Intrathecal administration of conditioned serum from different species resolves Chemotherapy-Induced neuropathic pain in mice via secretory exosomes.

Chemotherapy-induced peripheral neuropathy (CIPN) is the most prevalent neurological complication of chemotherapy for cancer, and has limited effective treatment options. Autologous conditioned serum (ACS) is an effective biologic therapy used by intra-articular injection for patients with osteoarthritis. However, ACS has not been systematically tested in the treatment of peripheral neuropathies such as CIPN. It has been generally assumed that the analgesic effect of this biologic therapy results from augmented concentrations of anti-inflammatory cytokines and growth factors. Here we report that a single intrathecal injection of human conditioned serum (hCS) produced long-lasting inhibition of paclitaxel chemotherapy-induced neuropathic pain (mechanical allodynia) in mice, without causing motor impairment. Strikingly, the analgesic effect of hCS in our experiments was maintained even 8 weeks after the treatment, compared with non-conditioned human serum (hNCS). Furthermore, the hCS transfer-induced pain relief in mice was fully recapitulated by rat or mouse CS transfer to mice of both sexes, indicating cross-species and cross-sex effectiveness. Mechanistically, CS treatment blocked the chemotherapy-induced glial reaction in the spinal cord and improved nerve conduction. Compared to NCS, CS contained significantly higher concentrations of anti-inflammatory and pro-resolving mediators, including IL-1Ra, TIMP-1, TGF-ß1, and resolvins D1/D2. Intrathecal injection of anti-TGF-ß1 and anti-Il-1Ra antibody transiently reversed the analgesic action of CS. Nanoparticle tracking analysis revealed that rat conditioned serum contained a significantly greater number of exosomes than NCS. Importantly, the removal of exosomes by high-speed centrifugation largely diminished the CS-produced pain relief, suggesting a critical involvement of small vesicles (exosomes) in the beneficial effects of CS. Together, our findings demonstrate that intrathecal CS produces a remarkable resolution of neuropathic pain mediated through a combination of small vesicles/exosomes and neuroimmune/neuroglial modulation.

Evaluation of Analgesic Practice Changes Following the Nuss Procedure in Pediatric Patients.

INTRODUCTION: Pectus excavatum repair by the Nuss procedure results in severe postoperative pain. Regional blocks and intercostal nerve cryoablation (INC) have emerged as potential strategies to manage analgesia. This study compares pain-related outcomes following these perioperative interventions. METHODS: We reviewed charts of patients <18 y who underwent the Nuss procedure at Duke Children's Hospital from July 2018 to June 2022. Patients were divided into three groups by analgesic strategy: no block, regional catheters, or INC, representing the chronologic change in our practice. The primary outcome was total and daily in-hospital opioid utilization measured by oral morphine equivalents (OMEs). Secondary outcomes included average daily pain scores, length of stay, opioid refills after discharge, and complications. RESULTS: Twenty-one patients were included and analyzed: no block (n = 6), regional catheters (n = 7), and INC (n = 8). INC-treated patients required significantly lower total postoperative, in-hospital OMEs (64 ± 47 [mean ± standard deviation]) than those with no block (270 ± 217, P = 0.04) or those with regional catheters (273 ± 176, P = 0.03). INC was associated with longer average operative times (161 ± 36 min) than no block (105 ± 21 min, P = 0.005) or regional catheters (90 ± 11 min, P < 0.001). INC-treated patients had shorter hospital length of stays (median 68 h) than those with regional catheters (median 74 h, P = 0.006). CONCLUSIONS: INC was associated with longer operative times but decreased in-hospital OMEs when compared to bilateral regional block catheters and multimodal analgesia alone.

Claudin-11 Tight Junctions in Myelin Are a Barrier to Diffusion and Lack Strong Adhesive Properties.

The radial component is a network of interlamellar tight junctions (TJs) unique to central nervous system myelin. Ablation of claudin-11, a TJ protein, results in the absence of the radial component and compromises the passive electrical properties of myelin. Although TJs are known to regulate paracellular diffusion, this barrier function has not been directly demonstrated for the radial component, and some evidence suggests that the radial component may also mediate adhesion between myelin membranes. To investigate the physical properties of claudin-11 TJs, we compared fresh, unfixed Claudin 11-null and control nerves using x-ray and neutron diffraction. In Claudin 11-null tissue, we detected no changes in myelin structure, stability, or membrane interactions, which argues against the notion that myelin TJs exhibit significant adhesive properties. Moreover, our osmotic stressing and D2O-H2O exchange experiments demonstrate that myelin lacking claudin-11 is more permeable to water and small osmolytes. Thus, our data indicate that the radial component serves primarily as a diffusion barrier and elucidate the mechanism by which TJs govern myelin function.

