Dihydroceramides Derived from Bacteroidetes Species Sensitize TRPV1 Channels.

Bacterial colonization of open wounds is common, and patients with infected wounds often report significantly elevated pain sensitivity at the wound site. Transient Receptor Potential Vanilloid Type 1 (TRPV1) channels are known to play an important role in pain signaling and may be sensitized under pro-inflammatory conditions. Bacterial membrane components, such as phosphoethanolamine dihydroceramide (PEDHC), phosphoglycerol dihydroceramide (PGDHC), and lipopolysaccharide (LPS), are released in the environment from the Gram-negative bacteria of the Bacteroidetes species colonizing the infected wounds. Here, we used intracellular calcium imaging and patch-clamp electrophysiology approaches to determine whether bacterially derived PEDHC, PGDHC, or LPS can modulate the activity of the TRPV1 channels heterologously expressed in HEK cells. We found that PEDHC and PGDHC can sensitize TRPV1 in a concentration-dependent manner, whereas LPS treatment does not significantly affect TRPV1 activity in HEK cells. We propose that sensitization of TRPV1 channels by Bacteroidetes-derived dihydroceramides may at least in part underlie the increased pain sensitivity associated with wound infections.

Epidemiological profile and severity of erythema nodosum leprosum in Brazil: a cross-sectional study.

BACKGROUND: Leprosy can cause acute reactions, which may be type 1 (reverse reaction) or type 2 (erythema nodosum leprosum - ENL). ENL has been classified as mild, moderate, or severe. In order to standardize the classification, the Erythema Nodosum Leprosum International Study (ENLIST) Group has developed an objective scale, the ENLIST ENL Severity Scale (EESS), which was the first validated severity scale of ENL in the world. The goal of the study was to describe the sociodemographic and clinical characteristics of patients with ENL attending a tertiary hospital in Piauí, Brazil, classifying them according to the EESS. METHODS: A descriptive cross-sectional observational study was conducted on 26 patients recruited sequentially from May 2017 to February 2018. Their data were statistically analyzed and compared against each other through a structured questionnaire. RESULTS: According to the score obtained in the scale, the patients were divided into two groups: mild ENL and moderate/severe ENL. The extent and number of nodules were related to the severity of the cases, and these data were statistically significant. The majority of the patients were male, between the ages of 31 and 49 years old, with low educational level, and residents in the urban area. CONCLUSIONS: This was the first study to use EESS in Brazil. This scale is easy to apply and allows for the enhancement of treatment protocols. The study also showed a correlation between the number and extension of nodules and the severity of the condition.

[An unvaccinated man with a painful arm and jaw]. / Een ongevaccineerde man met een pijnlijke arm en kaak.

BACKGROUND: Clostridium tetani is a gram-positive spore-forming bacterium that produces toxins and grows under anaerobic conditions. Infections with this bacterium can lead to local or generalised forms of tetanus. CASE DESCRIPTION: An 83-year-old man presented to the acute cardiac care unit with a painful left arm and jaw. Because the patient had a hypertonic left arm and was unable to open his mouth fully, the neurologist was consulted. The patient had been to the emergency department 9 days earlier for an infected wound after falling in the garden. He had not been actively or passively immunised against tetanus at that time. On inquiry, it appeared that the patient had also not been vaccinated as a child. We made a clinical diagnosis of tetanus. The patient was admitted and treated with tetanus immunoglobulin, metronidazole, diazepam and painkillers. He was also administered tetanus toxoid and the wound was cleaned. After 1 month and 7 months, the patient was again administered tetanus toxoid. CONCLUSION: Patients with a wound that may have come into contact with road grime, dirt or manure, should always be asked for their vaccination status, especially people from high-risk groups, such as the elderly.

Gut Microbiota Dysbiosis Enhances Migraine-Like Pain Via TNFα Upregulation.

