BACKGROUND: Despite optimal medical therapy, a significant proportion of patients\' blood pressure remains uncontrolled. Catheter-based renal denervation (RDN) has been proposed as a potential intervention for uncontrolled hypertension. We conducted an updated meta-analysis to assess the efficacy and safety of RDN in patients with uncontrolled hypertension, with emphasis on the differential effect of RDN in patients on and off antihypertensive medications.
RESULTS: Online databases were searched to identify randomized clinical trials comparing efficacy and safety of RDN versus control in patients with uncontrolled hypertension. Subgroup analyses were conducted for sham-controlled trials and studies that used RDN devices that have gained or are currently seeking US Food and Drug Administration approval. Fifteen trials with 2581 patients (RDN, 1723; sham, 858) were included. In patients off antihypertensive medications undergoing RDN, a significant reduction in 24-hour ambulatory (-3.70 [95% CI, -5.41 to -2.00] mm Hg), office (-4.76 [95% CI, -7.57 to -1.94] mm Hg), and home (-3.28 [95% CI, -5.96 to -0.61] mm Hg) systolic blood pressures was noted. In patients on antihypertensive medications, a significant reduction was observed in 24-hour ambulatory (-2.23 [95% CI, -3.56 to -0.90] mm Hg), office (-6.39 [95% CI, -11.49 to -1.30]), home (-6.08 [95% CI, -11.54 to -0.61] mm Hg), daytime (-2.62 [95% CI, -4.14 to -1.11]), and nighttime (-2.70 [95% CI, -5.13 to -0.27]) systolic blood pressures, as well as 24-hour ambulatory (-1.16 [95% CI, -1.96 to -0.35]), office (-3.17 [95% CI, -5.54 to -0.80]), and daytime (-1.47 [95% CI, -2.50 to -0.27]) diastolic blood pressures.
CONCLUSIONS: RDN significantly lowers blood pressure in patients with uncontrolled hypertension, in patients off and on antihypertensive medications, with a favorable safety profile. The efficacy of RDN was consistent in sham-controlled trials and contemporary trials using US Food and Drug Administration-approved devices.

Cancer cachexia is a prevalent and often fatal wasting condition that cannot be fully reversed with nutritional interventions. Muscle atrophy is a central component of the syndrome, but the mechanisms whereby cancer leads to skeletal muscle atrophy are not well understood. We performed single-nucleus multi-omics on skeletal muscles from a mouse model of cancer cachexia and profiled the molecular changes in cachexic muscle. Our results revealed the activation of a denervation-dependent gene program that upregulates the transcription factor myogenin. Further studies showed that a myogenin-myostatin pathway promotes muscle atrophy in response to cancer cachexia. Short hairpin RNA inhibition of myogenin or inhibition of myostatin through overexpression of its endogenous inhibitor follistatin prevented cancer cachexia-induced muscle atrophy in mice. Our findings uncover a molecular basis of muscle atrophy associated with cancer cachexia and highlight potential therapeutic targets for this disorder.

Hypertension is a leading risk factor for cardiovascular morbidity and mortality. Despite the widespread availability of both pharmacological and lifestyle therapeutic options, blood pressure control rates across the globe are worsening. In fact, only 23% of individuals with high blood pressure in the United States achieve treatment goals. In 2023, the US Food and Drug Administration approved renal denervation, a catheter-based procedure that ablates the renal sympathetic nerves, as an adjunctive treatment for patients in whom lifestyle modifications and antihypertensive medications do not adequately control blood pressure. This approval followed the publication of multiple randomized clinical studies using rigorous trial designs, all incorporating renal angiogram as the sham control. Most but not all of the new generation of trials reached their primary end point, demonstrating modest efficacy of renal denervation in lowering blood pressure across a spectrum of hypertension, from mild to truly resistant. Individual patient responses vary, and further research is needed to identify those who may benefit most. The initial safety profile appears favorable, and multiple ongoing studies are assessing longer-term efficacy and safety. Multidisciplinary teams that include hypertension specialists and adequately trained proceduralists are crucial to ensure that referrals are made appropriately with full consideration of the potential risks and benefits. Incorporating patient preferences and engaging in shared decision-making conversations will help patients make the best decisions given their individual circumstances. Although further research is clearly needed, renal denervation presents a novel treatment strategy for patients with uncontrolled blood pressure.

