The Fibromyalgia Pain Experience: A Scoping Review of the Preclinical Evidence for Replication and Treatment of the Affective and Cognitive Pain Dimensions.

Fibromyalgia is a chronic, widespread pain disorder that is strongly represented across the affective and cognitive dimensions of pain, given that the underlying pathophysiology of the disorder is yet to be identified. These affective and cognitive deficits are crucial to understanding and treating the fibromyalgia pain experience as a whole but replicating this multidimensionality on a preclinical level is challenging. To understand the underlying mechanisms, animal models are used. In this scoping review, we evaluate the current primary animal models of fibromyalgia regarding their translational relevance within the affective and cognitive pain realms, as well as summarize treatments that have been identified preclinically for attenuating these deficits.

Gonadal hormones impart male-biased behavioral vulnerabilities to immune activation via microglial mitochondrial function.

There is a strong male bias in the prevalence of many neurodevelopmental disorders such as autism spectrum disorder. However, the mechanisms underlying this sex bias remain elusive. Infection during the perinatal period is associated with an increased risk of neurodevelopmental disorder development. Here, we used a mouse model of early-life immune activation that reliably induces deficits in social behaviors only in males. We demonstrate that male-biased alterations in social behavior are dependent upon microglial immune signaling and are coupled to alterations in mitochondrial morphology, gene expression, and function specifically within microglia, the innate immune cells of the brain. Additionally, we show that this behavioral and microglial mitochondrial vulnerability to early-life immune activation is programmed by the male-typical perinatal gonadal hormone surge. These findings demonstrate that social behavior in males over the lifespan are regulated by microglia-specific mechanisms that are shaped by events that occur in early development.

Recombinant PilS: Cloning, Expression and Biochemical Characterization of a Pil-Fimbriae Subunit.

Pil-fimbriae is a type IV pili member, which is a remarkably versatile component with a wide variety of functions, including motility, attachment to different surfaces, electrical conductance, DNA acquisition, and secretion of a broad range of structurally distinct protein substrates. Despite the previous functional characterization of Pil, more studies are required to understand the regulation of Pil expression and production, since the exact mechanisms involved in these steps are still unknown. Therefore it is extremely important to have a protein with the correct secondary and tertiary structure that will enable an accurate characterization and a specific antisera generation. For this reason, the aim of this work was to generate potential tools for further investigations to comprehend the mechanisms involved in Pil regulation and its role in pathogenic E. coli infections with the obtaining of a precise native-like recombinant PilS and the corresponding antisera. The pilS gene was successfully cloned into an expression vector, and recombinant PilS (rPilS) was efficiently solubilized and purified by metal affinity chromatography. Protein characterization analyses indicated that rPilS presented native-like secondary and tertiary structures after the refolding process. The generated anti-rPilS sera efficiently recognized recombinant and native proteins from atypical enteropathogenic E. coli strains.

Effectiveness of Psychological Treatments for Borderline Personality Disorder and Predictors of Treatment Outcomes: A Multivariate Multilevel Meta-Analysis of Data from All Design Types.

We examined the effectiveness of psychotherapies for adult Borderline Personality Disorder (BPD) in a multilevel meta-analysis, including all trial types (PROSPERO ID: CRD42020111351). We tested several predictors, including trial- and outcome type (continuous or dichotomous), setting, BPD symptom domain and mean age. We included 87 studies (N = 5881) from searches between 2013 and 2019 in four databases. We controlled for differing treatment lengths and a logarithmic relationship between treatment duration and effectiveness. Sensitivity analyses were conducted by excluding outliers and by prioritizing total scale scores when both subscale and total scores were reported. Schema Therapy, Mentalization-Based Treatment and reduced Dialectical Behavior Therapy were associated with higher effect sizes than average, and treatment-as-usual with lower effect sizes. General severity and affective instability showed the strongest improvement, dissociation, anger, impulsivity and suicidality/self-injury the least. Treatment effectiveness decreased as the age of participants increased. Dichotomous outcomes were associated to larger effects, and analyses based on last observation carried forward to smaller effects. Compared to the average, the highest reductions were found for certain specialized psychotherapies. All BPD domains improved, though not equally. These findings have a high generalizability. However, causal conclusions cannot be drawn, although the design type did not influence the results.

Investigating the Use of Dry Matter Intake and Energy Balance Prepartum as Predictors of Digestive Disorders Postpartum.