Migraine is one of the most disabling neurological diseases worldwide; however, the mechanisms underlying migraine headache are still not fully understood and current therapies for such pain are inadequate. It has been suggested that inflammation and neuroimmune modulation in the gastrointestinal tract could play an important role in the pathogenesis of migraine headache, but how gut microbiomes contribute to migraine headache is unclear. In the present study, we investigated the effect of gut microbiota dysbiosis on migraine-like pain using broad-spectrum antibiotics and germ-free (GF) mice. We observed that antibiotics treatment-prolonged nitroglycerin (NTG)-induced acute migraine-like pain in wild-type (WT) mice and the pain prolongation was completely blocked by genetic deletion of tumor necrosis factor-alpha (TNFα) or intra-spinal trigeminal nucleus caudalis (Sp5C) injection of TNFα receptor antagonist. The antibiotics treatment extended NTG-induced TNFα upregulation in the Sp5C. Probiotics administration significantly inhibited the antibiotics-produced migraine-like pain prolongation. Furthermore, NTG-induced migraine-like pain in GF mice was markedly enhanced compared to that in WT mice and gut colonization with fecal microbiota from WT mice robustly reversed microbiota deprivation-caused pain enhancement. Together, our results suggest that gut microbiota dysbiosis contributes to chronicity of migraine-like pain by upregulating TNFα level in the trigeminal nociceptive system.

Near-Infrared Light-Sensitive Nano Neuro-Immune Blocker Capsule Relieves Pain and Enhances the Innate Immune Response for Necrotizing Infection.

Sensory neurons promote profound suppressive effects on neutrophils during Streptococcus pyogenes infection and contribute to the pathogenesis of necrotizing infection ("flesh-eating disease"). Thus, the development of new antibacterial agents for necrotizing infection is promising because of the clear streptococcal neuro-immune communication. Herein, based on the immune escape membrane exterior and competitive membrane functions of the glioma cell membrane, a novel nano neuro-immune blocker capsule was designed to prevent neuronal activation and improve neutrophil immune responses for necrotizing infection. These nano neuro-immune blockers could neutralize streptolysin S, suppress neuron pain conduction and calcitonin gene-related peptide release, and recruit neutrophils to the infection site, providing a strong therapeutic effect against necrotizing infection. Furthermore, nano neuro-immune blockers could serve as an effective inflammatory regulator and antibacterial agent via photothermal effects under near-infrared irradiation. In the Streptococcus pyogenes-induced necrotizing fasciitis mouse model, nano neuro-immune blockers showed significant therapeutic efficacy by ameliorating sensitivity to pain and promoting the antibacterial effect of neutrophils.

Contribution of spinal cord glial cells to L. amazonensis experimental infection-induced pain in BALB/c mice.

BACKGROUND: The cellular and molecular pathophysiological mecha\nisms of pain processing in neglected parasitic infections such as leishmaniasis remain unknown. The present study evaluated the participation of spinal cord glial cells in the pathophysiology of pain induced by Leishmania amazonensis infection in BALB/c mice. METHODS: Mice received intra-plantar (i.pl.) injection of L. amazonensis (1 × 105) and hyperalgesia, and paw edema were evaluated bilaterally for 40 days. The levels of TNF-α and IL-1ß, MPO activity, and histopathology were assessed on the 40th day. ATF3 mRNA expression was assessed in DRG cells at the 30th day post-infection. Blood TNF-α and IL-1ß levels and systemic parasite burden were evaluated 5-40 days after the infection. At the 30th day post-infection L. amazonensis, the effects of intrathecal (i.t.) treatments with neutralizing antibody anti-CX3CL1, etanercept (soluble TNFR2 receptor), and interleukin-1 receptor antagonist (IL-1ra) on infection-induced hyperalgesia and paw edema were assessed. In another set of experiments, we performed a time course analysis of spinal cord GFAP and Iba-1 (astrocytes and microglia markers, respectively) and used confocal immunofluorescence and Western blot to confirm the expression at the protein level. Selective astrocyte (α-aminoadipate) and microglia (minocycline) inhibitors were injected i.t. to determine the contribution of these cells to hyperalgesia and paw edema. The effects of i.t. treatments with glial and NFκB (PDTC) inhibitors on spinal glial activation, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation were also evaluated. Finally, the contribution of TNF-α and IL-1ß to CX3CL1 mRNA expression was investigated. RESULTS: L. amazonensis infection induced chronic mechanical and thermal hyperalgesia and paw edema in the infected paw. Mechanical hyperalgesia was also observed in the contralateral paw. TNF-α, IL-1ß, MPO activity, and epidermal/dermal thickness increased in the infected paw, which confirmed the peripheral inflammation at the primary foci of this infection. ATF3 mRNA expression at the ipsilateral DRG of the infected paw was unaltered 30 days post-infection. TNF-α and IL-1ß blood levels were not changed over the time course of disease, and parasitism increased in a time-dependent manner in the ipsilateral draining lymph node. Treatments targeting CX3CL1, TNF-α, and IL-1ß inhibited L. amazonensis-induced ongoing mechanical and thermal hyperalgesia, but not paw edema. A time course of GFAP, Iba-1, and CX3CR1 mRNA expression indicated spinal activation of astrocytes and microglia, which was confirmed at the GFAP and Iba-1 protein level at the peak of mRNA expression (30th day). Selective astrocyte and microglia inhibition diminished infection-induced ipsilateral mechanical hyperalgesia and thermal hyperalgesia, and contralateral mechanical hyperalgesia, but not ipsilateral paw edema. Targeting astrocytes, microglia and NFκB diminished L. amazonensis-induced GFAP, Iba-1, TNF-α, IL-1ß, CX3CR1 and CX3CL1 mRNA expression, and NFκB activation in the spinal cord at the peak of spinal cord glial cells activation. CX3CL1 mRNA expression was also detected in the ipsilateral DRG of infected mice at the 30th day post-infection, and the i.t. injection of TNF-α or IL-1ß in naïve animals induced CX3CL1 mRNA expression in the spinal cord and ipsilateral DRG. CONCLUSIONS: L. amazonensis skin infection produces chronic pain by central mechanisms involving spinal cord astrocytes and microglia-related production of cytokines and chemokines, and NFκB activation contributes to L. amazonensis infection-induced hyperalgesia and neuroinflammation.

