Highly specific σ2R/TMEM97 ligand FEM-1689 alleviates neuropathic pain and inhibits the integrated stress response.

The sigma 2 receptor (σ2R) was described pharmacologically more than three decades ago, but its molecular identity remained obscure until recently when it was identified as transmembrane protein 97 (TMEM97). We and others have shown that σ2R/TMEM97 ligands alleviate mechanical hypersensitivity in mouse neuropathic pain models with a time course wherein maximal antinociceptive effect is approximately 24 h following dosing. We sought to understand this unique antineuropathic pain effect by addressing two key questions: do these σ2R/TMEM97 compounds act selectively via the receptor, and what is their downstream mechanism on nociceptive neurons? Using male and female conventional knockout mice for Tmem97, we find that a σ2R/TMEM97 binding compound, FEM-1689, requires the presence of the gene to produce antinociception in the spared nerve injury model in mice. Using primary mouse dorsal root ganglion neurons, we demonstrate that FEM-1689 inhibits the integrated stress response (ISR) and promotes neurite outgrowth via a σ2R/TMEM97-specific action. We extend the clinical translational value of these findings by showing that FEM-1689 reduces ISR and p-eIF2α levels in human sensory neurons and that it alleviates the pathogenic engagement of ISR by methylglyoxal. We also demonstrate that σ2R/TMEM97 is expressed in human nociceptors and satellite glial cells. These results validate σ2R/TMEM97 as a promising target for further development for the treatment of neuropathic pain.

ephrin-B2 promotes nociceptive plasticity and hyperalgesic priming through EphB2-MNK-eIF4E signaling in both mice and humans.

Ephrin-B-EphB signaling can promote pain through ligand-receptor interactions between peripheral cells, like immune cells expressing ephrin-Bs, and EphB receptors expressed by DRG neurons. Previous studies have shown increased ephrin-B2 expression in peripheral tissues like synovium of rheumatoid and osteoarthritis patients, indicating the clinical significance of this signaling. The primary goal of this study was to understand how ephrin-B2 acts on mouse and human DRG neurons, which express EphB receptors, to promote pain and nociceptor plasticity. We hypothesized that ephrin-B2 would promote nociceptor plasticity and hyperalgesic priming through MNK-eIF4E signaling, a critical mechanism for nociceptive plasticity induced by growth factors, cytokines and nerve injury. Both male and female mice developed dose-dependent mechanical hypersensitivity in response to ephrin-B2, and both sexes showed hyperalgesic priming when challenged with PGE2 injection either to the paw or the cranial dura. Acute nociceptive behaviors and hyperalgesic priming were blocked in mice lacking MNK1 (Mknk1 knockout mice) and by eFT508, a specific MNK inhibitor. Sensory neuron-specific knockout of EphB2 using Pirt-Cre demonstrated that ephrin-B2 actions require this receptor. In Ca2+-imaging experiments on cultured DRG neurons, ephrin-B2 treatment enhanced Ca2+ transients in response to PGE2 and these effects were absent in DRG neurons from MNK1-/- and EphB2-PirtCre mice. In experiments on human DRG neurons, ephrin-B2 increased eIF4E phosphorylation and enhanced Ca2+ responses to PGE2 treatment, both blocked by eFT508. We conclude that ephrin-B2 acts directly on mouse and human sensory neurons to induce nociceptor plasticity via MNK-eIF4E signaling, offering new insight into how ephrin-B signaling promotes pain.

A Female-Specific Role for Calcitonin Gene-Related Peptide (CGRP) in Rodent Pain Models.

