del extremo proximal del húmero. Estudio prospectivo, observacional, analizando el patrón de fractura / Electromyographic axillary nerve injury in fractures of the proximal humerus: Prospective, observational study, analysing the fracture pattern

Objetivo: Descripción y análisis de la relación entre las fracturas de húmero proximal y la lesión traumática del nervio axilar circunflejo. Material y método: Estudio prospectivo, observacional, de una serie de casos consecutivos de fracturas de extremo proximal de húmero. Se realizó valoración radiográfica, clasificando las fracturas según el sistema AO (Arbeitsgemeinshaft für Osteosynsthesefragen, Asociación de Grupo de Trabajo para el Estudio de la Fijación Interna de las Fracturas), y electromiografía (EMG) para la evaluación de la lesión del nervio axilar. Resultados: De 105 casos consecutivos de fracturas de húmero proximal, 31 pacientes cumplían los criterios de inclusión. Muestra: 86% mujeres y 14% hombres con edad media de 71,8 años (30-96 años). De los pacientes incluidos en el estudio, 58% presentó una EMG normal o leve axonotmesis, 23% presentó neuropatía del nervio axilar sin denervación muscular y 19%, lesión con denervación del nervio axilar. Los pacientes que sufrieron fracturas complejas de húmero proximal (AO11B y AO11C) tuvieron más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG, siendo esta relación estadísticamente significativa (p < 0,001). Conclusiones: Los pacientes que sufren fracturas complejas de húmero proximal (AO11B y AO11C) tienen más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG (p < 0,001).(AU)

Objective: Description and analysis of the relation between the proximal humerus fracture patterns and the traumatic injury of the axillary nerve. Material and method: Prospective, observational study of a consecutive case series that analyzed proximal humerus fractures. Radiographic evaluation was performed, and AO (Arbeitsgemeinshaft für Osteosynsthesefragen) system was used to classify the fractures. Electromyography was used to diagnose the axillary nerve injury. Results: Thirty-one patients on 105 who had a proximal humerus fracture met inclusion criteria. Eighty-six percent of the patients included were women and 14% men. The mean age was 71.8 years (30–96 years). Of the patients included in the study, 58% had normal or mild axonotmesis EMG, 23% had axillary nerve neuropathy without muscle denervation and 19% had injury with axillary nerve denervation. Patients who suffered complex fractures of the proximal humerus (AO11B and AO11C) had a higher risk of presenting axillary neuropathy type lesions with muscle denervation in the EMG, this relationship being statistically significant (p<0.001). Conclusion: Patients who have more risk on presenting axillary nerve neuropathy with muscle denervation in electromyography are those who present complex proximal humerus fractures AO11B and AO11C (p<0.001).(AU)

[Translated article] Electromyographic axillary nerve injury in fractures of the proximal humerus: Prospective, observational study, analysing the fracture pattern / Lesión electromiográfica del nervio axilar en fracturas del extremo proximal del húmero. Estudio prospectivo, observacional, analizando el patrón de fractura

Objetivo: Descripción y análisis de la relación entre las fracturas de húmero proximal y la lesión traumática del nervio axilar circunflejo. Material y método: Estudio prospectivo, observacional, de una serie de casos consecutivos de fracturas de extremo proximal de húmero. Se realizó valoración radiográfica, clasificando las fracturas según el sistema AO (Arbeitsgemeinshaft für Osteosynsthesefragen, Asociación de Grupo de Trabajo para el Estudio de la Fijación Interna de las Fracturas), y electromiografía (EMG) para la evaluación de la lesión del nervio axilar. Resultados: De 105 casos consecutivos de fracturas de húmero proximal, 31 pacientes cumplían los criterios de inclusión. Muestra: 86% mujeres y 14% hombres con edad media de 71,8 años (30-96 años). De los pacientes incluidos en el estudio, 58% presentó una EMG normal o leve axonotmesis, 23% presentó neuropatía del nervio axilar sin denervación muscular y 19%, lesión con denervación del nervio axilar. Los pacientes que sufrieron fracturas complejas de húmero proximal (AO11B y AO11C) tuvieron más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG, siendo esta relación estadísticamente significativa (p < 0,001). Conclusiones: Los pacientes que sufren fracturas complejas de húmero proximal (AO11B y AO11C) tienen más riesgo de presentar lesiones tipo neuropatía axilar con denervación muscular en la EMG (p < 0,001).(AU)