A young girl with a painful rash.

The speed with which this rash spread and the fact that the patient's skin sloughed off when pressure was applied made the diagnosis clear.

[Perianal abscess after anal intercourse should raise suspicion of rectal gonorrhoeae infection].

Neisseria gonorrhoeae infection is a sexually transmitted disease. Rectal gonorrhoea is often asymptomatic, the most common symptoms are anal pain, bleeding and purulent discharge. This case report describes a younger man, who experienced increasing anal pain and later fever after anal intercourse. N. gonorrhoeae infection was verified, before a clinical examination revealed a perianal abscess. During incision of the abscess an anal fistula was suspected, and six weeks after primary surgery and treatment with relevant antibiotics, transanal ultrasonography showed perianal scarring and no signs of anocutaneous fistula.

Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice.

Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.

Bacteremia Possibly Caused by Helicobacter cinaedi and Associated with Painful Erythema in Rheumatoid Arthritis with Malignant Lymphoma.

We herein report the case of a 69-year-old woman with rheumatoid arthritis (RA) and malignant lymphoma who developed Helicobacter cinaedi bacteremia after starting rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. She had a recurrent fever and painful erythema for 13 months before the diagnosis was made. This delayed diagnosis was attributable to the underlying RA, which typically presents with various cutaneous manifestations and elevated C-reactive protein levels. The erythema on the thighs, abdomen, and left forearm improved following treatment with intravenous aminobenzyl penicillin; she received antibiotics for six weeks. This case emphasizes the importance of recognizing this opportunistic infection in immunocompromised patients.

Cranial neuropathy and severe pain due to early disseminated Borrelia burgdorferi infection.

A 61-year-old man presented to the emergency department in the summer with a right seventh cranial nerve lower motor neuron palsy and worsening paraesthesias for 6 weeks. He had debilitating pain at the scalp and spine. Prior work up was unrevealing. The patient resided in the upper Midwest region of the USA and worked outdoors, optimising the landscape for white tailed deer. Repeat cerebrospinal fluid testing revealed a lymphocytic pleocytosis and positive IgM Lyme serology. Brain MRI demonstrated enhancement of multiple cranial nerves bilaterally. He was diagnosed with early Lyme neuroborreliosis and treated with 28 days of intravenous ceftriaxone. While the painful meningoradiculitis, also known as Bannwarth syndrome, is more commonly seen in Europe, facial palsy is more frequently encountered in the USA. Clinical manifestations of neuroborreliosis are important to recognise as the classic presentation varies by geography and on occasion repeat serological testing may be necessary.

Unusual case of prosthetic joint infection caused by Francisella Tularensis.

Tularaemia is a zoonotic infection caused by Francisella tularensis.Ulceroglandular, glandular, oculoglandular, pharyngeal, typhoidal and pneumonic types are the different types of the disease. Infection of prosthetic joints occurs at an exceedingly uncommon rate. We report a case of prosthetic joint infection involving the hip with F. tularensis, which to the best of our knowledge after a thorough literature review is the second of its kind.