We aimed to investigate a sexually dimorphic role of calcitonin gene-related peptide (CGRP) in rodent models of pain. Based on findings in migraine where CGRP has a preferential pain-promoting effect in female rodents, we hypothesized that CGRP antagonists and antibodies would attenuate pain sensitization more efficaciously in female than male mice and rats. In hyperalgesic priming induced by activation of interleukin 6 signaling, CGRP receptor antagonists olcegepant and CGRP8-37 both given intrathecally, blocked, and reversed hyperalgesic priming only in females. A monoclonal antibody against CGRP, given systemically, blocked priming specifically in female rodents but failed to reverse it. In the spared nerve injury model, there was a transient effect of both CGRP antagonists, given intrathecally, on mechanical hypersensitivity in female mice only. Consistent with these findings, intrathecally applied CGRP caused a long-lasting, dose-dependent mechanical hypersensitivity in female mice but more transient effects in males. This CGRP-induced mechanical hypersensitivity was reversed by olcegepant and the KCC2 enhancer CLP257, suggesting a role for anionic plasticity in the dorsal horn in the pain-promoting effects of CGRP in females. In spinal dorsal horn slices, CGRP shifted GABAA reversal potentials to significantly more positive values, but, again, only in female mice. Therefore, CGRP may regulate KCC2 expression and/or activity downstream of CGRP receptors specifically in females. However, KCC2 hypofunction promotes mechanical pain hypersensitivity in both sexes because CLP257 alleviated hyperalgesic priming in male and female mice. We conclude that CGRP promotes pain plasticity in female rodents but has a limited impact in males.SIGNIFICANCE STATEMENT The majority of patients impacted by chronic pain are women. Mechanistic studies in rodents are creating a clear picture that molecular events promoting chronic pain are different in male and female animals. We sought to build on evidence showing that CGRP is a more potent and efficacious promoter of headache in female than in male rodents. To test this, we used hyperalgesic priming and the spared nerve injury neuropathic pain models in mice. Our findings show a clear sex dimorphism wherein CGRP promotes pain in female but not male mice, likely via a centrally mediated mechanism of action. Our work suggests that CGRP receptor antagonists could be tested for efficacy in women for a broader variety of pain conditions.

Factors Associated With Delay of Diagnosis of Hepatocellular Carcinoma in Patients With Cirrhosis.

BACKGROUND & AIMS: We examined the frequency of and factors associated with delays in diagnosis of hepatocellular carcinoma (HCC) in a cohort of patients with cirrhosis in the Veterans Health Administration. METHODS: In a retrospective study, we collected and analyzed data from the Veterans Health Administration's electronic health records. We used a multivariate logistic regression model to identify factors associated with a delay in diagnosis of HCC of more than 60 days following a red flag (defined as the earliest date at which a diagnosis of HCC could have been made, based on American Association for the Study of Liver Disease 2005 guidelines). We used multivariate Cox proportional hazards model to evaluate the effects of delayed diagnosis on survival, adjusting for patient and provider characteristics. RESULTS: Among 655 patients with cirrhosis and a diagnosis of HCC from 2006 through 2011, 46.9% had a delay in diagnosis of more than 60 days following a red flag for HCC. Delays in diagnosis for more than 60 days were significantly associated with lack of provider adherence to the guidelines (adjusted odds ratio [OR], 4.82; 95% CI, 3.12-7.45), a diagnostic imaging evaluation instead of only measurement of alfa fetoprotein (adjusted OR, 2.63; 95% CI, 1.09-6.24), and diagnosis as an incidental finding during examination for an unrelated medical problem (compared with an HCC-related assessment) (adjusted OR, 2.26; 95% CI, 1.09-4.67). Diagnostic delays of 60 days or more were associated with lower mortality compared to patients without a delay in diagnosis (unadjusted hazard ratio, 0.57; 95% CI, 0.47-0.68 and adjusted hazard ratio, 0.63; 95% CI, 0.50-0.78). CONCLUSIONS: Nearly half of veterans with cirrhosis have delays in diagnosis of HCC of 60 days or more after a red flag, defined by guidelines. Interventions are needed to improve timely follow-up of red flags for HCC and adherence to guidelines, to increase early detection of HCC.

Human Tyrosinase: Temperature-Dependent Kinetics of Oxidase Activity.

