Characterization of pain-related behaviors in a rat model of acute-to-chronic low back pain: single vs. multi-level disc injury.

Introduction: Low back pain is the most common type of chronic pain. We examined pain-related behaviors across 18 weeks in rats that received injury to one or two lumbar intervertebral discs (IVD) to determine if multi-level disc injuries enhance/prolong pain. Methods: Twenty-three Sprague-Dawley adult female rats were used: 8 received disc puncture (DP) of one lumbar IVD (L5/6, DP-1); 8 received DP of two lumbar IVDs (L4/5 & L5/6, DP-2); 8 underwent sham surgery. Results: DP-2 rats showed local (low back) sensitivity to pressure at 6- and 12-weeks post-injury, and remote sensitivity to pressure (upper thighs) at 12- and 18-weeks and touch (hind paws) at 6, 12 and 18-weeks. DP-1 rats showed local and remote pressure sensitivity at 12-weeks only (and no tactile sensitivity), relative to Sham DP rats. Both DP groups showed reduced distance traveled during gait testing over multiple weeks, compared to pre-injury; only DP-2 rats showed reduced distance relative to Sham DP rats at 12-weeks. DP-2 rats displayed reduced positive interactions with a novel adult female rat at 3-weeks and hesitation and freezing during gait assays from 6-weeks onwards. At study end (18-weeks), radiological and histological analyses revealed reduced disc height and degeneration of punctured IVDs. Serum BDNF and TNFα levels were higher at 18-weeks in DP-2 rats, relative to Sham DP rats, and levels correlated positively with remote sensitivity in hind paws (tactile) and thighs (pressure). Discussion: Thus, multi-level disc injuries resulted in earlier, prolonged and greater discomfort locally and remotely, than single-level disc injury. BDNF and TNFα may have contributing roles.

Key Anatomical Concepts, Landmarks, and Proposed Terminology for Nerve-Sparing Gynecologic Surgery: A Narrative Review.

OBJECTIVE: To synthesize the terminology utilized in nerve-sparing surgical literature and propose standardized and nonconflicting terms to allow for consistent vocabulary. DESIGN: We performed a literature search on PubMed using the search terms "pelvis" and "nerve-sparing." Nongynecologic surgery and animal studies were excluded. A narrative review was performed, focusing on nerves, fasciae, ligaments, and retroperitoneal spaces. Terms from included papers were discussed by all authors, who are surgeons versed in nerve-sparing procedures and one anatomist, and recommendations were made regarding the most appropriate terms based on the frequency of occurrence in the literature and the possibility of overlapping names with other structures. RESULTS: 224 articles were identified, with 81 included in the full-text review. Overall, 48% of articles focused on cervical cancer and 26% on deeply infiltrating endometriosis. Findings were synthesized both narratively and visually. Inconsistencies in pelvic anatomical nomenclature were prevalent across publications. The structure with the most varied terminology was the rectal branch of the inferior hypogastric plexus with 14 names. A standardized terminology for pelvic autonomic nerve structures, fasciae, ligaments, and retroperitoneal spaces was proposed to avoid conflicting terms. CONCLUSION: Surgeons and anatomists should use consistent terminology to facilitate increased uptake of nerve-sparing techniques in gynecologic surgery through a better understanding of surgical technique description. We have proposed a standardized terminology believed to facilitate this goal.

Teaching the tutors: use of an OSTE to train medical students to be peer tutors.