One objective was to evaluate the association of dry matter intake as a percentage of body weight (DMI%BW) and energy balance (EB) prepartum and postpartum, and energy-corrected milk (ECM) postpatum with digestive disorders postpartum. For this, ANOVA was used, and DMI%BW, EB, and ECM were the outcome variables, and left displaced abomasum (LDA), indigestion, and other digestive disorders (ODDZ) were the explanatory variables. The main objective was to evaluate prepartum DMI%BW and EB as predictors of digestive disorders. For this, logistic regression was used, and LDA, indigestion, and ODDZ were the outcome variables and DMI%BW and EB were the explanatory variables. Data from 689 cows from 11 experiments were compiled. Left displaced abomasum was not associated with prepartum DMI%BW or EB. Postpartum data were normalized to the day of the event (day 0). Cows that developed LDA had lesser postpartum DMI%BW on days -24, -23, -12, -7 to 0 and from days 1 to 8, 10 to 12, and 14 and 16, lesser postpartum EB from days -7 to -5, -3 to 0, and 12, and lesser postpartum energy-corrected milk on days -19, -2, -1, 0, 7, 9, 10, 15, and 17 relative to diagnosis than cows without LDA. Cows that developed indigestion had lesser prepartum DMI%BW and EB than cows without indigestion, and lesser postpartum DMI%BW on days -24, -1, 0, 1, and 2, and greater DMI%BW on day 26, lesser ECM on days -24, -2, -1, 0, 1, and 2 relative to diagnosis. Postpartum EB was not associated with indigestion postpartum. Cows that developed ODDZ had lesser prepartum DMI%BW on day -8 and from days -5 to -2, lesser prepartum EB on day -8 and from days -5 to -2, and lesser postpartum DMI%BW than cows without ODDZ. Each 0.1 percentage point decrease in the average DMI%BW and each Mcal decrease in the average EB in the last 3 days prepartum increased the odds of having indigestion by 9% each. Cutoffs for DMI%BW and EB during the last 3 days prepartum to predict indigestion were established and were ≤1.3%/day and ≤0.68 Mcal/day, respectively. In summary, measures of prepartum DMI%BW and EB were associated with indigestion and ODDZ postpartum and were predictors of indigestion postpartum, although the effect sizes were small.

Addressing the punitive parent mode in schema therapy for borderline personality disorder: Short-term effects of the empty chair technique as compared to cognitive challenging.

BACKGROUND AND OBJECTIVES: In Schema Therapy (ST) for Borderline Personality Disorder (BPD) patients the empty chair technique (EC) is often used to diminish the 'punitive parent mode' (PP). The present study is a first attempt to assess whether EC is more effective in reducing the PP than a standard Cognitive Behavioral Therapy technique (CT). METHODS: We utilized a counterbalanced, crossover design comparing one EC session to one CT session in twenty patients with a primary BPD diagnosis who had started ST. Before and after each intervention we assessed credibility, power, and valence of the PP-associated core belief and how much power patients felt over this core belief (dominance). Patients also completed a working alliance inventory. An interview was conducted to explore subjective views regarding the interventions. RESULTS: Both techniques reduced power and credibility of the PP-associated core belief and increased dominance. CT reduced credibility more strongly than EC. Still, patients preferred EC as they felt it was better able to elicit feelings during the session and believed it would be more effective than CT when administered repeatedly. LIMITATIONS: A complex technique was tested early in treatment and only once, effects might be different later in treatment and when applied repeatedly. Moreover, only short-term effects were assessed in a rather small sample. CONCLUSION: Both EC and CT help combat the PP in BPD patients, with CT being more effective in reducing credibility after one session. However, patients preferred EC and suggest multiple sessions might be needed to truly elucidate differences between both techniques.

Determinants of losses in the latent tuberculosis cascade of care in Brazil: A retrospective cohort study.