BACKGROUND: Low back pain (LBP) is the leading global cause of disability. Patients with moderate to severe LBP who respond positively to a diagnostic medial nerve branch block can be offered radiofrequency denervation (RFD). However, high-quality evidence on the effectiveness of RFD is lacking.
METHODS: RADICAL (RADIofrequenCy denervAtion for Low back pain) is a double-blind, parallel-group, superiority randomised controlled trial. A total of 250 adults listed for RFD will be recruited from approximately 20 National Health Service (NHS) pain and spinal clinics. Recruitment processes will be optimised through qualitative research during a 12-month internal pilot phase. Participants will be randomised in theatre using a 1:1 allocation ratio to RFD or placebo. RFD technique will follow best practice guidelines developed for the trial. Placebo RFD will follow the same protocol, but the electrode tip temperature will not be raised. Participants who do not experience a clinically meaningful improvement in pain 3 months after randomisation will be offered the alternative intervention to the one provided at the outset without disclosing the original allocation. The primary clinical outcome will be pain severity, measured using a pain Numeric Rating Scale, at 3 months after randomisation. Secondary outcomes will be assessed up to 2 years after randomisation and include disability, health-related quality of life, psychological distress, time to pain recovery, satisfaction, adverse events, work outcomes and healthcare utilisation. The primary statistical analyses will be by intention to treat and will follow a prespecified analysis plan. The primary economic evaluation will take an NHS and social services perspective and estimate the discounted cost per quality-adjusted life-year and incremental net benefit of RFD over the 2-year follow-up period.
BACKGROUND: Ethics approval was obtained from the London-Fulham Research Ethics Committee (21/LO/0471). Results will be disseminated in open-access publications and plain language summaries.
BACKGROUND: ISRCTN16473239.

OBJECTIVE: To explore the relevant factors affecting the efficacy of microscopic spermatic cord surgery and build a predictive model for postoperative pain relief.
METHODS: A retrospective analysis was conducted on the clinical data of 324 patients with spermatic cord pain who visited the Department of Urology at Peking University People\'s Hospital between October 2015 and April 2023. This cohort included 212 patients with varicocele-related spermatic cord pain and 112 patients with idiopathic spermatic cord pain. All the patients underwent microsurgical procedures: varicocele-related pain was treated with microsurgical varicocelectomy, and idiopathic pain was treated with microsurgical denervation of the spermatic cord. The patients were categorized into effective and ineffective groups based on whether their pain had decreased by more than 50% six months post-surgery compared with pre-surgery levels. Baseline data were preliminarily screened for clinical indicators using t tests and univariate analysis. Clinical predictor variables [age, duration of pain, diameter of varicocele, patient health questionnaire-9 (PHQ-9) score, generalized anxiety disorder-7 (GAD-7) score] were selected using Lasso regression. A clinical prediction model for effective pain relief following microscopic spermatic cord surgery was constructed using Logistic regression and presented as a nomogram. The model\'s internal validation was performed using the bootstrap method. Its predictive power and clinical utility were evaluated through the concor-dance index, the area under the receiver operating characteristic curve, and calibration plots.
RESULTS: Post-microscopic varicocele ligation, 156 patients (73.58%) experienced significant pain relief, as did 94 patients (83.93%) following microscopic denervation. Independent predictors for postoperative outcomes included age, PHQ-9 score, GAD-7 score, chronic pain duration, and varicocele diameter, differing slightly between varicocele-related and idiopathic pain groups. The models demonstrated excellent predictive ability, with areas under the curve of 0.909 and 0.913 for varicocele and idiopathic groups, respectively, and high concordance indices.
CONCLUSIONS: The postoperative efficacy prediction model based on age, pain duration, PHQ-9 score, GAD-7 score, and varicocele diameter has good predictive ability and clinical applicability, and can be used in clinical practice.

