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Abstract Background In immunopathological diseases, such as multiple sclerosis (MS), genetic and environmental factors that contribute to the initiation and progression of the disease are often discussed. The Theiler murine encephalomyelitis virus-induced demyelination disease (TMEV-IDD) model used to study MS reflects this: genetically susceptible mice infected intra-cerebrally with TMEV develop a chronic demyelination disease. TMEV-IDD can be induced in resistant mouse strains by inducing innate immunity with lipopolysaccharide (LPS). Interestingly, Toll-like receptor 4 (TLR4) is the cognate receptor for LPS and its activation can induces up-regulation of other TLRs, such as TLR7 (the receptor for TMEV) and 9, known to be involved in autoimmunity. Up-regulation of TLRs could be involved in precipitating an autoimmune susceptible state. Consequently, we looked at TLR expression in the susceptible (SJL/J) and resistant (C57BL/6) strains of mice infected with TMEV. The resistant mice were induced to develop TMEV-IDD by two LPS injections following TMEV infection. Results Both strains were found to up-regulate multiple TLRs (TLR2, 7 and 9) following the TMEV infection. Expression of these TLRs and of viral mRNA was significantly greater in infected SJL/J mice. The susceptible SJL/J mice showed up-regulation of TLR3, 6 and 8, which was not seen in C57BL/6 mice. Conclusion Expression of TLRs by susceptible mice and the up-regulation of the TLRs in resistant mice could participate in priming the mice toward an autoimmune state and develop TMEV-IDD. This could have implications on therapies that target TLRs to prevent the emergence of conditions such as MS in patients at risk for the disease.

Importance: Because inadvertent damage of parathyroid glands can lead to postoperative hypocalcemia, their identification and preservation, which can be challenging, are pivotal during total thyroidectomy., Objective: To determine if intraoperative imaging systems using near-infrared autofluorescence (NIRAF) light to identify parathyroid glands could improve parathyroid preservation and reduce postoperative hypocalcemia., Design, Setting, and Participants: This randomized clinical trial was conducted from September 2016 to October 2018, with a 6-month follow-up at 3 referral hospitals in France. Adult patients who met eligibility criteria and underwent total thyroidectomy were randomized. The exclusion criteria were preexisting parathyroid diseases., Interventions: Use of intraoperative NIRAF imaging system during total thyroidectomy., Main Outcomes and Measures: The primary outcome was the rate of postoperative hypocalcemia (a corrected calcium <8.0 mg/dL [to convert to mmol/L, multiply by 0.25] at postoperative day 1 or 2). The main secondary outcomes were the rates of parathyroid gland autotransplantation and inadvertent parathyroid gland resection., Results: A total of 245 of 529 eligible patients underwent randomization. Overall, 241 patients were analyzed for the primary outcome (mean [SD] age, 53.6 [13.6] years; 191 women [79.3%]): 121 who underwent NIRAF-assisted thyroidectomy and 120 who underwent conventional thyroidectomy (control group). The temporary postoperative hypocalcemia rate was 9.1% (11 of 121 patients) in the NIRAF group and 21.7% (26 of 120 patients) in the control group (between-group difference, 12.6% [95% CI, 5.0%-20.1%]; P = .007). There was no significant difference in permanent hypocalcemia rates (0% in the NIRAF group and 1.6% [2 of 120 patients] in the control group). Multivariate analyses accounting for center and surgeon heterogeneity and adjusting for confounders, found that use of NIRAF reduced the risk of hypocalcemia with an odds ratio of 0.35 (95% CI, 0.15-0.83; P = .02). Analysis of secondary outcomes showed that fewer patients experienced parathyroid autotransplantation in the NIRAF group than in the control group: respectively, 4 patients (3.3% [95% CI, 0.1%-6.6%) vs 16 patients (13.3% [95% CI, 7.3%-19.4%]; P = .009). The number of inadvertently resected parathyroid glands was significantly lower in the NIRAF group than in the control group: 3 patients (2.5% [95% CI, 0.0%-5.2%]) vs 14 patients (11.7% [95% CI, 5.9%-17.4%], respectively; P = .006)., Conclusions and Relevance: The use of NIRAF for the identification of the parathyroid glands may help improve the early postoperative hypocalcemia rate significantly and increase parathyroid preservation after total thyroidectomy., Trial Registration: ClinicalTrials.gov Identifier: NCT02892253.

