Rejected

Low back pain (LBP) is a common musculoskeletal symptom, which can be developed in multiple clinical diseases. It is widely recognized that intervertebral disc (IVD) degeneration (IVDD) is one of the leading causes of LBP. However, the pathogenesis of IVD-related LBP is still controversial, and the treatment means are also insufficient to date. In recent decades, the role of structure and function changes of sensory nervous system in the induction and the maintenance of LBP is drawing more and more attention. With the progress of IVDD, IVD cell exhaustion and extracellular matrix degradation result in IVD structural damage, while neovascularization, innervation and inflammatory activation further deteriorate the microenvironment of IVD. New nerve ingrowth into degenerated IVD amplifies the impacts of IVD-derived nociceptive molecules on sensory endings. Moreover, IVDD is usually accompanied with disc herniation, which could injure and inflame affected nerves. Under mechanical and pro-inflammatory stimulation, the pain-transmitting pathway exhibits a sensitized function state and ultimately leads to LBP. Hence, relevant pathogenic factors, such as neurotrophins, ion channels, inflammatory factors, etc., are supposed to serve as promising therapeutic targets for LBP. The purpose of this review is to comprehensively summarize the current evidence on 1) the pathological changes of sensory nervous system during IVDD and their association with LBP, and 2) potential therapeutic strategies for LBP targeting relevant pathogenic factors.

We report a case of a 15-year-old female presenting with a serious multisystemic inflammatory illness during a surge of SARS-CoV-2 (COVID-19) cases in our county. The initial clinical findings of sore throat and neck stiffness, followed by signs of sepsis, raised suspicion of Lemierre syndrome early in her hospital course. However, the presence of severe respiratory distress, multifocal pneumonia with pleural effusion on chest radiograph, acute kidney injury, and the discovery of coronary artery ectasia, pointed to the new entity "multisystem inflammatory syndrome in children (MIS-C)." Immune modulatory treatment was thus considered. However, progressive neck pain and swelling, coupled with the eventual growth of Fusobacterium necrophorum on blood culture, eventually led to the correct diagnosis of Lemierre syndrome.

In low-resource settings, treatment is often given empirically without knowledge on the etiology due to lack of diagnostics. In the search for reliable rapid tests to guide treatment work-up, we evaluated whether two biomarkers could differentiate bacterial from non-bacterial infections in acute febrile patients.

Duloxetine, a serotonin-norepinephrine reuptake inhibitor, is currently recommended as a useful medicine to chronic pain including low back pain. However, as the analogy of classical selective serotonin reuptake inhibitors, there is a concern to deteriorate osteoporosis with remaining to clarify the exact mechanism of duloxetine in bone metabolism. We have previously reported that prostaglandin E (PGE) induces the synthesis of both osteoprotegerin (OPG) and interleukin-6 (IL-6), essential regulators of bone metabolism, in osteoblast-like MC3T3-E1 cells. Based upon them, we herein investigated the mechanism whereby the effect of duloxetine on the synthesis of OPG and IL-6 induced by PGE in these cells. Duloxetine enhanced the release from MC3T3-E1 cells of both OPG and IL-6 stimulated by PGE. However, reboxetine, a selective and specific inhibitor of norepinephrine reuptake, failed to affect the PGE-induced release of OPG or IL-6. Oppositely, fluvoxamine and sertraline, agents belonging to the class of selective serotonin reuptake inhibitor, upregulated the PGE-stimulated release of both OPG and IL-6. Duloxetine amplified the expression of OPG mRNA and IL-6 mRNA stimulated by PGE. Duloxetine strengthened the PGE-induced p38 MAP kinase phosphorylation, which was amplified by fluvoxamine as well. SB203880, an inhibitor of p38 MAP kinase, suppressed the amplifying effects by duloxetine or fluvoxamine on the PGE-stimulated release of OPG and IL-6. These results strongly suggest that duloxetine could strengthen osteoblast activation by PGE through the upregulation of p38 MAP kinase, leading to increasing the synthesis of OPG and IL-6.

Oxaliplatin-induced peripheral neuropathy is characterized by an acute hyperexcitability syndrome triggered/exacerbated by cold. The mechanisms underlying oxaliplatin-induced peripheral neuropathy are unclear, but the alteration of ion channel expression and activity plays a well-recognized central role. Recently, we found that oxaliplatin leads to cytosolic acidification in dorsal root ganglion (DRG) neurons. Here, we investigated the early impact of oxaliplatin on the proton-sensitive TREK potassium channels. Following a 6-h oxaliplatin treatment, both channels underwent a transcription upregulation that returned to control levels after 42 h. The overexpression of TREK channels was also observed after in vivo treatment in DRG cells from mice exposed to acute treatment with oxaliplatin. Moreover, both intracellular pH and TREK channel transcription were similarly regulated after incubation with amiloride, an inhibitor of the Na/H exchanger. In addition, we studied the role of oxaliplatin-induced acidification on channel behavior, and, as expected, we observed a robust positive modulation of TREK channel activity. Finally, we focused on the impact of this complex modulation on capsaicin-evoked neuronal activity finding a transient decrease in the average firing rate following 6 h of oxaliplatin treatment. In conclusion, the early activation of TREK genes may represent a mechanism of protection against the oxaliplatin-related perturbation of neuronal excitability.