Human tyrosinase (Tyr) is involved in pigment biosynthesis, where mutations in its corresponding gene TYR have been linked to oculocutaneous albinism 1, an autosomal recessive disorder. Although the enzymatic capabilities of Tyr have been well-characterized, the thermodynamic driving forces underlying melanogenesis remain unknown. Here, we analyze protein binding using the diphenol oxidase behavior of Tyr and van 't Hoff temperature-dependent analysis. Recombinant Tyr was expressed and purified using a combination of affinity and size-exclusion chromatography. Michaelis-Menten constants were measured spectrophotometrically from diphenol oxidase reactions of Tyr, using L-3,4-dihydroxyphenylalanine (L-DOPA) as a substrate, at temperatures: 25, 31, 37, and 43 °C. Under the same conditions, the Tyr structure and the L-DOPA binding activity were simulated using 3 ns molecular dynamics and docking. The thermal Michaelis-Menten kinetics data were subjected to the van 't Hoff analysis and fitted with the computational model. The temperature-dependent analysis suggests that the association of L-DOPA with Tyr is a spontaneous enthalpy-driven reaction, which becomes unfavorable at the final step of dopachrome formation.

Between source and sea: The role of wastewater treatment in reducing marine microplastics.

Wastewater treatment plants (WWTPs) are a focal point for the removal of microplastic (MP) particles before they are discharged into aquatic environments. WWTPs are capable of removing substantial quantities of larger MP particles but are inefficient in removing particles with any one dimension of less than 100 µm, with influents and effluents tending to have similar quantities of these smaller particles. As a single WWTP may release >100 billion MP particles annually, collectively WWTPs are significant contributors to the problem of MP pollution of global surface waters. Currently, there are no policies or regulations requiring the removal of MPs during wastewater treatment, but as concern about MP pollution grows, the potential for wastewater technologies to capture particles before they reach surface waters has begun to attract attention. There are promising technologies in various stages of development that may improve the removal of MP particles from wastewater. Better incentivization could speed up the research, development and adoption of innovative practices. This paper describes the current state of knowledge regarding MPs, wastewater and relevant policies that could influence the development and deployment of new technologies within WWTPs. We review existing technologies for capturing very small MP particles and examine new developments that may have the potential to overcome the shortcomings of existing methods. The types of collaborations needed to encourage and incentivize innovation within the wastewater sector are also discussed, specifically strong partnerships among scientific and engineering researchers, industry stakeholders, and policy decision makers.

Benefits and limitations of noninvasive prenatal aneuploidy screening.

The introduction of noninvasive prenatal screening (NIPS) using cell-free DNA (cfDNA) is the newest option for aneuploidy screening during pregnancy. Compared with other aneuploidy screening options, NIPS offers a higher detection rate for trisomy 21 with a low false-positive rate. However, pretest and post-test patient counseling is essential and should include a discussion of the benefits and limitations, the screening rather than diagnostic nature of the test, and the association of a test failure with an increased risk of aneuploidy. Refer patients for genetic counseling when appropriate, particularly if test failure occurs due to a low fetal fraction or if maternal mosaicism or malignancy is suspected.

Randomized phase I clinical trial of anti-α-synuclein antibody BIIB054.

BACKGROUND: Pathological and genetic evidence implicates toxic effects of aggregated α-synuclein in the pathophysiology of neuronal dysfunction and degeneration in Parkinson's disease. Immunotherapy targeting aggregated α-synuclein is a promising strategy for delaying disease progression. OBJECTIVE: This study (NCT02459886) evaluated the safety, tolerability, and pharmacokinetics of BIIB054, a human-derived monoclonal antibody that preferentially binds to aggregated α-synuclein, in healthy volunteers and participants with Parkinson's disease. METHODS: A total of 48 healthy volunteers (age 40-65, 19 women) and 18 Parkinson's disease participants (age 47-75, 5 women, Hoehn and Yahr stage ≤2.5) were in the study. Volunteers were enrolled into 6 single-dose cohorts of BIIB054 (range 1-135 mg/kg) or placebo, administered intravenously; Parkinson's disease participants received a single dose of BIIB054 (15 or 45 mg/kg) or placebo. All participants were evaluated for 16 weeks with clinical, neuroimaging, electrocardiogram, and laboratory assessments. Serum and cerebrospinal fluid BIIB054 concentrations were measured. BIIB054/α-synuclein complexes were measured in plasma. RESULTS: Most adverse events were mild and assessed by investigators as unrelated to the study drug. Pharmacokinetic parameters for volunteers and the Parkinson's disease participants were similar. BIIB054 serum exposure and maximum concentrations were dose proportional during the dose range studied. In volunteers and the Parkinson's disease participants, the serum half-life of BIIB054 was 28 to 35 days; the cerebrospinal fluid-to-serum ratio ranged from 0.13% to 0.56%. The presence of BIIB054/α-synuclein complexes in plasma was confirmed; all Parkinson's disease participants showed almost complete saturation of the BIIB054/α-synuclein complex formation. CONCLUSIONS: BIIB054 has favorable safety, tolerability, and pharmacokinetic profiles in volunteers and Parkinson's disease participants, supporting further clinical development. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Sexual activity as a trigger for intracranial hemorrhage.