Background: Recent evidence has indicated an increased risk of Barrett's esophagus (BE) in the long term after sleeve gastrectomy (SG)., Aim: The aim of the study is to investigate the spectrum of gastroesophageal reflux disease (GERD) symptoms as well as the prevalence of BE, at minimum 5 years after SG in patients who underwent SG in different bariatric centers of two countries: France and Italy., Patients and Methods: Five high volume outpatient centers dedicated to bariatric surgery that routinely perform upper GI endoscopy before any bariatric procedures were invited to participate in the study. From January 2017 to June 2018, each center during scheduled postoperative evaluation after surgery asked a minimum 10 consecutive patients, which had performed SG at least 5 years before and with no evidence of BE preoperatively, to undergo another upper GI endoscopy., Results: Ninety (66 F) consecutive patients were enrolled. The mean follow-up was 78 ± 15 months, and the mean total body weight loss was 25 ± 12%. The prevalence of BE was 18.8% with no significant difference among centers. Weight loss failure was significantly associated with BE (p < 0.01). The prevalence of GERD symptoms, erosive esophagitis, and the usage of PPIs increased from 22%, 10%, and 22% before the SG to 76%, 41%, and 52% at the time of follow-up, respectively (p < 0.05)., Conclusions: This multicenter study show a high rate of BE at least 5 years after SG. Weight loss failure was significantly associated with BE. We suggest to provide systematic endoscopy in these patients to rule out this condition.

Aim: Transient small bowel stoma is usually closed 9-12 weeks after initial operation (late closure). Since these stoma have a poor physiological and psychological impact with frequent social consequences, we wanted to estimate feasibility and results of early closure of small bowel stoma., Patients and Method: From January 1998 to December 2001, 39 patients (21 women and 18 men, mean age: 64 years) with a transient small bowel stoma were elected for early closure. Early closure was performed only if the patient was in good condition, and without developing wound or general sepsis. In the other patients, the stoma was closed in the usually recommended delay (> 8 weeks). Fifteen patients had an early closure of their stoma in a mean delay of 10.0 +/- 0.8 days after the initial procedure. Twenty-four patients had a late closure of their stoma in a mean delay of 11.4 +/- 3.7 weeks., Results: There were no postoperative deaths and no intestinal fistula. Four (10%) wound abscesses occurred and were managed without any surgical procedure, 3 in the early closure group (20%) and 1 in the late closure group (4%) (P=0.85, NS). Time to recovered bowel activity and to resumed oral feeding were equivalent in the two groups. The mean length of hospital stay was longer in the delayed group (34.5 +/- 18.6 days) than in the early group (23.1 +/- 4.6 days) (P<0.01)., Conclusion: Early closure of bowel stoma can be performed without major complications in elective patients. This procedure shortens hospital stay.

Stressful events have been implicated in the provocation of depressive illness. Inasmuch as immunological challenge, and particularly cytokine administration, engender neuroendocrine and central neurochemical changes reminiscent of those provoked by psychogenic stressors, it was suggested that immune activation may also contribute to affective illness. The present report provides a brief overview of the neurochemical sequelae of acute and repeated interleukin-1beta (IL-1beta), tumour necrosis factor-alpha (TNF-alpha) and IL-2 treatment, describes some of the synergisms associated with these treatments, as well as their potential interactions with psychogenic stressors. In addition, a discussion is provided concerning the fact that cytokines, like stressors, may have time-dependent proactive effects, so that re-exposure to the treatments provoke greatly augmented neurochemical changes (sensitization). Given that the effects of cytokines are evident within hypothalamic, as well as extrahypothalamic sites, including various limbic regions, it is suggested that cytokines may impact on emotional changes, including depression.

Objective: To find out if early closure of a defunctioning small bowel stoma (day 10) was feasible and safe., Design: Prospective non-randomised study., Setting: University hospital, France., Interventions: During a 42-month period (January 1998-June 2001), all patients with a temporary small bowel stoma were elected for early closure on postoperative day 10 in a non-randomised prospective study. The procedure was considered only if the patient was not taking steroids, was in good condition, and had not developed wound or general sepsis after the initial operation. Other patients' stomas were closed after the usually recommended delay (>8 weeks)., Main Outcome Measures: Postoperative complications, delay to recover bowel activity, and to resume oral feeding, and duration of hospital stay., Results: Thirty-six patients were included in the study: 14 patients in the early group and 22 in the delayed group. There were no postoperative deaths. Three patients developed wound abscesses, two in the early group and one in the delayed group. The median (range) duration of hospital stay was longer in the delayed group: 36 (14-84) days, than in the early group: 22 (18-29) days (p < 0.01)., Conclusions: Small bowel stomas can be closed in selected healthy patients on postoperative day 10 without major complications.

Cytokines and neuropeptides may be involved in seizure-associated processes. Following amygdala kindling in rats, we determined alterations of IL-1beta, IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type I (IL-1RI), IL-1 receptor accessory proteins (IL-1R AcPs) I and II, TNF-alpha, TGF-beta1, neuropeptide Y (NPY), glycoprotein 130 (gp 130) and pro-opiomelanocortin (POMC) mRNA levels in the parietal, prefrontal and piriform cortices, amygdala, hippocampus and hypothalamus. Messenger RNAs expression in all brain regions was determined 2 h or 3 weeks following the last generalized convulsive seizure triggered from the ipsilateral kindled amygdala. The same brain region sample was used to assay for changes of all mRNA components. The results show that the 2 h-kindled group exhibited a significant up-regulation of IL-1beta, IL-1RI, TNF-alpha and TGF-beta1 mRNAs in all three cortical brain regions, amygdala and hippocampus. The largest up-regulation occurred in the prefrontal cortex (about 30-fold induction for IL-1beta and TNF-alpha mRNAs). IL-1R AcP I and II mRNA levels were also up-regulated in the cortical regions. No changes in IL-1beta, IL-1RI or TNF-alpha mRNA levels occurred in the 3 week-kindled group. NPY mRNA levels increased in the hippocampus, prefrontal and piriform cortices in the 2 h-kindled group, while IL-1Ra, gp 130, or POMC mRNA levels did not change in any group. The overall profile of mRNA changes shows specificity of transcriptional modulation induced by amygdala kindling. The data support a role of cytokines and NPY in the adaptive mechanisms associated with generalized seizure activity, with implications for neuroprotection, neuronal dysfunction and vulnerability associated with epileptic activity.