What are the barriers to training residents in aortic root surgery?

BACKGROUND AND AIM OF THE STUDY: Aortic root surgery is a technically demanding procedure that is performed infrequently by most surgeons, with national mortality rates over 10%. The study aim was to identify the barriers to training residents in this operation. METHODS: By using univariate and multivariate logistic regression analysis, all consecutive adults (n = 356) undergoing aortic root reconstruction at The Mount Sinai Medical Center between 2007 and 2011 were retrospectively compared according to whether a resident or faculty surgeon performed the procedure. Surveys were then conducted to determine reasons why residents did not perform cases, and to evaluate outcomes of aortic root surgery performed by recent graduates of the program. RESULTS: Surgical techniques among patients included: root replacement (81%, n = 290) using homograft, composite bioprosthetic or mechanical valved conduits; Ross procedures (17%, n = 53); and other root surgery such as valve-sparing procedures (2%, n = 7). Residents performed 32% (n = 66/204) of cases when they were scrubbed. The incidence of mortality was lower for cases performed by residents (2%, n = 2) compared to faculty (4%, n = 12) (p=0.335), and no significant differences in cardiopulmonary bypass or cross-clamp times, early morbidity or late survival were observed. The most common reasons given why scrubbed residents did not perform cases were a mismatch between the skill of the resident and case complexity (46%, n = 94), followed by the faculty surgeon's preference (41%, n = 83). Recent program graduates had collectively performed 30 aortic root procedures independently as faculty surgeons, and with no mortality; however, most expressed a continued preference for more senior help on such cases. CONCLUSION: Residents can safely perform aortic root surgery under appropriate supervision. The greatest challenge involved in improving resident training in aortic root surgery lies in routinely matching resident skills with case complexity and teaching expertise.

Does payer status impact clinical outcomes after cardiac surgery? A propensity analysis.

BACKGROUND: Medicaid patients bear proportionately greater financial responsibility for the cost of outpatient care and medication than non-Medicaid patients. We hypothesized that this difference in provision of continuing care would be associated with adverse clinical outcomes after cardiac surgery. MATERIALS AND METHODS: In a retrospective cohort analysis, 5056 consecutive adult patients undergoing cardiac surgery at a single institution between 2005 and 2010 were divided according to payer status. Propensity scores were calculated using 16 preoperative and demographic variables for each patient, and 461 1:1 propensity score-matched pairs were analyzed. Patient socioeconomic position was determined using aggregate data derived from zip codes. The main outcome measures were early mortality, postoperative complications, and patient survival. RESULTS: In multivariate analysis, Medicaid was found to be an independent predictor of worse survival after cardiac surgery (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2-3.7; P = .01). No significant difference was observed in operative mortality in the 2 groups. After propensity score matching and controlling for socioeconomic position, the only independent predictors of worse midterm survival were an ejection fraction = 30% (HR, 1.7; 95% CI, 1.1-2.7; P = .02) and a higher logistic EuroSCORE (HR, 1.03; 95% CI, 1.0-1.1; P = .02). CONCLUSIONS: Comorbidity and lower socioeconomic status appear to be more important predictors of late mortality after cardiac surgery than payer status, which does not have a significant impact on survival.

Exosomes mediate sensory hair cell protection in the inner ear.

Hair cells, the mechanosensory receptors of the inner ear, are responsible for hearing and balance. Hair cell death and consequent hearing loss are common results of treatment with ototoxic drugs, including the widely used aminoglycoside antibiotics. Induction of heat shock proteins (HSPs) confers protection against aminoglycoside-induced hair cell death via paracrine signaling that requires extracellular heat shock 70-kDa protein (HSP70). We investigated the mechanisms underlying this non-cell-autonomous protective signaling in the inner ear. In response to heat stress, inner ear tissue releases exosomes that carry HSP70 in addition to canonical exosome markers and other proteins. Isolated exosomes from heat-shocked utricles were sufficient to improve survival of hair cells exposed to the aminoglycoside antibiotic neomycin, whereas inhibition or depletion of exosomes from the extracellular environment abolished the protective effect of heat shock. Hair cell-specific expression of the known HSP70 receptor TLR4 was required for the protective effect of exosomes, and exosomal HSP70 interacted with TLR4 on hair cells. Our results indicate that exosomes are a previously undescribed mechanism of intercellular communication in the inner ear that can mediate nonautonomous hair cell survival. Exosomes may hold potential as nanocarriers for delivery of therapeutics against hearing loss.