BACKGROUND: Intracranial hemorrhage (ICH) has been reported in association with sexual activity. A case-series of patients with ICH following sexual activity is presented to further elucidate the role of the physiologic sexual response as a trigger of ICH. METHOD: A retrospective review of the medical record was performed, identifying patients presenting with ICH temporally related to sexual activity. Clinical and radiographic data were collected and reported. RESULTS: Sixteen patients presented with non-traumatic ICH temporally related to sexual activity. Eight (50 %) patients presented with aneurysmal subarachnoid hemorrhage, four (25 %) with angiogram-negative subarachnoid hemorrhage, two (12.5 %) with a ruptured arteriovenous malformation, and two (12.5 %) with an intracerebral basal ganglia hemorrhage. Overall average age was 49.9 (range, 28-74) years. Sexual activity involved male-female intercourse in 14 (87.5 %) patients and masturbation in 2 (12.5 %) patients. CONCLUSIONS: Sexual-activity-related ICH is rare and includes various etiologies. The human sexual response in associated with dramatic increases in arterial blood pressure, which likely underlies the association.

Pivotal role of HIV and EBV replication in the long-term persistence of monoclonal gammopathy in patients on antiretroviral therapy.

A high prevalence of monoclonal gammopathy (MG) has been observed in HIV-infected patients. We explored the conditions associated with long-term persistence of serum monoclonal protein (M protein) in HIV-infected patients on antiretroviral therapy (ART). Of 21 patients with MG, M protein disappeared in 12 patients (58%) over 5 years of ART. Higher level of serum γ-globulin and higher percentages of circulating plasmablasts and plasma cells were observed in patients with persistent MG compared with patients with transient MG. MG persistence was associated with the cumulative time of detectable plasma HIV RNA after ART initiation, detection of Epstein-Barr virus (EBV) DNA in plasma, and a high level of EBV DNA in B cells. Poor control of HIV replication and detectable EBV replication in plasma were both associated with long-term MG persistence in patients on ART. In the case of viral control, MG associated with HIV infection is usually transient.

Contribution to the risk characterization of ciguatoxins: LOAEL estimated from eight ciguatera fish poisoning events in Guadeloupe (French West Indies).

From 2010 to 2012, 35 ciguatera fish poisoning (CFP) events involving 87 individuals who consumed locally-caught fish were reported in Guadeloupe (French West Indies). For 12 of these events, the presence of ciguatoxins (CTXs) was indicated in meal remnants and in uncooked fish by the mouse bioassay (MBA). Caribbean ciguatoxins (C-CTXs) were confirmed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Using a cell-based assay (CBA), and the only available standard Pacific ciguatoxin-1 (P-CTX-1), the lowest toxins level detected in fish samples causing CFP was 0.022 µg P-CTX-1 equivalent (eq.)·kg(-1) fish. Epidemiological and consumption data were compiled for most of the individuals afflicted, and complete data for establishing the lowest observable adverse effects level (LOAEL) were obtained from 8 CFP events involving 21 individuals. Based on toxin intakes, the LOAEL was estimated at 4.2 ng P-CTX-1 eq./individual corresponding to 48. 4 pg P-CTX-1 eq.kg(-1) body weight (bw). Although based on limited data, these results are consistent with the conclusions of the European Food Safety Authority (EFSA) opinion which indicates that a level of 0.01 µg P-CTX-1 eq.kg(-1) fish, regardless of source, should not exert effects in sensitive individuals when consuming a single meal. The calculated LOAEL is also consistent with the U.S. Food and Drug Administration guidance levels for CTXs (0.1 µg C-CTX-1 eq.kg(-1) and 0.01 µg P-CTX-1 eq.kg(-1) fish).

