Local anesthetic delivery via surgical drain provides improved pain control versus direct skin infiltration following axillary node dissection for breast cancer.

BACKGROUND: Axillary node dissection has a central role in the surgical management of breast cancer; however, it is associated with a significant risk of lymphoedema and chronic pain. Peri-operative administration of local anesthesia reduces acute and persistent post-surgical pain, but there is currently no consensus on the optimal method of local anesthetic delivery. METHODS: Patients undergoing axillary dissection for breast cancer were randomly assigned to receive a one-off dose of levobupivacaine 0.5% (up to 2 mg/kg) following surgery, either via the surgical drain or by direct skin infiltration. Post-operative pain control at rest and on shoulder abduction was assessed using a numerical rating scale. Total analgesia consumption 48 h after surgery was also recorded. RESULTS: Pain scores were significantly lower when local anesthesia was administered via surgical drain at both 3 and 12 h after surgery; this trend extended to 24 h post-operatively. However, pain scores on shoulder abduction did not differ at the 12 or 24 h time points. No differences were found in the total analgesia consumption or length of hospital stay between treatment groups. DISCUSSION: This study demonstrates that local anesthetic delivery via a surgical drain provides improved pain control compared to direct skin infiltration following axillary node dissection. This is likely to be important for the management of acute pain in the immediate post-operative period; however, further studies may be required to validate this in specific patient subgroups, e.g., breast-conserving surgery versus mastectomy.

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients.

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology.

RNA-Seq of Huntington's disease patient myeloid cells reveals innate transcriptional dysregulation associated with proinflammatory pathway activation.

Innate immune activation beyond the central nervous system is emerging as a vital component of the pathogenesis of neurodegeneration. Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. The systemic innate immune system is thought to act as a modifier of disease progression; however, the molecular mechanisms remain only partially understood. Here we use RNA-sequencing to perform whole transcriptome analysis of primary monocytes from thirty manifest HD patients and thirty-three control subjects, cultured with and without a proinflammatory stimulus. In contrast with previous studies that have required stimulation to elicit phenotypic abnormalities, we demonstrate significant transcriptional differences in HD monocytes in their basal, unstimulated state. This includes previously undetected increased resting expression of genes encoding numerous proinflammatory cytokines, such as IL6 Further pathway analysis revealed widespread resting enrichment of proinflammatory functional gene sets, while upstream regulator analysis coupled with Western blotting suggests that abnormal basal activation of the NFĸB pathway plays a key role in mediating these transcriptional changes. That HD myeloid cells have a proinflammatory phenotype in the absence of stimulation is consistent with a priming effect of mutant huntingtin, whereby basal dysfunction leads to an exaggerated inflammatory response once a stimulus is encountered. These data advance our understanding of mutant huntingtin pathogenesis, establish resting myeloid cells as a key source of HD immune dysfunction, and further demonstrate the importance of systemic immunity in the potential treatment of HD and the wider study of neurodegeneration.