Objective: Description and analysis of the relation between the proximal humerus fracture patterns and the traumatic injury of the axillary nerve. Material and method: Prospective, observational study of a consecutive case series that analyzed proximal humerus fractures. Radiographic evaluation was performed, and AO (Arbeitsgemeinshaft für Osteosynsthesefragen) system was used to classify the fractures. Electromyography was used to diagnose the axillary nerve injury. Results: Thirty-one patients on 105 who had a proximal humerus fracture met inclusion criteria. Eighty-six percent of the patients included were women and 14% men. The mean age was 71.8 years (30–96 years). Of the patients included in the study, 58% had normal or mild axonotmesis EMG, 23% had axillary nerve neuropathy without muscle denervation and 19% had injury with axillary nerve denervation. Patients who suffered complex fractures of the proximal humerus (AO11B and AO11C) had a higher risk of presenting axillary neuropathy type lesions with muscle denervation in the EMG, this relationship being statistically significant (p<0.001). Conclusion: Patients who have more risk on presenting axillary nerve neuropathy with muscle denervation in electromyography are those who present complex proximal humerus fractures AO11B and AO11C (p<0.001).(AU)

Renal denervation in the management of hypertension.

Arterial hypertension is a global leading cause of cardiovascular, cerebrovascular, and renal disease, as well as mortality. Although pharmacotherapy is safe and effective in lowering blood pressure (BP) and cardiovascular disease risk, BP control remains poor, and the mortality rates associated with high BP have been steadily increasing. Device-based therapies have been investigated to overcome barriers to pharmacotherapy, including non-adherence and low rates of persistence to daily medications. Among these device-based therapies, catheter-based renal denervation (RDN) has been most extensively examined over the past 15 years. In this state-of-the-art article, we summarise the rationale for RDN, review the available evidence, provide recommendations for a safe procedure, and discuss the role of RDN in current guidelines and clinical practice.

Dimorphic effect of TFE3 in determining mitochondrial and lysosomal content in muscle following denervation.

BACKGROUND: Muscle atrophy is a common consequence of the loss of innervation and is accompanied by mitochondrial dysfunction. Mitophagy is the adaptive process through which damaged mitochondria are removed via the lysosomes, which are regulated in part by the transcription factor TFE3. The role of lysosomes and TFE3 are poorly understood in muscle atrophy, and the effect of biological sex is widely underreported. METHODS: Wild-type (WT) mice, along with mice lacking TFE3 (KO), a transcriptional regulator of lysosomal and autophagy-related genes, were subjected to unilateral sciatic nerve denervation for up to 7 days, while the contralateral limb was sham-operated and served as an internal control. A subset of animals was treated with colchicine to capture mitophagy flux. RESULTS: WT females exhibited elevated oxygen consumption rates during active respiratory states compared to males, however this was blunted in the absence of TFE3. Females exhibited higher mitophagy flux rates and greater lysosomal content basally compared to males that was independent of TFE3 expression. Following denervation, female mice exhibited less muscle atrophy compared to male counterparts. Intriguingly, this sex-dependent muscle sparing was lost in the absence of TFE3. Denervation resulted in 45% and 27% losses of mitochondrial content in WT and KO males respectively, however females were completely protected against this decline. Decreases in mitochondrial function were more severe in WT females compared to males following denervation, as ROS emission was 2.4-fold higher. In response to denervation, LC3-II mitophagy flux was reduced by 44% in females, likely contributing to the maintenance of mitochondrial content and elevated ROS emission, however this response was dysregulated in the absence of TFE3. While both males and females exhibited increased lysosomal content following denervation, this response was augmented in females in a TFE3-dependent manner. CONCLUSIONS: Females have higher lysosomal content and mitophagy flux basally compared to males, likely contributing to the improved mitochondrial phenotype. Denervation-induced mitochondrial adaptations were sexually dimorphic, as females preferentially preserve content at the expense of function, while males display a tendency to maintain mitochondrial function. Our data illustrate that TFE3 is vital for the sex-dependent differences in mitochondrial function, and in determining the denervation-induced atrophy phenotype.