Close relationship between immunoglobulin secreting-cells and Epstein-Barr virus reservoir in patients infected with HIV.

Individuals infected with HIV have higher circulating Epstein-Barr virus (EBV) DNA load compared to healthy carriers. This study investigated whether level of spontaneous immunoglobulin secreting cells, one of the major hallmarks of HIV infection, is associated with an increase of EBV DNA load in PBMCs and the spontaneous EBV lytic cycle ex vivo in patients infected with HIV. Spontaneous virus production by cells infected with EBV and EBV DNA loads in PBMCs from which CD8(+) T-cells were removed were measured in 20 HIV-aviremic and 14 HIV-viremic patients. The number of circulating immunoglobulin-secreting cells (Ig-SCs) and CD8(+) T-lymphocyte activation were also investigated. Patients with detectable HIV RNA in plasma exhibited higher spontaneous ex vivo EBV secretion and higher levels of EBV DNA in PBMCs than their aviremic counterparts. In the two groups observed, a positive correlation was found between PBMCs EBV DNA viral load and Ig-SCs, CD38(bright) expression on CD8(+) T-cells and EBV DNA load in cell culture supernatants. These findings suggest that B-cell polyclonal activation and B-cell terminal differentiation into Ig-SCs may fuel EBV DNA reservoir and promote EBV production ex vivo in patients infected with HIV.

Comparison of EBV DNA viral load in whole blood, plasma, B-cells and B-cell culture supernatant.

Epstein-Barr virus (EBV) genome quantitation in whole blood is used widely for therapeutic monitoring of EBV-associated disorders in immunosuppressed individuals and in patients with EBV-associated lymphoma. However, the most appropriate biological material to be used for EBV DNA quantitation remains a subject of debate. This study compare the detection rate and levels of EBV DNA from whole blood, plasma, enriched B-cells, and B-cell short-term culture supernatant using quantitative real-time PCR. Samples were collected from 33 subjects with either HIV infection or B-cell lymphoma. Overall, EBV DNA was detected in 100% of enriched B-cell samples, in 82% of B-cell culture supernatants, in 57% of plasma, and 42% of whole blood samples. A significant correlation for EBV viral load was found between enriched B-cell and B-cell culture supernatant material (ρ = 0.92; P < 0.0001), but no significant correlation existed between EBV DNA levels in whole blood and enriched B-cells (ρ = -0.02; P = 0.89), whole blood and plasma (ρ = 0.24; P = 0.24), or enriched B-cells and plasma (ρ = 0.08; P = 0.77). Testing of enriched B-cells appeared to be the most sensitive method for detection of EBV DNA as well as for exploration of the cellular reservoir. Quantitation of EBV DNA in plasma and B-cell culture supernatant may be of interest to assess EBV reactivation dynamics and response to treatment as well as to decipher EBV host-pathogen interactions in various clinical scenarios.

Practice guidelines for the supervising professional: intraoperative neurophysiological monitoring.

The American Society of Neurophysiological Monitoring (ASNM) was founded in 1988 as the American Society of Evoked Potential Monitoring. From the beginning, the Society has been made up of physicians, doctoral degree holders, technologists, and all those interested in furthering the profession. The Society changed its name to the ASNM and held its first Annual Meeting in 1990. It remains the largest worldwide organization dedicated solely to the scientifically based advancement of intraoperative neurophysiology. The primary goal of the ASNM is to assure the quality of patient care during monitored procedures along the neuraxis. This goal is accomplished through programs in education, advocacy of basic and clinical research, and publication of guidelines. The ASNM is committed to the development of medically sound and clinically relevant guidelines for intraoperative neurophysiology. Guidelines are formulated based on exhaustive literature review, recruitment of expert opinion, and broad consensus among ASNM membership. Input is likewise sought from sister societies and related constituencies. Adherence to a literature-based, formalized process characterizes the construction of all ASNM guidelines. The guidelines covering the Professional Practice of intraoperative monitoring were established by a committee of nearly 30 total participants and ultimately endorsed by the Board of Directors of ASNM on January 24th 2013. That document follows.