Fever, bone pain and erectile dysfunction. Where is the cat?

Cat-scratch disease is due to Bartonella henselae and commonly presents as a localised papular lesion with regional lymphadenopathy. We report the case of a young man suffering general symptoms and dysautonomy characterised by an erectile dysfunction due to an invasive cat-scratch disease. He was successfully treated by tetracyclines during 3 weeks.

Topical Opioids and Antimicrobials for the Management of Pain, Infection, and Infection-Related Odors in Malignant Wounds: A Systematic Review.

PROBLEM IDENTIFICATION: Patients with malignant wounds report pain, distress from odor and exudate, decreased self-esteem, and poor quality of life. This systematic review explores topical opioids, antimicrobials, and odor-reducing agents for preventing or managing malignant wound pain, infection, and odor.
. LITERATURE SEARCH: MEDLINE®, EMBASE, the Cochrane Library, CINAHL®, and reference lists were searched to identify relevant studies.
. DATA EVALUATION: Eligible study designs included interventions with pre- and postintervention data. Data extraction and risk-of-bias assessments were conducted using the Cochrane approach.
. SYNTHESIS: No studies evaluated opioid use. Five studies (four randomized, controlled trials) evaluated topical antimicrobials for infection and odor. All studies reported clinically (but generally not statistically) significant improvements in outcomes.
. CONCLUSIONS: Although not as prevalent as before, 5%-10% of tumors, particularly in breast cancer, sarcoma, and melanoma, are expected to fungate. Gaps in the literature exist for use of topical opioids and antimicrobials for managing pain, odor, and infection control in malignant wounds.
. IMPLICATIONS FOR RESEARCH: Current recommendations for topical control of malignant wounds are based on case reports and observational studies in patients with breast cancer. Robust, controlled trials of topical opioid and antimicrobial use are warranted in patients with melanoma, breast, or head and neck cancer.

Recurrent Yeast Infections and Vulvodynia: Can We Believe Associations Based on Self-Reported Data?

OBJECTIVE: We determined whether self-reported new or recurrent yeast infections were a risk factor for and/or consequence of vulvodynia and then determined the extent to which various levels of misclassification of self-reported yeast infections influenced these results. MATERIALS AND METHODS: In this case-control study we retrospectively assessed self-reported new and recurrent yeast infections prior and subsequent to first vulvar pain onset among 216 clinically confirmed cases and during a similar time period for 224 general population controls. RESULTS: A history of >10 yeast infections before vulvodynia onset was strongly but imprecisely associated with currently diagnosed vulvodynia after adjustment for age, age at first intercourse, and history of urinary tract infections [adjusted odds ratio = 5.5, 95% confidence interval (CI) 1.7-17.8]. Likewise, a history of vulvodynia was associated with a twofold risk of subsequent new or recurrent onset of yeast infections after adjustment for age, age at first intercourse, and history of yeast infections before vulvodynia onset (comparable time period among controls, 95% CI 1.5-2.9). Bias analyses showed that our observed associations were an underestimation of the true association when nondifferential misclassification of self-reported yeast infections and certain differential misclassification scenarios were present. However, if women with vulvodynia more frequently misreported having them when they truly did not, our observed associations were an overestimate of the truth. CONCLUSIONS: There appears to be a positive relationship between yeast infections preceding and following the diagnosis of vulvodynia, but this relationship varies from strong to nonexistent depending on the relative accuracy of the recalled diagnosis of yeast infections among cases and controls. To better understand the bidirectional associations between yeast infections and vulvodynia, future validation studies are needed to determine the extent to which misclassification of self-reported yeast infections differs between women with and without vulvodynia.

Gut microbiota is critical for the induction of chemotherapy-induced pain.

Chemotherapy-induced pain is a dose-limiting condition that affects 30% of patients undergoing chemotherapy. We found that gut microbiota promotes the development of chemotherapy-induced mechanical hyperalgesia. Oxaliplatin-induced mechanical hyperalgesia was reduced in germ-free mice and in mice pretreated with antibiotics. Restoring the microbiota of germ-free mice abrogated this protection. These effects appear to be mediated, in part, by TLR4 expressed on hematopoietic cells, including macrophages.