Belt electrode tetanus muscle stimulation reduces denervation-induced atrophy of rat multiple skeletal muscle groups.

Belt electrode-skeletal muscle electrical stimulation (B-SES) involves the use of belt-shaped electrodes to contract multiple muscle groups simultaneously. Twitch contractions have been demonstrated to protect against denervation-induced muscle atrophy in rats, possibly through mitochondrial biosynthesis. This study examined whether inducing tetanus contractions with B-SES suppresses muscle atrophy and identified the underlying molecular mechanisms. We evaluated the effects of acute (60 Hz, 5 min) and chronic (60 Hz, 5 min, every alternate day for one week) B-SES on the tibialis anterior (TA) and gastrocnemius (GAS) muscles in Sprague-Dawley rats using belt electrodes attached to both ankle joints. After acute stimulation, a significant decrease in the glycogen content was observed in the left and right TA and GAS, suggesting that B-SES causes simultaneous contractions in multiple muscle groups. B-SES enhanced p70S6K phosphorylation, an indicator of the mechanistic target of rapamycin complex 1 activity. During chronic stimulations, rats were divided into control (CONT), denervation-induced atrophy (DEN), and DEN + electrically stimulated with B-SES (DEN + ES) groups. After seven days of treatment, the wet weight (n = 8-11 for each group) and muscle fiber cross-sectional area (CSA, n = 6 for each group) of the TA and GAS muscles were reduced in the DEN and DEN + ES groups compared with that in the CON group. The DEN + ES group showed significantly higher muscle weight and CSA than those in the DEN group. Although RNA-seq and pathway analysis suggested that mitochondrial biogenesis is a critical event in this phenomenon, mitochondrial content showed no difference. In contrast, ribosomal RNA 28S and 18S (n = 6) levels in the DEN + ES group were higher than those in the DEN group, even though RNA-seq showed that the ribosome biogenesis pathway was reduced by electrical stimulation. The mRNA levels of the muscle proteolytic molecules atrogin-1 and MuRF1 were significantly higher in DEN than those in CONT. However, they were more suppressed in DEN + ES than those in DEN. In conclusion, tetanic electrical stimulation of both ankles using belt electrodes effectively reduced denervation-induced atrophy in multiple muscle groups. Furthermore, ribosomal biosynthesis plays a vital role in this phenomenon.

[Selective Neurectomy in Spastic Paralysis of the Upper Extremity]. / Die hyperselektive Neurektomie bei spastischen Lähmungen der oberen Extremität.

Selective neurectomy refers to the targeted transection of motor nerve fibres at their entry into the muscle in order to reduce the increased muscle tone in cases of spastic paralysis. This procedure has regained popularity in recent years, especially in the upper extremity. First and foremost, it requires an exact knowledge of the topographical anatomy of muscle innervation. To be able to control the extent and localisation of the denervation, the terminal nerve branches must be visualized precisely during the procedure. For a meaningful reduction of muscle tone, 2/3 to 4/5 of nerve fibres must be resected. This article presents the historical development, principles and operative details of this technique as well as clinical results.

Impact of renal denervation on patients with coronary microvascular dysfunction: study rationale and design.