First-year medical students are often challenged by the rapid pace and large volume of content that must be learned. Peer teaching has emerged as a supportive educational strategy. However, the most effective strategies for training peer tutors (PTs) for their role are not known. This paper examines the use of an Objective Structured Teaching Exercise (OSTE) to augment PT training sessions. Applying deliberate practice as a conceptual framework, an OSTE was used to provide tutors with an opportunity to practice their skills and receive feedback about their performance when meeting with a student presenting with a challenge. The newly trained PTs were required to assess a standardized student, determine challenge(s) being experienced, and present options to address the challenge(s). Standardized students evaluated the tutors' performance and a pre- and post-OSTE questionnaire was used to determine whether the OSTE was effective in increasing the confidence level of PTs to effectively assess and support students seeking help. Participants reported an increase in confidence in their ability to assess areas requiring improvement, understand the active learning strategies, and suggest appropriate active learning study strategies. Evaluations completed by standardized students documented that newly trained PTs accurately diagnosed the challenge presented in the OSTE and in most cases PTs asked all relevant questions to assess. Increased self-efficacy promotes PT's capacity to perform their work and feedback during an OSTE can further advance required skills. Aggregate OSTE results can also inform efforts to enhance the PT training program.NEW & NOTEWORTHY This novel application of the Objective Structured Teaching Exercise (OSTE) was done to enhance tutors' skills as valued members of our integrated academic support program. The OSTE provided feedback to the tutors and enabled us to identify a need for enhanced tutor training in active learning strategies. The OSTE can be adapted for use in other health science educational programs to enhance their training programs and to assess tutor's skills in preparation for their role.

Anatomical Location of the Vesical Branches of the Inferior Hypogastric Plexus in Human Cadavers.

We have demonstrated in canines that somatic nerve transfer to vesical branches of the inferior hypogastric plexus (IHP) can be used for bladder reinnervation after spinal root injury. Yet, the complex anatomy of the IHP hinders the clinical application of this repair strategy. Here, using human cadavers, we clarify the spatial relationships of the vesical branches of the IHP and nearby pelvic ganglia, with the ureteral orifice of the bladder. Forty-four pelvic regions were examined in 30 human cadavers. Gross post-mortem and intra-operative approaches (open anterior abdominal, manual laparoscopic, and robot-assisted) were used. Nerve branch distances and diameters were measured after thorough visual inspection and gentle dissection, so as to not distort tissue. The IHP had between 1 to 4 vesical branches (2.33 ± 0.72, mean ± SD) with average diameters of 0.51 ± 0.06 mm. Vesical branches from the IHP arose from a grossly visible pelvic ganglion in 93% of cases (confirmed histologically). The pelvic ganglion was typically located 7.11 ± 6.11 mm posterolateral to the ureteral orifice in 69% of specimens. With this in-depth characterization, vesical branches from the IHP can be safely located both posterolateral to the ureteral orifice and emanating from a more proximal ganglionic enlargement during surgical procedures.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral and anal sphincter function. Part 4: Effectiveness of the motor reinnervation.

In pilot work, we showed that somatic nerve transfers can restore motor function in long-term decentralized dogs. We continue to explore the effectiveness of motor reinnervation in 30 female dogs. After anesthesia, 12 underwent bilateral transection of coccygeal and sacral (S) spinal roots, dorsal roots of lumbar (L)7, and hypogastric nerves. Twelve months postdecentralization, eight underwent transfer of obturator nerve branches to pelvic nerve vesical branches, and sciatic nerve branches to pudendal nerves, followed by 10 mo recovery (ObNT-ScNT Reinn). The remaining four were euthanized 18 mo postdecentralization (Decentralized). Results were compared with 18 Controls. Squat-and-void postures were tracked during awake cystometry. None showed squat-and-void postures during the decentralization phase. Seven of eight ObNT-ScNT Reinn began showing such postures by 6 mo postreinnervation; one showed a return of defecation postures. Retrograde dyes were injected into the bladder and urethra 3 wk before euthanasia, at which point, roots and transferred nerves were electrically stimulated to evaluate motor function. Upon L2-L6 root stimulation, five of eight ObNT-ScNT Reinn showed elevated detrusor pressure and four showed elevated urethral pressure, compared with L7-S3 root stimulation. After stimulation of sciatic-to-pudendal transferred nerves, three of eight ObNT-ScNT Reinn showed elevated urethral pressure; all showed elevated anal sphincter pressure. Retrogradely labeled neurons were observed in L2-L6 ventral horns (in laminae VI, VIII, and IX) of ObNT-ScNT Reinn versus Controls in which labeled neurons were observed in L7-S3 ventral horns (in lamina VII). This data supports the use of nerve transfer techniques for the restoration of bladder function.NEW & NOTEWORTHY This data supports the use of nerve transfer techniques for the restoration of bladder function.