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglia (DRGs) neurons via MNK-eIF4E signaling to promote pain sensitization in mice. Activation of stimulator of interferon response cGAMP interactor 1 (STING) signaling is pivotal for type I IFN induction. We hypothesized that vinorelbine, a chemotherapeutic and activator of STING, would cause a neuropathic pain-like state in mice via STING signaling in DRG neurons associated with IFN production. Vinorelbine caused tactile allodynia and grimacing in wild-type (WT) mice and increased p-IRF3, type I IFNs, and p-eIF4E in peripheral nerves. Supporting our hypothesis, vinorelbine failed to induce IRF3-IFNs-MNK-eIF4E in StingGt/Gt mice and, subsequently, failed to cause pain. The vinorelbine-elicited increase of p-eIF4E was not observed in Mknk1-/- (MNK1 knockout) mice in peripheral nerves consistent with the attenuated pro-nociceptive effect of vinorelbine in these mice. Our findings show that activation of STING signaling in the periphery causes a neuropathic pain-like state through type I IFN signaling to DRG nociceptors.

Emergency Palliative Care: Severe Acute Neurological Injury With Poor Prognosis.

In this segment of the emergency palliative care case series, we present a patient who arrives at a small community emergency department with acute intracranial hemorrhage, aspiration, and respiratory failure. Usual care includes aggressive airway management with intubation and mechanical ventilation, and a recommendation from stroke neurologists and neurosurgeons at the tertiary care center to transfer the patient. The patient's wife has some understanding that the prognosis is likely to be poor, and asks that the patient not be transferred if he is unlikely to return to independent function. A general neurologist is consulted to provide a prognostic opinion, and goals-of-care discussions are facilitated by a palliative care consultant. After expedited evaluation, the neurologist provides a prognostic assessment, while the palliative care clinician explores potential next steps with the patient's wife, based upon his known goals and values, ultimately leading to high-value goal-concordant end-of-life care for the patient and his family.

Chemical weathering and CO2 consumption in the upper Nyong Basin rivers (Central Africa): Insights on climatic and anthropogenic forcing in humid tropical environments.

A hydrological and hydrochemical database (produced by the M-TROPICS critical zone observatory) in the upper Nyong Basin from 1998 to 2017 was used to evaluate the river's response to climatic and anthropogenic forcing and examine chemical weathering processes. SiO2 and HCO3- constitute about 85 % of the Total dissolved solids (TDS) load, equivalent to 0.12 × 109 kg. y-1. Electrical conductivity (EC), Total dissolved solids (TDS), major cations, major anions (except F- and NO3-) and alkalinity (Alk) vary seasonally and follow a predictable model with discharge. Atlantic Meridional Mode oscillation controls the long-term water chemistry. Atmospheric input and silicate weathering are the main factors influencing the Nyong rivers chemistry. However, several indices supported the progressive water quality deterioration by human activities, namely: the excess of Cl- and SO42- after the substraction of atmospheric inputs, the basic pH observed for specific samples, long-term increase in the values of pH, EC, TDS, EC, Mg2+, Ca2+, F-, NO3-, HCO3-, Alk, SiO2 and Dissolved Organic Carbon. Runoff and physical erosion have an important control on chemical erosion in the upper Nyong Basin rivers. The chemical erosion rate (3.3 t.km-2.y-1) equals the silicate weathering rate. The CO2 consumption rate, in the Nyong rivers, is lower than the global average (98× 103 for silicate weathering and 246 × 103 mol.km-2.y-1 for chemical erosion) and estimated at 52.3 × 103 for silicate weathering and 54.1 × 103 mol.km-2.y-1 for chemical erosion. At Olama, the most downstream location of the monitoring setup, the Nyong River Basin consumed 1 × 109 mol.y-1 of CO2 by chemical erosion.