AIMS: Long-standing hypertension may cause an impairment in microvascular coronary circulation, which is involved in many different cardiac conditions. Renal sympathetic denervation (RDN) has been successfully proven as a valuable therapeutic choice for patients with resistant hypertension; moreover, the procedure looks promising in other settings, such as heart failure and atrial fibrillation, given its ability to downregulate the sympathetic nervous system, which is a recognized driver in these conditions as well as in microvascular dysfunction progression. The aim of this study is to explore the effect of RDN on coronary physiology in patients with ascertained coronary microvascular dysfunction and resistant hypertension. METHODS: This is a multicenter, prospective, nonrandomized, open-label, interventional study. Consecutive patients with resistant hypertension, nonobstructive coronary artery disease (NOCAD) and documented microvascular dysfunction will be enrolled. Patients will undergo RDN by Spyral Symplicity 3 (Medtronic Inc, Minneapolis, Minnesota, USA) and reassessment of coronary microvascular function 6 months after the procedure. Primary endpoint will be the difference in the index of microcirculatory resistance. CONCLUSION: The IMPRESSION study seeks to evaluate if there is any pleiotropic effect of the RDN procedure that results in modulation of microvascular function; if observed, this would be the first evidence showing RDN as a valuable therapy to revert hypertension-related microvascular dysfunction.

Redundant nerve roots on magnetic resonance imaging can predict ongoing denervation in patients with lumbar spinal stenosis.

INTRODUCTION/AIMS: Redundant nerve roots (RNRs) are abnormally elongated and tortuous nerve roots that develop secondary to degenerative spinal stenosis. RNRs have been associated with poorer clinical outcomes after decompression surgery; however, studies on their clinical characteristics are limited. This study aimed to investigate the association between RNRs and denervation potentials, that is, abnormal spontaneous activity (ASA), on electromyography. METHODS: We retrospectively reviewed data of patients who underwent an electrodiagnostic study of the lower extremities between January 2020 and March 2023. Of these, patients with lumbar central spinal stenosis, as seen on magnetic resonance imaging, were included. We analyzed clinical and imaging data, including presence of ASA, and compared them according to the presence of RNRs. Multivariable logistic regression analysis was employed to identify factors associated with development of ASA. RESULTS: Among the 2003 patients screened, 193 were included in the study. RNRs were associated with advanced age (p < .001), longer symptom duration (p = .009), smaller cross-sectional area of the dural sac at the stenotic level (p < .001), and higher frequency of ASA (p < .001). Higher probability of ASA was correlated with greater RNR severity (p < .001). In the multivariable logistic regression analysis, ASA occurrence was associated with smaller cross-sectional area, multiple stenotic sites, and severe-grade RNRs. DISCUSSION: The presence of RNRs, particularly severe-grade RNRs, was identified as a significant risk factor for the development of ASA on electromyography. This finding may aid physicians in estimating the prognosis of patients with central spinal stenosis.

Investigation into a new denervation model of the sciatic nerve zones in rats: Selective motor or sensorial denervation.

OBJECTIVE: This study aimed to introduce a reliable and useful model of selective sensorial or motor denervations of the sciatic nerve in rats with clinical and laboratory outcomes. METHODS: The surgical technique was determined via detailed cadaveric dissections of rat sciatic nerve roots and cross-sectional histoanatomy. Forty animals were divided into the sham, sensorial denervation (SD), motor denervation (MD), and combined denervation (CD) groups and evaluated clinically via the pinch test and observation. Electrophysiological tests, retrograde neuronal labeling, and histologic and radiographic studies were performed. The weights of the muscles innervated by the sciatic nerve were measured. RESULTS: The nerve root topography at the L4 level was consistent. Hemilaminectomy satisfactorily exposed all the roots contributing to the sciatic nerve and selectively denervated its sensorial and motor zones. Sensorial denervation caused foot deformities and wound problems, which were more severe in SD than in MD and CD. Nerve histomorphometry, electrophysiological tests, retrograde neuronal labeling studies, and measurements of the muscle weights also verified the denervations. CONCLUSION: This study has shown the feasibility of selective (sensory or motor) sciatic nerve denervation through a single-level hemilaminectomy. The surgical technique is reliable and has a confounding effect on gait. Sensorial denervation had more severe foot problems than motor and combined denervation in rats.