Systemic Inflammation, Sleep, and Psychological Factors Determine Recovery Trajectories for People With Neck Pain: An Exploratory Study.

We conducted an explorative prospective cohort study with 6 months follow-up to 1) identify different pain and disability trajectories following an episode of acute neck pain, and 2) assess whether neuroimmune/endocrine, psychological, behavioral, nociceptive processing, clinical outcome, demographic and management-related factors differ between these trajectories. Fifty people with acute neck pain (ie, within 2 weeks of onset) were included. At baseline, and at 2, 4, 6, 12, and 26 weeks follow-up, various neuroimmune/endocrine (eg, inflammatory cytokines and endocrine factors), psychological (eg, stress symptoms), behavioral (eg, sleep disturbances), nociceptive processing (eg, condition pain modulation), clinical outcome (eg, trauma), demographic factors (eg, age), and management-related factors (eg, treatment received) were assessed. Latent class models were performed to identify outcome trajectories for neck pain and disability. Linear mixed models or the Pearson chi-square test were used to evaluate differences in these factors between the trajectories at baseline and at each follow-up assessment and over the entire 6 months period. For pain, 3 trajectories were identified. The majority of patients were assigned to the "Moderate pain - Favourable recovery" trajectory (n = 25; 50%) with smaller proportions assigned to the "Severe pain - Favourable recovery" (n = 16; 32%) and the "Severe pain - Unfavourable recovery" (n = 9; 18%) trajectories. For disability, 2 trajectories were identified: "Mild disability - Favourable recovery" (n = 43; 82%) and "Severe disability - Unfavourable recovery" (n = 7; 18%). Ongoing systemic inflammation (increased high-sensitive C-reactive protein), sleep disturbances, and elevated psychological factors (such as depression, stress and anxiety symptoms) were mainly present in the unfavorable outcome trajectories compared to the favorable outcome trajectories. PERSPECTIVE: Using exploratory analyses, different recovery trajectories for acute neck pain were identified based on disability and pain intensity. These trajectories were influenced by systemic inflammation, sleep disturbances, and psychological factors.

Potentiation of Collagen Deposition by the Combination of Substance P with Transforming Growth Factor Beta in Rat Skin Fibroblasts.

A role for substance P has been proposed in musculoskeletal fibrosis, with effects mediated through transforming growth factor beta (TGFß). We examined the in vitro effects of substance P on proliferation, collagen secretion, and collagen deposition in rat primary dermal fibroblasts cultured in medium containing 10% fetal bovine serum, with or without TGFß. In six-day cultures, substance P increased cell proliferation at concentrations from 0.0002 to 100 nM. TGFß increased proliferation at concentrations from 0.0002 to 2 pg/mL, although higher concentrations inhibited proliferation. Substance P treatment alone at concentrations of 100, 0.2, and 0.00002 nM did not increase collagen deposition per cell, yet when combined with TGFß (5 ng/mL), increased collagen deposition compared to TGFß treatment alone. Substance P treatment (100 nM) also increased smooth muscle actin (SMA) expression at 72 h of culture at a level similar to 5 ng/mL of TGFß; only TGFß increased SMA at 48 h of culture. Thus, substance P may play a role in potentiating matrix deposition in vivo when combined with TGFß, although this potentiation may be dependent on the concentration of each factor. Treatments targeting substance P may be a viable strategy for treating fibrosis where both substance P and TGFß play roles.