Minimal information for studies of extracellular vesicles 2018 (MISEV2018): a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines.

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles ("MISEV") guidelines for the field in 2014. We now update these "MISEV2014" guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points.

Cisplatin is retained in the cochlea indefinitely following chemotherapy.

Cisplatin chemotherapy causes permanent hearing loss in 40-80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity.

Does prior coronary bypass surgery present a unique risk for reoperative valve surgery?

BACKGROUND: Prior coronary surgery has been associated with a higher incidence of adverse outcomes after reoperative cardiac surgery compared with previous valve surgery. It is unclear whether this association is primarily due to greater patient comorbidity or the technical challenges posed by mediastinal reentry and operation in the setting of previous bypass grafts. This study was therefore designed to examine whether previous coronary artery bypass grafting (CABG) is a significant risk factor for adverse outcomes after reoperative cardiac surgery. METHODS: From a prospective database of 1,093 consecutive adults who underwent reoperative cardiac surgery between 2000 and 2010, 363 patients undergoing isolated reoperative valve surgery were divided according to whether or not the previous surgery included CABG (group I, n = 133) or not (group II, n = 230). Propensity-adjusted multivariate analysis was performed in order to determine independent predictors of any morbidity or mortality, or decreased survival. RESULTS: Patients in group I were more likely to be elderly (p < 0.001), and have greater body mass indexes (p = 0.04), low ejection fractions (p = 0.001), and comorbidities of cerebrovascular disease (p = 0.04), peripheral vascular disease (p = 0.003), and diabetes (p < 0.001) compared with group II. Patent grafts were present in 94% (n = 111). Although group I patients were significantly more likely to experience major postoperative complications and had worse survival, after propensity adjustment no significant difference was observed in either any morbidity or mortality (p = 0.4) or in survival (p = 0.4). CONCLUSIONS: A history of CABG does not appear to present a unique risk in reoperative valve surgery. The major determinant of adverse outcomes is morbidity, not prior bypass grafts.

Lobe-specific mediastinal nodal dissection is sufficient during lobectomy by video-assisted thoracic surgery or thoracotomy for early-stage lung cancer.

BACKGROUND: Lobectomy with complete mediastinal lymphadenectomy is considered standard for patients with early-stage non-small cell lung cancer (NSCLC). However, the benefits of complete lymphadenectomy are unproven. There is evidence suggesting a predictable pattern of mediastinal nodal drainage. This study analyzed the frequency and pattern of mediastinal nodal disease and its impact on outcome in patients with early-stage NSCLC. METHODS: Patients with clinical N0/N1 NSCLC staged with CT scans and PET scans were identified. Disease involvement of resected nodal stations was recorded. Patterns of recurrence in patients who underwent lobectomy with complete mediastinal systematic lymph node sampling (SLNS) were compared with those who underwent lobe-specific mediastinal SLNS. RESULTS: From July 2004 to April 2011, 370 patients were identified. Complete SLNS was performed in 282 patients. Fifteen patients (5.3%) in the group with complete SLNS were found to have N2 disease after pathologic evaluation. Patients with left-sided tumors were more likely to have pathologic N2 disease than were patients with right-sided tumors (P = .03). Only one patient (0.36%) had positive N2 disease in the distal mediastinum while skipping lobe-specific mediastinal nodes. In addition, patients with complete SLNS had a rate of recurrence similar to that of the group that had lobe-specific mediastinal evaluation (20.6% vs 18.2%, P = .68). CONCLUSIONS: Mediastinal N2 metastases follow predictable lobe-specific patterns in patients with negative preoperative CT scans and PET scans. Lobe-specific N2 nodal evaluation results in a recurrence rate similar to that of complete mediastinal evaluation. Lobe-specific mediastinal nodal evaluation appears acceptable in patients with early-stage NSCLC.