Efficacy of radiofrequency in lumbar facet joint pain: a systematic review and meta-analysis of placebo-controlled randomized controlled trials.

BACKGROUND: Lumbar facet joint pain (LFJP) is one of the main causes of chronic low back pain (LBP) and can be treated using radiofrequency (RF) sensory denervation. The aim of this work is to analyze the efficacy of RF in LFJP through a systematic review and meta-analysis of randomized controlled trials (RCTs) with placebo control. MATERIALS AND METHODS: A systematic search was conducted in the Medline (PubMed), Scopus, Web of Science databases, and the Cochrane Central Register of Controlled Trials (CENTRAL). The variables of interest were pain, functional status, quality of life (QoL), and global perceived effect (GPE) measured at different time intervals: short (< 3 months), medium (> 3 and < 12 months), and long term (> 12 months). RESULTS: Eight RCTs with placebo control were included. RF showed significant benefits over placebo in pain relief in the short (MD - 1.01; 95% CI - 1.98 to -0.04; p = 0.04), medium (MD - 1.42; 95% CI - 2.41 to - 0.43; p = 0.005), and long term (MD - 1.12; 95% CI - 1.57 to - 0.68; p < 0.001), as well as improvement in functional disability in the short (SMD - 0.94; 95% CI - 1.73 to - 0.14; p = 0.02) and long term (SMD - 0.74; 95% CI - 1.09 to - 0.39; p < 0.001). No statistically significant differences were observed in QoL or quantitative GPE, but benefits for RF were observed in dichotomous GPE in the medium (OR 0.19; 95% CI 0.07-0.52; p = 0.001) and long term (OR 0.22; 95% CI 0.06-0.78; p = 0.02). Subgroup analyses showed more benefits for RF in LBP < 1 year in the short term and in RCTs that did not require performing an MRI for patient selection. CONCLUSIONS: RF demonstrated significant improvement in pain and functionality, but the benefits in terms of QoL and GPE are inconclusive. Future clinical trials should investigate the long-term effects of RF, its impact on quality of life, and define appropriate criteria for patient selection.

Teres minor denervation and pathologies resulting in shoulder joint instability and rotator cuff tears: A retrospective cross-sectional MRI study.

Teres minor denervation (TMD) has gained increasing attention in recent years, particularly with the advent of magnetic resonance imaging (MRI). The potential association between TMD and shoulder instability or rotator cuff tear remains a subject of interest in the orthopedic community. In this retrospective and cross-sectional study, authors aim to investigate the potential association between TMD and shoulder instability or rotator cuff tears. Authors retrospectively analyzed MRI findings from 105 patients with TMD, focusing on rotator cuff pathologies, posterior labrocapsular complex (PLCC) tears, and posteroinferior glenohumeral joint capsule alterations. Authors assessed the association between TMD and rotator cuff and PLCC tears. For the multivariate analysis, partial proportional odds models were constructed for subscapularis (SSC) and SSP tears. Rotator cuff tears were present in 82.9% of subjects, with subscapularis (SSC) tears being the most frequent (77.1%). A significant association was observed between TMD and rotator cuff pathology (P = .002). PLCC tears were found in 82.3% of patients, and humeral position relative to the osseous glenoid was noted in 60% of patients with TMD. A significant association was identified between TMD and shoulder instability or labral/capsular abnormalities (P < .001). More than half of the cases exhibited a long tethering appearance toward the axillary neurovascular bundle on T1-weighted sagittal images. Our findings suggest that TMD is significantly associated with rotator cuff tears and shoulder instability. This study highlights the importance of identifying and treating PLCC tears in patients with TMD to address shoulder instability. Further research is needed to elucidate the role of TMD in the pathogenesis of shoulder instability and rotator cuff pathology.