Poor sleep versus exercise: A duel to decide whether pain resolves or persists after injury.

Poor sleep is thought to enhance pain via increasing peripheral and/or central sensitization. Aerobic exercise, conversely, relives pain via reducing sensitization, among other mechanisms. This raises two clinical questions: (1) does poor sleep contribute to the transition from acute-to-persistent pain, and (2) can exercise protect against this transition? This study tested these questions and explored underlying mechanisms in a controlled injury model. Twenty-nine adult female Sprague-Dawley rats performed an intensive lever-pulling task for 4 weeks to induce symptoms consistent with clinical acute-onset overuse injury. Rats were then divided into three groups and exposed for 4 weeks to either: voluntary exercise via access to a running wheel, sleep disturbance, or both. Pain-related behaviours (forepaw mechanical sensitivity, reflexive grip strength), systemic levels of brain derived neurotrophic factor (BDNF), estradiol and corticosterone, and white blood cells (WBC) were assessed pre-injury, post-injury and post-intervention. Mechanical sensitivity increased post-injury and remained elevated with sleep disturbance alone, but decreased to pre-injury levels with exercise both with and without sleep disturbance. Reflexive grip strength decreased post-injury but recovered post-intervention-more with exercise than sleep disturbance. BDNF increased with sleep disturbance alone, remained at pre-injury levels with exercise regardless of sleep, and correlated with mechanical sensitivity. WBCs and estradiol increased with exercise alone and together with sleep disturbance, respectively. Corticosterone was not impacted by injury/intervention. Findings provide preliminary evidence for a role of poor sleep in the transition from acute-to-persistent pain, and the potential for aerobic exercise to counter these effects. BDNF might have a role in these relationships.

Let's Focus on the Fibrosis in Dupuytren Disease: Cell Communication Network Factor 2 as a Novel Target.

Dupuytren disease is a progressive, benign fibroproliferative disorder of the hands that can lead to debilitating hand contractures. Once symptomatic, treatment involves either surgical intervention, specifically fasciectomy or percutaneous needle aponeurotomy, or enzymatic degradation with clostridial collagenase. Currently, collagenase is the only pharmacotherapy that has been approved for the treatment of Dupuytren contracture. There is a need for a pharmacotherapeutic that can be administered to limit disease progression and prevent recurrence after treatment. Targeting the underlying fibrotic pathophysiology is critical. We propose a novel target to be considered in Dupuytren disease-cell communication network factor 2/connective tissue growth factor-an established mediator of musculoskeletal tissue fibrosis.

Blocking CCN2 Reduces Established Bone Loss Induced by Prolonged Intense Loading by Increasing Osteoblast Activity in Rats.

We have an operant model of reaching and grasping in which detrimental bone remodeling is observed rather than beneficial adaptation when rats perform a high-repetition, high-force (HRHF) task long term. Here, adult female Sprague-Dawley rats performed an intense HRHF task for 18 weeks, which we have shown induces radial trabecular bone osteopenia. One cohort was euthanized at this point (to assay the bone changes post task; HRHF-Untreated). Two other cohorts were placed on 6 weeks of rest while being simultaneously treated with either an anti-CCN2 (FG-3019, 40 mg/kg body weight, ip; twice per week; HRHF-Rest/anti-CCN2), or a control IgG (HRHF-Rest/IgG), with the purpose of determining which might improve the trabecular bone decline. Results were compared with food-restricted control rats (FRC). MicroCT analysis of distal metaphysis of radii showed decreased trabecular bone volume fraction (BV/TV) and thickness in HRHF-Untreated rats compared with FRCs; responses improved with HRHF-Rest/anti-CCN2. Rest/IgG also improved trabecular thickness but not BV/TV. Histomorphometry showed that rest with either treatment improved osteoid volume and task-induced increases in osteoclasts. Only the HRHF-Rest/anti-CCN2 treatment improved osteoblast numbers, osteoid width, mineralization, and bone formation rate compared with HRHF-Untreated rats (as well as the latter three attributes compared with HRHF-Rest/IgG rats). Serum ELISA results were in support, showing increased osteocalcin and decreased CTX-1 in HRHF-Rest/anti-CCN2 rats compared with both HRHF-Untreated and HRHF-Rest/IgG rats. These results are highly encouraging for use of anti-CCN2 for therapeutic treatment of bone loss, such as that induced by chronic overuse. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Extracellular Acetylated Histone 3.3 Induces Inflammation and Lung Tissue Damage.