BACKGROUND: The present study evaluated factors associated with losses in the latent tuberculosis infection (LTBI) cascade of care in contacts of tuberculosis (TB) patients, in a referral center from a highly endemic region in Brazil. METHODS: Contacts of 1672 TB patients were retrospectively studied between 2009 and 2014. Data on TB screening by clinical investigation, radiographic examination and tuberculin skin test (TST) were extracted from medical records. Losses in the cascade of care and TB incidence within 2-year follow-up were calculated. RESULTS: From a total of 1180 TB contacts initially identified, only 495 were examined (58% loss), and 20 were diagnosed with active TB at this stage. Furthermore, 435 persons returned for TST result interpretation and 351 (∼81%) were TST positive. Among those with positive TST, 249 (73%) were treated with isoniazid for 6 months whereas 51 abandoned therapy early. Three individuals who did not receive LTBI treatment, one with incomplete treatment and another who completed treatment developed active TB. A logistic regression analysis revealed that increases in age were associated with losses in the LTBI cascade independent of other clinical and epidemiological characteristics. CONCLUSIONS: Major losses occur at initial stages and older patients are at higher risk of not completing the LTBI cascade of care.

Plasma Cytokine Levels in Overweight Versus Obese Disease-Free Perimenopausal Women.

OBJECTIVE: To evaluate the plasma cytokine levels during T cell-mediated inflammatory responses and compare the metabolic markers between overweight and obese perimenopausal women without systemic diseases. METHODS: Sixty perimenopausal women were divided into two groups (overweight and obese). Participants in both groups had their waist-to-height ratio (WHtR) measured and blood samples collected for the evaluation of estradiol, fasting glucose, leptin, high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-10, IL-17A levels, and lipid profile. RESULTS: In univariate analysis, women with obesity showed increased WHtR, fasting glucose, leptin, and IL-6 (p < 0.05) levels; however, significant differences were not observed in IL-10 or IL-17A (p > 0.05) levels. In the receiver operating characteristic curve, the highest areas under the curve were shown for leptin (0.856) and IL-6 (0.706). IL-6 levels correlated with both hs-CRP (r = 0.302, p = 0.020) and leptin (r = 0.294, p = 0.022). However, in multivariate analysis, IL-6 was not associated with a greater likelihood of obesity (OR = 1.61; 95% CI: 0.82-3.15; p = 0.16), when potential confounders were considered. CONCLUSION: IL-6 levels varied between overweight and obese perimenopausal women, and this association was weaker when adjusted for other clinical variables.

Predicting possible zonisamide hypersensitivity syndrome.

UNLABELLED: Zonisamide (ZNS) is an anticonvulsant (AC) that contains a sulpha moiety potentially triggering hypersensitivity syndrome reactions (HSR). The lymphocyte toxicity assay (LTA) is an in vitro drug rechallenge test, which is believed to reflect a decreased capacity of the individual to detoxify reactive metabolites. The study examined whether cross-reactivity is present between ZNS and other AC and/or sulphonamides and if this HSR may be predicted using the LTA. The second aim was to determine age-related differences in ZNS-induced HSR. LTA was previously validated in patients who received sulphamethoxazole (SMX) or AC. METHODS: Forty adult patients who displayed clinical HSR to SMX (20) or AC (20) participated in the study. Each group was represented with an equal number of individuals above and below the age of 60. LTA-SMX, LTA-AC and LTA-ZNS from 20 patients who previously presented a clinical reaction to one of the drugs and who had a positive LTA result to the specific drug were compared with 20 individuals who received the same drugs but did not present reactions. Binary logistic regression was used to evaluate the statistical significance. RESULTS: In vitro results correlated with the clinical diagnosis. LTA presented a significant difference (P < 0.0001) between control and hypersensitive patients. In each age group, only a single patient had a severe clinical manifestation of SMX-HSR. These individuals tested positive to both SMX and ZNS. CONCLUSIONS: Sulphamethoxazole-HSR but not AC-HSR patients may present a cross-reactivity to ZNS-HSR. The use of LTA to predict a possible ZNS reaction is recommended for SMX-sensitive individuals who prescribed ZNS.

Immunopathogenesis of hypersensitivity syndrome reactions to sulfonamides.