Paclitaxel, a primary chemotherapeutic agent used to treat numerous solid malignancies, is commonly associated with debilitating peripheral neuropathy. However, a satisfactory gold-standard monotherapy for this neuropathic pain is not currently available. A combination strategy of two or more medications with different properties may achieve more beneficial effects than monotherapy. Thus, we investigated the analgesic efficacies and spinal mechanisms of the combination strategy, including bee venom acupuncture (BVA) and venlafaxine (VLX) against paclitaxel-induced allodynia in mice. Four intraperitoneal infusions of paclitaxel on alternating days (2 mg/kg/day) induced cold and mechanical allodynia for at least 1 week as assessed using acetone and the von Frey hair test, respectively. Co-treatment of BVA (1.0 mg/kg, s.c., ST36) with VLX (40 mg/kg, i.p.) at the medium dose produced a longer-lasting and additive effect than each monotherapy at the highest dose (BVA, 2.5 mg/kg; VLX, 60 mg/kg). Spinal pre-administration of idazoxan (α-adrenergic receptor antagonist, 10 μg), methysergide (mixed 5-HT/5-HT receptor antagonist, 10 μg), or MDL-72222 (5-HT receptor antagonist, 10 μg) abolished this analgesia. These results suggest that the combination therapy with BVA and VLX produces long-lasting and additive analgesic effects on paclitaxel-induced allodynia, via the spinal noradrenergic and serotonergic mechanism, providing a promising clinical strategy.

Persistent or recurrent back and leg pain following spinal surgery, known as failed back surgery syndrome (FBSS), significantly limits daily life activities. A lumbar epidural injection can reduce adhesions, inflammation, and nerve compression, although the epidural space can be distorted due to dura mater and epidural tissues changes after spinal surgery. This study analyzed subdural injection during lumbar epidural injection in FBSS patients. We retrospectively analyzed data from 155 patients who received a lumbar interlaminar epidural injection to manage FBSS. We grouped the patients based on the injected contrast medium appearance in the subdural (group S) or epidural spaces (group E) in fluoroscopic contrast images. Demographic, clinical, surgical and fluoroscopic data were recorded and evaluated, as were the pain scores before and after injection. There were 59 patients (38.1%) in the subdural group. Injection distance from the surgery level differed between the groups. Risk of subdural injection at level 1 distance from the surgery level had an odds ratio of 0.374, and at level ≥2, it was 0.172, when compared to level 0. Subdural incidence differed with the distance from surgical site. Physicians should strive to reduce subdural incidence when the injection is planned at surgery site in FBSS.

Despite the evidence to suggest a high rate of cerebrovascular complications in patients with SARS-CoV-2, reports indicate a falling rate of new ischemic stroke diagnoses. An observed decrease in emergency department visits should come as no shock during times of major crises, as patients prioritize avoiding exposure to SARS-CoV-2 against the acute situation that they may perceive as mild symptoms of a headache, lethargy, difficulty speaking, and numbness. In the central and south Texas regions where we practice, we suspect that patient admission, treatment, and discharge volumes for acute stroke treatment have decreased significantly since COVID-19 related shelter-at-home orders were issued. Symptoms of stroke are frequently noticed by another family member, friend, or community member before they are recognized by the patients themselves, and perhaps these symptoms are going unnoticed due to limited face-to-face encounters. This emphasizes the importance of patient education on stroke warning signs and symptoms during the current times of isolation and social-distancing. The central Texas population, already saddled with above-average rates of cardiovascular and cerebrovascular disease, has a higher stroke mortality rate compared to Texas and U.S. averages; however, the number of patients presenting to emergency departments with acute ischemic stroke diagnoses are lower than average. Our viewpoint aims to present the relative literature to-date and outline our ongoing analyses in the highly-affected and diverse stroke populations from San Antonio and Austin, TX. To put it simply: where did all our stroke patients go?

A number of inherited conditions cause chronic itch as a part of the recognized phenotype. Advances in the understanding of the genetic factors that cause these diseases elucidates the molecular underpinning of itch as a symptom. Our knowledge of the causes of chronic itch has also advanced, providing an opportunity to integrate the genetic pathophysiology with the molecular landscape of chronic itch mediators. This article reviews select genodermatoses that have itch as a predominant feature with a focus on the pathophysiology of the disease, how it may lead to itch and potential therapeutic targets.

To report the surgical technique and outcome for correction of complete unilateral duplication of the left urinary tract in a dog.