Physical (neurogenic) stressors may influence immune functioning and interleukin-1beta (IL-1beta) mRNA levels within several brain regions. The present study assessed the effects of an acute or repeated naturalistic, psychogenic stressor (predator exposure) on brain cytokine and neuropeptide mRNAs. Acute predator (ferret) exposure induced stress-like behavioral effects, including elicitation of a startle response and reduced exploratory behaviors; these responses diminished after 30 sessions. Moreover, acute and repeated predator exposure, like acute restraint stress, increased plasma corticosterone levels measured 5 min later, but not 2 h after stressor exposure. In contrast, none of the stressors used influenced IL-1beta, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory proteins I and II, or tumor necrosis factor-alpha mRNA levels in the prefrontal cortex, amygdala, hippocampus, or hypothalamus. Likewise, there were no stressor effects on transforming growth factor-beta1, neuropeptide Y, glycoprotein 130, or leptin receptor mRNAs in brain regions. Thus, the naturalistic/psychogenic stressor used does not affect any of the brain cytokine component mRNAs studied. It is suggested that this type of stressor activates homeostatic mechanisms (e.g., glucocorticoid release), which act to preclude brain cytokine alterations that would otherwise favor neuroinflammatory/neuroimmunological responses and the consequent increase of brain sensitivity to neurotoxic and neurodegenerative processes.

Cytokine-cytokine interactions play a role in health and are crucial during immunological and inflammatory responses in disease. Cytokine interactions can result in additive, antagonist, or synergistic activities in maintaining physiological functions such as feeding, body temperature, and sleep, as well as in anorectic, pyrogenic, and somnogenic neurological manifestations of acute and chronic disease. These interactions involve signaling homology, convergence of signaling pathways, and/or positive or negative feedbacks within and among cytokine systems. The interplay of cytokines with neurotransmitters, peptides/neuropeptides, and hormones also influence cytokine action in the brain. Interactive chemical cascades involving cytokines are consistent with the homeostatic physiological mechanisms and with the multi-humoral, pleiotropic, and redundant processes that occur during acute and chronic disease.

Interferon-alpha (IFN-alpha) immunotherapy is associated with significant adverse neurological effects, including anorexia, which can be a limiting factor in immunotherapy. Thus, it is important to develop strategies that could ameliorate IFN-alpha-induced neurological manifestations without significantly affecting its immunomodulating properties. In this study, we tested the hypothesis that an endogenous feeding-enhancing peptide, neuropeptide Y (NPY), could inhibit IFN-alpha-induced anorexia in rats. The results show that IFN-alpha induced significant anorexia when administered centrally into the third cerebral ventricle at an immunotherapeutically relevant dose (1,350 IU/rat). Heat-inactivated IFN-alpha had no effect. NPY (5.0 microg/rat) counteracted the IFN-alpha-induced anorexia when administered 3 or 10 h following IFN-alpha, or when it was concomitantly administered with IFN-alpha. The data suggest that NPY and its agonists could represent a potential novel intervention for IFN-alpha immunotherapy-associated anorexia.

Fish oil supplementation is suggested as possible mean to improve neurological manifestations of chronic diseases and cytokine immunotherapies. Preclinical and clinical studies show that fish oil supplementation seems able to reduce disease-associated anorexia and body weight loss. This improvement could be due to shifts in metabolism and changes in proinflammatory cytokine production and action. ω-3 Polyunsaturated fatty acids (PUFAs), especially eicosapentaenoic acid, are used as substrates for eicosanoid synthesis, competing for enzymes with arachidonic acid, which is a substrate for the synthesis of proinflammatory immunomodulators, such as prostaglandin E2. Fish oil supplementation is generally found to lower production of cytokines including interleukin-1 and tumor necrosis factor-α, thereby reducing various immune responses, including inflammation. However, conflicting results regarding the effects of fish oil interventions have been reported. The main factor that emerges from the contradictory reports is the variety of models, assays and methodologies that have been used. This brief review presents an overall perspective on the potential use of ω-3 PUFAs as a nutritional intervention to ameliorate disease-associated and cytokine-induced neurological manifestations. We conclude that substantial further research is required to understand the exact nature of n-3 PUFA-induced immunomodulation in health and disease.