Cytokines play a role in the immunopathological and molecular mechanisms of sulfonamide-induced hypersensitivity reactions (HSRs). The objective of this study was to analyze the reliability and correlation between the clinical symptoms observed in affected patients (n = 86) because of a sulfonamide-induced HSR and their lymphocyte toxicity assay (LTA) values. Another goal was to determine the cytokine secretion in the patient's sera and their expression in the peripheral blood mononuclear cells (PBMCs) and to explore whether a correlation exists among positive LTA score, cytokine levels, and HSR occurrence. The final goal is to determine whether these measures could be used to predict the likelihood of a patient to experience an HSR during sulfonamide treatment. Such a predictive ability would be valuable to the clinician to know whether the patient would tolerate sulfonamides or whether an alternative antibiotic should be prescribed. The LTA showed a good correlation with the clinical involvement of patients with hypersensitivity syndromes. In addition, the pro-inflammatory cytokines presented significant differences in patients that had rash, fever, and organ involvement than in control patients or any of the other patient groups. Expression of tumor necrosis factor alpha (TNF-alpha) is significantly higher in patients presenting rash, fever, and organ involvement versus all other groups. It is concluded that a positive LTA is a predictor for sulfonamide-induced true HSR. In addition, T-helper cell 1 cytokines [TNF-alpha, interleukins (ILs) 1 and 2] as well as the chemokine regulated upon activation, normal T-cell expressed and secreted (RANTES) control the pathogenesis of sulfonamide-induced HSR and may be used in early diagnosis of the syndrome.

Cytokine--chemokine and apoptotic signatures in patients with hepatitis C.

Cytokines and chemokines are proteins that play a critical role in the regulation of immunity and inflammation in patients with chronic Hepatitis C. The aim of our study was to correlate serum cytokines, chemokines and apoptosis in non-treated chronic hepatitis C patients with various degrees of inflammation and fibrosis. We studied 778 patients: 59 had low Knodell fibrosis score and low Knodell histological activity index; 372 had mild fibrosis and low histological activity index; 270 had moderate fibrosis and moderate histological activity index; and, 77 had high fibrosis and high histological activity index on their biopsy. Serum cytokines, chemokines and apoptosis were measured by enzyme-linked-immunosorbent-assay. Multivariate analysis was employed for statistical purposes. A positive correlation was seen between the degree of inflammation and tumor necrosis factor-alpha (TNF-alpha) levels (r = 0.92) in non-cirrhotic patients and between interleukin 2 in all patients (r = 0.85). Interleukin-8 increased significantly at higher histological activity indices and continued to increase in patients with cirrhosis. Transforming growth factor-beta (TGF-beta) levels increased significantly with the severity of fibrosis, but decreased in cirrhotics. In conclusion, cytokines, chemokines and apoptosis levels reflect the progression of inflammation and fibrosis in hepatitis C infected patients, but their signatures differ.

Monitoring adverse drug reactions to sulfonamide antibiotics in human immunodeficiency virus-infected individuals.

Patients infected with the human immunodeficiency virus (HIV) are at higher risk for adverse drug reactions from trimethoprim-sulfamethoxazole (TMP-SMX) than the HIV-negative population. Studying the HIV-positive population the authors aimed to validate the predictive and diagnostic value of the lymphocyte toxicity assay (LTA) for adverse drug reactions. Patient lymphocytes were analyzed for toxicity to SMX and TMP. Of 35 enrolled HIV patients, 18 had TMP-SMX hypersensitivity syndrome reaction (HSR); 10 tolerated the drug; and 5 had never received the drug. When cases with HSR were compared with controls that tolerated the drugs, cytotoxicity was higher for cases: 29.5% +/- 10.1% versus 19.3% +/- 11.2% for SMX (P < 0.022) and 25.0% +/- 11.9% versus 16.3% +/- 11.0% for TMP (P < 0.04). The authors' proposed threshold value for assigning positive results for TMP and SMX hypersensitivities was 22.5%. The LTA has a strong potential for use as a diagnostic tool to assess TMP-SMX hypersensitivity in HIV-infected individuals. Larger patient populations, as well as in vitro studies are needed to further address the reasons for elevated results in immunocompromised patients and to validate the usefulness of the test.

Ethanol signals for apoptosis in cultured skin cells.

Ethanol is commonly used in cosmetic and pharmaceutical preparations. To test whether ethanol may cause apoptosis in skin cells, we treated A431 epidermoid skin cells and neonatal human primary skin cells with different concentrations of ethanol, for different time periods. Ethanol was toxic to cells in both a dose- and time-dependent manner and increased the percentage of cells undergoing apoptosis. Treatment of cells with 40 and 100 mM ethanol increased release of the proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) into culture medium and increased its expression in cells. The TNF-alpha was toxic to A431 epidermoid skin cells at concentrations similar to those released by cells on exposure to ethanol. Ethanol-treated cells examined by electron microscopy showed organelle damage, condensed chromatin, and apoptotic bodies. Therefore, even at low concentrations, ethanol may induce apoptosis in skin cells by enhancing the effects of TNF-alpha.