Extracellular histones, part of the protein group known as damage-associated molecular patterns (DAMPs), are released from damaged or dying cells and can instigate cellular toxicity. Within the context of chronic obstructive pulmonary disease (COPD), there is an observed abundance of extracellular histone H3.3, indicating potential pathogenic implications. Notably, histone H3.3 is often found hyperacetylated (AcH3.3) in the lungs of COPD patients. Despite these observations, the specific role of these acetylated histones in inducing pulmonary tissue damage in COPD remains unclear. To investigate AcH3.3's impact on lung tissue, we administered recombinant histones (rH2A, rH3.3, and rAcH3.3) or vehicle solution to mice via intratracheal instillation. After 48 h, we evaluated the lung toxicity damage and found that the rAcH3.3 treated animals exhibited more severe lung tissue damage compared to those treated with non-acetylated H3.3 and controls. The rAcH3.3 instillation resulted in significant histological changes, including alveolar wall rupture, epithelial cell damage, and immune cell infiltration. Micro-CT analysis confirmed macroscopic structural changes. The rAcH3.3 instillation also increased apoptotic activity (cleavage of caspase 3 and 9) and triggered acute systemic inflammatory marker activation (TNF-α, IL-6, MCP-3, or CXCL-1) in plasma, accompanied by leukocytosis and lymphocytosis. Confocal imaging analysis confirmed lymphocytic and monocytic/macrophage lung infiltration in response to H3.3 and AcH3.3 administration. Taken together, our findings implicate extracellular AcH3.3 in inducing cytotoxicity and acute inflammatory responses, suggesting its potential role in promoting COPD-related lung damage progression.

Blocking CCN2 Reduces Established Palmar Neuromuscular Fibrosis and Improves Function Following Repetitive Overuse Injury.

The matricellular protein cell communication factor 2/connective tissue growth factor (CCN2/CTGF) is critical to development of neuromuscular fibrosis. Here, we tested whether anti-CCN2 antibody treatment will reduce established forepaw fibro-degenerative changes and improve function in a rat model of overuse injury. Adult female rats performed a high repetition high force (HRHF) task for 18 weeks. Tissues were collected from one subset after 18 wks (HRHF-Untreated). Two subsets were provided 6 wks of rest with concurrent treatment with anti-CCN2 (HRHF-Rest/anti-CCN2) or IgG (HRHF-Rest/IgG). Results were compared to IgG-treated Controls. Forepaw muscle fibrosis, neural fibrosis and entheseal damage were increased in HRHF-Untreated rats, compared to Controls, and changes were ameliorated in HRHF-Rest/anti-CCN2 rats. Anti-CCN2 treatment also reduced phosphorylated-ß-catenin (pro-fibrotic protein) in muscles and distal bone/entheses complex, and increased CCN3 (anti-fibrotic) in the same tissues, compared to HRHF-Untreated rats. Grip strength declines and mechanical sensitivity observed in HRHF-Untreated improved with rest; grip strength improved further in HRHF-Rest/anti-CCN2. Grip strength declines correlated with muscle fibrosis, entheseal damage, extraneural fibrosis, and decreased nerve conduction velocity, while enhanced mechanical sensitivity (a pain-related behavior) correlated with extraneural fibrosis. These studies demonstrate that blocking CCN2 signaling reduces established forepaw neuromuscular fibrosis and entheseal damage, which improves forepaw function, following overuse injury.