Increased T-cell activation and Th1 cytokine concentrations prior to the diagnosis of B-cell lymphoma in HIV infected patients.

BACKGROUND: Despite the use of combined antiretroviral therapy, HIV-infected individuals have a higher risk of developing B-cell lymphoma compared to the general population. We aim to explore whether lymphocyte activation, increase in Th1 response as well as markers of EBV reactivation, may precede lymphoma diagnosis. METHODS: Thirteen cases and 26 controls matched on CD4(+) T-cell count and HIV plasma viral load were identified. Samples were collected 0 to 5 years prior to B-cell lymphoma diagnosis. Seven out of 13 (54 %) and 16/26 (61.5 %) of cases and controls were receiving antiretroviral therapy at the time of sampling, respectively. CD8(+) T-cell activation and Th1 cytokine concentrations were measured before lymphoma onset, together with IgG antibodies directed against viral capsid antigen (VCA) and serum levels of EBV DNA. RESULTS: A higher level of CD8(+) T-cell activation was observed in patients developing lymphoma. Four out of seven Th1 cytokine serum concentrations were significantly higher in patients with lymphoma than in the control group: IL-2R, IL-12p40/70, IFN-γ-inducible protein 10 (IP-10) and monokine induced by IFN-γ (MIG). Anti-VCA IgG level were significantly higher in cases than in controls. Four cases (30 %) but no controls had detectable EBV DNA in serum. CONCLUSION: A higher level of T-cell activation, Th1 cytokine serum concentration and markers of EBV replication, preceded B-cell lymphoma diagnosis. This may suggest that viral antigen stimulation is associated with the genesis of lymphoma in HIV-infected patients.

Vinorelbine causes a neuropathic pain-like state in mice via STING and MNK1 signaling associated with type I interferon induction.

Type I interferons (IFNs) increase the excitability of dorsal root ganglion (DRG) neurons via activation of MNK-eIF4E translation signaling to promote pain sensitization in mice. Activation of STING signaling is a key component of type I IFN induction. Manipulation of STING signaling is an active area of investigation in cancer and other therapeutic areas. Vinorelbine is a chemotherapeutic that activates STING and has been shown to cause pain and neuropathy in oncology clinical trials in patients. There are conflicting reports on whether STING signaling promotes or inhibits pain in mice. We hypothesized that vinorelbine would cause a neuropathic pain-like state in mice via STING and signaling pathways in DRG neurons associated with type I IFN induction. Vinorelbine (10 mg/kg, i.v.) induced tactile allodynia and grimacing in WT male and female mice and increased p-IRF3 and type I IFN protein in peripheral nerves. In support of our hypothesis, vinorelbine-mediated pain was absent in male and female StingGt/Gt mice. Vinorelbine also failed to induce IRF3 and type I IFN signaling in these mice. Since type I IFNs engage translational control via MNK1-eIF4E in DRG nociceptors, we assessed vinorelbine-mediated p-eIF4E changes. Vinorelbine increased p-eIF4E in DRG in WT animals but not in StingGt/Gt or Mknk1-/- (MNK1 KO) mice. Consistent with these biochemical findings, vinorelbine had an attenuated pro-nociceptive effect in male and female MNK1 KO mice. Our findings support the conclusion that activation of STING signaling in the peripheral nervous system causes a neuropathic pain-like state that is mediated by type I IFN signaling to DRG nociceptors.

Intramedullary brachytherapy for the treatment of long bone metastatic disease: A case report.

Case: A 56-year-old woman with metastatic melanoma and femoral lesions with impending pathologic fracture was indicated for intramedullary brachytherapy (IMBT) and intramedullary nail. Conclusions: IMBT + intramedullary nail is a new technique for the treatment of long bone metastases. IMBT maximizes radiation to the tumor and minimizes radiation to surrounding tissues. It allows the patient to resume systemic treatment expediently. Our cadaver model and patient were both treated for femoral metastases; however, this technique allows for the treatment of any long bone. This is a safe technique that minimizes treatment time compared with other standard radiation regimens.