UNASSIGNED: This study aimed to systematically evaluate the effectiveness and safety of renal denervation (RDN) in managing heart failure with reduced ejection fraction (HFrEF).
UNASSIGNED: A comprehensive search was done in multiple databases: Cochrane Library, PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data, and VIP Database for Chinese Technical Periodicals. All clinical trials investigating RDN treatment for HFrEF through 15 March 2024 were gathered. The quality of the included studies was evaluated utilizing the Cochrane risk assessment tool. The pertinent data were gathered, and a meta-analysis was done using Review Manager 5.3, accompanied by sensitivity and publication bias analyses.
UNASSIGNED: After applying the inclusion and exclusion criteria, eight randomized controlled trials (RCTs) were selected for analysis, encompassing 314 patients; 154 patients underwent RDN treatment during hospitalization, while 150 were randomized to the control group to receive medication therapy. The meta-analysis demonstrated that compared to medication therapy, RDN contributed to a 9.59% increase in left ventricular ejection fraction (LVEF) (95% CI: 7.92-11.27, Z = 11.20, p < 0.01); a decrease in brain natriuretic peptide (BNP) (95% CI: -364.19--191.75, Z = 6.32, p < 0.01); a decrease in N-terminal pro B-type natriuretic peptide (NT-proBNP) (95% CI: -1300.15--280.95, Z = 3.04, p < 0.01); a decrease in the New York Heart Association (NYHA) classification (95% CI: -1.58--0.34, Z = 3.05, p < 0.01); a 90.00-m increase in 6-min walk test (6MWT) (95% CI: 68.24-111.76, Z = 8.11, p < 0.01); a reduction of 4.05 mm in left ventricular end-diastolic diameter (LVEDD) (95% CI: -5.65--2.48, Z = 5.05, p < 0.01); a decrease of 4.60 heart beats·min-1 (95% CI: -8.83--0.38, Z = 2.14, p < 0.05); and a 4.67-mm reduction in left atrial diameter (LAD) (95% CI: -6.40--2.93, Z = 5.27, p < 0.01). Left ventricular end-systolic diameter (LVESD) and systolic/diastolic blood pressure (OSBP/ODBP) were similar between groups (p > 0.01). As the safety indicator, estimated glomerular filtration rate (eGFR) improved by 7.11 in the RDN group [ml/(min·1.73 m2)] (95% CI: 1.10-13.12, Z = 2.32, p < 0.05). LVEF, BNP, 6MWT, LVEDD, LAD and eGFR were meta-analyzed using a fixed-effects model, the other indicators a random-effects model.
UNASSIGNED: RDN significantly ameliorated cardiac function in HFrEF patients while exhibiting commendable safety.

BACKGROUND: Fat infiltration of skeletal muscle has been recognized as a common feature of many degenerative muscle disorders. Retinol binding protein 4 (RBP4) is an adipokine that has been demonstrated to be correlated with the presence and severity of sarcopenia in the elderly. However, the exact role and the underlying mechanism of RBP4 in muscle atrophy remains unclear.
METHODS: Denervation-induced muscle atrophy model was constructed in wild-type and RBP4 knockout mice. To modify the expression of RBP4, mice were received intramuscular injection of retinol-free RBP4 (apo-RBP4), retinol-bound RBP4 (holo-RBP4) or oral gavage of RBP4 inhibitor A1120. Holo-RBP4-stimulated C2C12 myotubes were treated with siRNAs or specific inhibitors targeting signalling receptor and transporter of retinol 6 (STRA6)/Janus kinase 2 (JAK2)/Signal transducer and activator of transcription 3 (STAT3) pathway. Fat accumulation, myofibre cross-sectional area, myotube diameter and the expression of muscle atrophy markers and myogenesis markers were analysed.
RESULTS: The expression levels of RBP4 in skeletal muscles were significantly up-regulated more than 2-fold from 7 days and sustained for 28 days after denervation. Immunofluorescence analysis indicated that increased RBP4 was localized in the infiltrated fatty region in denervated skeletal muscles. Knockout of RBP4 alleviated denervation-induced fatty infiltration and muscle atrophy together with decreased expression of atrophy marker Atrogin-1 and MuRF1 as well as increased expression of myogenesis regulators MyoD and MyoG. By contrast, injection of retinol-bound holo-RBP4 aggregated denervation-induced ectopic fat accumulation and muscle atrophy. Consistently, holo-RBP4 stimulation also had a dose-dependent effect on the reduction of C2C12 myotube diameter and myofibre cross-sectional area, as well as on the increase of Atrogin-1and MuRF1 expression and decrease of MyoD and MyoG expression. Mechanistically, holo-RBP4 treatment increased the expression of its membrane receptor STRA6 (>3-fold) and promoted the phosphorylation of downstream JAK2 and STAT3. Inhibition of STRA6/JAK2/STAT3 pathway either by specific siRNAs or inhibitors could decrease the expression of Atrogin-1 and MuRF1 (>50%) and decrease the expression of MyoD and MyoG (>3-fold) in holo-RBP4-treated C2C12 myotube. RBP4 specific pharmacological antagonist A1120 significantly inhibited the activation of STRA6/JAK2/STAT3 pathway, ameliorated ectopic fat infiltration and protected against denervation-induced muscle atrophy (30% increased myofibre cross-sectional area) in mice.
CONCLUSIONS: In conclusion, our data reveal that RBP4 promotes fat infiltration and muscle atrophy through a STRA6-dependent and JAK2/STAT3 pathway-mediated mechanism in denervated skeletal muscle. Our results suggest that lowering RBP4 levels might serve as a promising therapeutic approach for prevention and treatment of muscle atrophy.