Nerve transfer for restoration of lower motor neuron-lesioned bladder, urethral, and anal sphincter function in a dog model. Part 3. nicotinic receptor characterization.

Very little is known about the physiological role of nicotinic receptors in canine bladders, although functional nicotinic receptors have been reported in bladders of many species. Utilizing in vitro methods, we evaluated nicotinic receptors mediating bladder function in dogs: control (9 female and 11 male normal controls, 5 sham operated), Decentralized (9 females, decentralized 6-21 mo), and obturator-to-pelvic nerve transfer reinnervated (ObNT-Reinn; 9 females; decentralized 9-13 mo, then reinnervated with 8-12 mo recovery). Muscle strips were collected, mucosa-denuded, and mounted in muscle baths before incubation with neurotransmitter antagonists, and contractions to the nicotinic receptor agonist epibatidine were determined. Strip response to epibatidine, expressed as percent potassium chloride, was similar (∼35% in controls, 30% in Decentralized, and 24% in ObNT-Reinn). Differentially, epibatidine responses in Decentralized and ObNT-Reinn bladder strips were lower than controls after tetrodotoxin (TTX, a sodium channel blocker that inhibits axonal action potentials). Yet, in all groups, epibatidine-induced strip contractions were similarly inhibited by mecamylamine and hexamethonium (ganglionic nicotinic receptor antagonists), SR 16584 (α3ß4 neuronal nicotinic receptor antagonist), atracurium and tubocurarine (neuromuscular nicotinic receptor antagonists), and atropine (muscarinic receptor antagonist), indicating that nicotinic receptors (particularly α3ß4 subtypes), neuromuscular and muscarinic receptors play roles in bladder contractility. In control bladder strips, since tetrodotoxin did not inhibit epibatidine contractions, nicotinic receptors are likely located on nerve terminals. The tetrodotoxin inhibition of epibatidine-induced contractions in Decentralized and ObNT-Reinn suggests a relocation of nicotinic receptors from nerve terminals to more distant axonal sites, perhaps as a compensatory mechanism to recover bladder function.

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice.

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.

Mechanisms involved in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox)-derived reactive oxygen species (ROS) modulation of muscle function in human and dog bladders.

Roles of redox signaling in bladder function is still under investigation. We explored the physiological role of reactive oxygen species (ROS) and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) in regulating bladder function in humans and dogs. Mucosa-denuded bladder smooth muscle strips obtained from 7 human organ donors and 4 normal dogs were mounted in muscle baths, and trains of electrical field stimulation (EFS) applied for 20 minutes at 90-second intervals. Subsets of strips were incubated with hydrogen peroxide (H2O2), angiotensin II (Ang II; Nox activator), apocynin (inhibitor of Noxs and ROS scavenger), or ZD7155 (specific inhibitor of angiotensin type 1 (AT1) receptor) for 20 minutes in continued EFS trains. Subsets treated with inhibitors were then treated with H2O2 or Ang II. In human and dog bladders, the ROS, H2O2 (100µM), caused contractions and enhanced EFS-induced contractions. Apocynin (100µM) attenuated EFS-induced strip contractions in both species; subsequent treatment with H2O2 restored strip activity. In human bladders, Ang II (1µM) did not enhance EFS-induced contractions yet caused direct strip contractions. In dog bladders, Ang II enhanced both EFS-induced and direct contractions. Ang II also partially restored EFS-induced contractions attenuated by prior apocynin treatment. In both species, treatment with ZD7155 (10µM) inhibited EFS-induced activity; subsequent treatment with Ang II did not restore strip activity. Collectively, these data provide evidence that ROS can modulate bladder function without exogenous stimuli. Since inflammation is associated with oxidative damage, the effects of Ang II on bladder smooth muscle function may have pathologic implications.

Meniscal degeneration is prognostic of destabilzing meniscal tear and accelerated knee osteoarthritis: Data from the Osteoarthritis Initiative.