Impact of renal denervation on cardiac remodeling in resistant hypertension: A meta-analysis.

Twelve studies involving 433 patients were included. After RDN treatment, LVMI decreased by 13.08 g/m2 (95% confidence interval [CI]: -18.38, -7.78; p < .00001), PWTd decreased by 0.60 mm (95% CI: -0.87, -0.34; p < .00001), IVSTd decreased by 0.78 mm (95% CI: -1.06, -0.49; p < .00001), and LVEF increased by 1.80% (95% CI: 0.71, 2.90; p = .001). However, there were no statistically significant improvements in LVIDd (95% CI: -1.40, 0.24; p = .17) and diastolic function (E/A) (95% CI: -0.04, 0.14; p = .28). Drug treatment for resistant hypertension (RH) is challenging. Renal denervation (RDN) is one of the most promising treatments for RH. Although studies have shown RDN can control blood pressure, the impacts of RDN on cardiac remodeling and cardiac function are unclear. This meta-analysis evaluated the effect of RDN on cardiac structure and function in patients with RH. PubMed, Embase, and Cochrane were used to conduct a systematic search. The main inclusion criteria were studies on patients with RH who received RDN and reported the changes in echocardiographic parameters before and after RDN. Echocardiographic parameters included left ventricular mass index (LVMI), end-diastolic left ventricular internal dimension (LVIDd), left ventricular end-diastolic posterior wall thickness (PWTd), end-diastolic interventricular septum thickness (IVSTd), E/A, and left ventricular ejection fraction (LVEF). Data was analyzed using RevMan. Twelve studies involving 433 patients were included. After RDN treatment, LVMI decreased by 13.08g/m2 (95%confidence interval [CI]: -18.38, -7.78, p < .00001), PWTd decreased by 0.60mm (95% CI: -0.87, -0.34, p < 0.00001), IVSTd decreased by 0.78mm (95% CI: -1.06, -0.49, p < .00001), and LVEF increased by 1.80% (95% CI: 0.71, 2.90, p = .001). However, there were no statistically significant improvements in LVIDd (95% CI: -1.40, 0.24, p = .17) and diastolic function (E/A) (95% CI: -0.04, 0.14, p =.28). This meta-analysis finds that RDN can improve left ventricular hypertrophy and ejection fraction in patients with RH but has no significant effect on LVIDd and diastolic function. However, more studies are warranted due to the lack of a strict control group, a limited sample size, and research heterogeneity.

Lingual Denervation Improves the Efficacy of Anti-PD-1 Immunotherapy in Oral Squamous Cell Carcinomas by Downregulating TGFß Signaling.

PURPOSE: Intratumoral nerve infiltration relates to tumor progression and poor survival in oral squamous cell carcinoma (OSCC). How neural involvement regulates antitumor immunity has not been well characterized. This study aims to investigate molecular mechanisms of regulating tumor aggressiveness and impairing antitumor immunity by nerve-derived factors. EXPERIMENTAL DESIGN: We performed the surgical lingual denervation in an immunocompetent mouse OSCC model to investigate its effect on tumor growth and the efficacy of anti-PD-1 immunotherapy. A trigeminal ganglion neuron and OSCC cell coculture system was established to investigate the proliferation, migration, and invasion of tumor cells and the PD-L1 expression. Both the neuron-tumor cell coculture in vitro model and the OSCC animal model were explored. RESULTS: Lingual denervation slowed down tumor growth and improved the efficacy of anti-PD-1 treatment in the OSCC model. Coculturing with neurons not only enhanced the proliferation, migration, and invasion but also upregulated TGFß-SMAD2 signaling and PD-L1 expression of tumor cells. Treatment with the TGFß signaling inhibitor galunisertib reversed nerve-derived tumor aggressiveness and downregulated PD-L1 on tumor cells. Similarly, lingual denervation in vivo decreased TGFß and PD-L1 expression and increased CD8+ T-cell infiltration and the expression of IFNγ and TNFα within tumor. CONCLUSIONS: Neural involvement enhanced tumor aggressiveness through upregulating TGFß signaling and PD-L1 expression in OSCC, while denervation of OSCC inhibited tumor growth, downregulated TGFß signaling, enhanced activities of CD8+ T cells, and improved the efficacy of anti-PD-1 immunotherapy. This study will encourage further research focusing on denervation as a potential adjuvant therapeutic approach in OSCC. SIGNIFICANCE: This study revealed the specific mechanisms for nerve-derived cancer progression and impaired antitumor immunity in OSCC, providing a novel insight into the cancer-neuron-immune network as well as pointing the way for new strategies targeting nerve-cancer cross-talk as a potential adjuvant therapeutic approach for OSCC.