暂无摘要。

The dystrophin protein has well-characterized roles in force transmission and maintaining membrane integrity during muscle contraction. Studies have reported decreased expression of dystrophin in atrophying muscles during wasting conditions, and that restoration of dystrophin can attenuate atrophy, suggesting a role in maintaining muscle mass. Phosphorylation of S3059 within the cysteine-rich region of dystrophin enhances binding between dystrophin and β-dystroglycan, and mimicking phosphorylation at this site by site-directed mutagenesis attenuates myotube atrophy in vitro. To determine whether dystrophin phosphorylation can attenuate muscle wasting in vivo, CRISPR-Cas9 was used to generate mice with whole body mutations of S3059 to either alanine (DmdS3059A) or glutamate (DmdS3059E), to mimic a loss of, or constitutive phosphorylation of S3059, on all endogenous dystrophin isoforms, respectively. Sciatic nerve transection was performed on these mice to determine whether phosphorylation of dystrophin S3059 could attenuate denervation atrophy. At 14 days post denervation, atrophy of tibialis anterior (TA) but not gastrocnemius or soleus muscles, was partially attenuated in DmdS3059E mice relative to WT mice. Attenuation of atrophy was associated with increased expression of β-dystroglycan in TA muscles of DmdS3059E mice. Dystrophin S3059 phosphorylation can partially attenuate denervation-induced atrophy, but may have more significant impact in less severe modes of muscle wasting.

The Goldblatt model of hypertension (2K-1C) in rats is characterized by renal sympathetic nerve activity (rSNA). We investigated the effects of unilateral renal denervation of the clipped kidney (DNX) on sodium transporters of the unclipped kidneys and the cardiovascular, autonomic, and renal functions in 2K-1C and control (CTR) rats. The mean arterial pressure (MAP) and rSNA were evaluated in experimental groups. Kidney function and NHE3, NCC, ENaCβ, and ENaCγ protein expressions were assessed. The glomerular filtration rate (GRF) and renal plasma flow were not changed by DNX, but the urinary (CTR: 0.0042 ± 0.001; 2K-1C: 0.014 ± 0.003; DNX: 0.005 ± 0.0013 mL/min/g renal tissue) and filtration fractions (CTR: 0.29 ± 0.02; 2K-1C: 0.51 ± 0.06; DNX: 0.28 ± 0.04 mL/min/g renal tissue) were normalized. The Na+/H+ exchanger (NHE3) was reduced in 2K-1C, and DNX normalized NHE3 (CTR: 100 ± 6; 2K-1C: 44 ± 14, DNX: 84 ± 13%). Conversely, the Na+/Cl- cotransporter (NCC) was increased in 2K-1C and was reduced by DNX (CTR: 94 ± 6; 2K-1C: 144 ± 8; DNX: 60 ± 15%). In conclusion, DNX in Goldblatt rats reduced blood pressure and proteinuria independently of GRF with a distinct regulation of NHE3 and NCC in unclipped kidneys.