The objective of this study was to assess the prognostic potential of magnetic resonance (MR)-detected meniscal degeneration in relation to incident destabilizing meniscal tears (radial, complex, root, or macerated) or accelerated knee osteoarthritis (AKOA). We used existing MR data from a case-control study of three groups from the Osteoarthritis Initiative without radiographic KOA at baseline: AKOA, typical KOA, and no KOA. From these groups, we included people without medial and lateral meniscal tear at baseline (n = 226) and 48-month meniscal data (n = 221). Intermediate-weighted fat-suppressed MR images annually from baseline to the 48-month visit were graded using a semiquantitative meniscal tear classification criterion. Incident destabilizing meniscal tear was defined as progressing from an intact meniscus to a destabilizing tear by the 48-month visit. We used two logistic regression models to assess whether: (1) presence of medial meniscal degeneration was associated with an incident medial destabilizing meniscal tear, and (2) presence of meniscal degeneration in either meniscus was associated with incident AKOA over the next 4 years. People with the presence of a medial meniscal degeneration had three times the odds of developing an incident destabilizing medial meniscal tear within 4 years compared with a person without medial meniscus degeneration (odds ratio [OR]: 3.03; 95% confidence interval [CI]: 1.40-6.59). People with meniscal degeneration had five times the odds of developing incident AKOA within 4 years compared with a person without meniscal degeneration in either meniscus (OR: 5.04; 95% CI: 2.57-9.89). Meniscal degeneration on MR is clinically meaningful as it relates to future poor outcomes.

Pharmacotherapies in Dupuytren Disease: Current and Novel Strategies.

Dupuytren disease is a benign, progressive fibroproliferative disorder of the hands. To date, only one pharmacotherapy (clostridial collagenase) has been approved for use in Dupuytren disease. There is a great need for additional nonsurgical methods that can be used to either avoid the risks of invasive treatments or help minimize recurrence rates following treatment. A number of nonsurgical modalities have been discussed in the past and continue to appear in discussions among hand surgeons, despite highly variable and often poor or no long-term clinical data. This article reviews many of the pharmacotherapies discussed in the treatment of Dupuytren disease and novel therapies used in inflammation and fibrosis that offer potential treatment options.

Organ- and function-specific anatomical organization of vagal fibers supports fascicular vagus nerve stimulation.

Vagal fibers travel inside fascicles and form branches to innervate organs and regulate organ functions. Existing vagus nerve stimulation (VNS) therapies activate vagal fibers non-selectively, often resulting in reduced efficacy and side effects from non-targeted organs. The transverse and longitudinal arrangement of fibers inside the vagal trunk with respect to the functions they mediate and organs they innervate is unknown, however it is crucial for selective VNS. Using micro-computed tomography imaging, we tracked fascicular trajectories and found that, in swine, sensory and motor fascicles are spatially separated cephalad, close to the nodose ganglion, and merge caudad, towards the lower cervical and upper thoracic region; larynx-, heart- and lung-specific fascicles are separated caudad and progressively merge cephalad. Using quantified immunohistochemistry at single fiber level, we identified and characterized all vagal fibers and found that fibers of different morphological types are differentially distributed in fascicles: myelinated afferents and efferents occupy separate fascicles, myelinated and unmyelinated efferents also occupy separate fascicles, and small unmyelinated afferents are widely distributed within most fascicles. We developed a multi-contact cuff electrode to accommodate the fascicular structure of the vagal trunk and used it to deliver fascicle-selective cervical VNS in anesthetized and awake swine. Compound action potentials from distinct fiber types, and physiological responses from different organs, including laryngeal muscle, cough, breathing, and heart rate responses are elicited in a radially asymmetric manner, with consistent angular separations that agree with the documented fascicular organization. These results indicate that fibers in the trunk of the vagus nerve are anatomically organized according to functions they mediate and organs they innervate and can be asymmetrically activated by fascicular cervical VNS.