Impact of Antihypertensive Medication Changes After Renal Denervation Among Different Patient Groups: SPYRAL HTN-ON MED.

BACKGROUND: The SPYRAL HTN-ON MED (Global Clinical Study of Renal Denervation With the Symplicity Spyral Multi-electrode Renal Denervation System in Patients With Uncontrolled Hypertension in the Absence of Antihypertensive Medications)trial showed significant office and nighttime systolic blood pressure (BP) reductions in patients with hypertension following renal denervation (RDN) compared with sham-control patients, despite similar 24-hour BP reductions. We compared antihypertensive medication and BP changes among prespecified subpopulations. METHODS: The multicenter, randomized, sham-controlled, blinded SPYRAL HTN-ON MED trial (n=337) evaluated BP changes after RDN compared with a sham procedure in patients with hypertension prescribed 1 to 3 antihypertensive drugs. Most patients (n=187; 54%) were enrolled outside the United States, while 156 (46%) US patients were enrolled, including 60 (18%) Black Americans. RESULTS: Changes in detected antihypertensive drugs were similar between RDN and sham group patients in the outside US cohort, while drug increases were significantly more common in the US sham group compared with the RDN group. Patients from outside the United States showed significant reductions in office and 24-hour mean systolic BP at 6 months compared with the sham group, whereas BP changes were similar between RDN and sham in the US cohort. Within the US patient cohort, Black Americans in the sham control group had significant increases in medication burden from baseline through 6 months (P=0.003) but not in the RDN group (P=0.44). CONCLUSIONS: Patients enrolled outside the United States had minimal antihypertensive medication changes between treatment groups and had significant office and 24-hour BP reductions compared with the sham group. Increased antihypertensive drug burden in the US sham cohort, especially among Black Americans, may have diluted the treatment effect in the combined trial population. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02439775.

The effects of renal denervation on blood pressure, cardiac hypertrophy, and sympathetic activity during the established phase of hypertension in spontaneously hypertensive rats.

This study aimed to investigate whether renal denervation (RDN) reduces blood pressure and attenuates cardiac hypertrophy with decreasing sympathetic activity in spontaneously hypertensive rats (SHRs), a model of essential hypertension, during the established phase of hypertension. We performed RDN or sham operation in 15-weeks-old SHRs. Thirty days after RDN, mean blood pressure measured by telemetry, heart weight, left ventricular wall thickness assessed by echocardiography, and urinary norepinephrine levels were significantly decreased in the RDN group compared to the Sham group. Furthermore, oxidative stress, as indicated by thiobarbituric acid reactive substances, in the rostral ventrolateral medulla, a pivotal region regulating basal sympathetic tone, was significantly decreased in the RDN group. In conclusion, RDN reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in SHRs. These findings highlight the sympathoinhibitory effect of RDN and suggest that RDN may be a potential therapy for hypertensive cardiac hypertrophy. Renal denervation reduces blood pressure and attenuates cardiac hypertrophy with sympathoinhibition in the established phase of hypertension in spontaneously hypertensive rats. This study highlights the sympathoinhibitory effect of renal denervation and suggests that renal denervation may be a potential therapy for hypertensive cardiac hypertrophy.