Cardiometabolic Risk and Its Relationship With Visceral Adiposity in Children With Cerebral Palsy.

Context: Adults with cerebral palsy (CP) display a higher prevalence of cardiometabolic disease compared with the general population. Studies examining cardiometabolic disease risk in children with CP are limited. Objective: The purpose of this study was to determine if children with CP exhibit higher cardiometabolic risk than typically developing children, and to examine its relationship with visceral adiposity and physical activity. Methods: Thirty ambulatory children with CP and 30 age-, sex-, and race-matched typically developing control children were tested for blood lipids, glucose, and the homeostatic model assessment of insulin resistance (HOMA-IR). Visceral fat was assessed using dual-energy x-ray absorptiometry. Physical activity was assessed using accelerometer-based monitors. Results: Children with CP had higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol (non-HDL-C), glucose, prevalence of dyslipidemia, prevalence of prediabetes, and visceral fat mass index (VFMI) and lower physical activity than controls (all P < .05). In the groups combined, non-HDL-C and glucose were positively related to VFMI (r = 0.337 and 0.313, respectively, P < .05), and non-HDL-C and HOMA-IR were negatively related to physical activity (r = -0.411 and -0.368, respectively, P < .05). HOMA-IR was positively related to VFMI in children with CP (r = 0.698, P < .05), but not in controls. Glucose was not related to physical activity in children with CP, but it was negatively related in controls (r = -0.454, P < .05). Conclusion: Children with CP demonstrate early signs of cardiometabolic disease, which are more closely related to increased visceral adiposity than decreased physical activity.

Restoring bladder function using motor and sensory nerve transfers: a cadaveric feasibility study.

OBJECTIVE: Bladder dysfunction after nerve injury has a variable presentation, and extent of injury determines whether the bladder is spastic or atonic. The authors have proposed a series of 3 nerve transfers for functional innervation of the detrusor muscle and external urethral sphincter, along with sensory innervation to the genital dermatome. These transfers are applicable to only cases with low spinal segment injuries (sacral nerve root function is lost) and largely preserved lumbar function. Transfer of the posterior branch of the obturator nerve to the vesical branch of the pelvic nerve provides a feasible mechanism for patients to initiate detrusor contraction by thigh adduction. External urethra innervation (motor and sensory) may be accomplished by transfer of the vastus medialis nerve to the pudendal nerve. The sensory component of the pudendal nerve to the genitalia may be further enhanced by transfer of the saphenous nerve (sensory) to the pudendal nerve. The main limitations of coapting the nerve donors to their intrapelvic targets are the bifurcation or arborization points of the parent nerve. To ensure that the donor nerves had sufficient length and diameter, the authors sought to measure these parameters. METHODS: Twenty-six pelvic and anterior thigh regions were dissected in 13 female cadavers. After the graft and donor sites were clearly exposed and the branches identified, the donor nerves were cut at suitable distal sites and then moved into the pelvis for tensionless anastomosis. Diameters were measured with calipers. RESULTS: The obturator nerve was bifurcated a mean ± SD (range) of 5.5 ± 1.7 (2.0-9.0) cm proximal to the entrance of the obturator foramen. In every cadaver, the authors were able to bring the posterior division of the obturator nerve to the vesical branch of the pelvic nerve (located internal to the ischial spine) in a tensionless manner with an excess obturator nerve length of 2.0 ± 1.2 (0.0-5.0) cm. The distance between the femoral nerve arborization and the anterior superior iliac spine was 9.3 ± 1.8 (6.5-15.0) cm, and the distance from the femoral arborization to the ischial spine was 12.9 ± 1.4 (10.0-16.0) cm. Diameters were similar between donor and recipient nerves. CONCLUSIONS: The chosen donor nerves were long enough and of sufficient caliber for the proposed nerve transfers and tensionless anastomosis.