TNF-α and Chronic Fatigue Syndrome

Based upon the clinical presentation of chronic fatigue syndrome (CFS), we hypothesized that proinflammatory cytokines may play a role in the pathogenesis of the disease. We therefore undertook a retrospective cross-sectional study to examine the role of TNF- in patients with CFS. Our results suggest a significant increase serum TNF- in patients with CFS (P < 0.0001) compared to non-CFS controls. This study supports the further examination of the role of proinflammatory mediators in CFS. Furthermore, the clinical testing of TNF- blockers and other antiinflammatory agents for the treatment of this disease is warranted.     

CC-chemokine MIP-1α in the spinal cord contributes to nerve injury-induced neuropathic pain

We investigated the involvement of spinal macrophage inflammatory protein-1α (MIP-1α), an inflammatory chemokine, in partial sciatic nerve ligation (PSL)-induced neuropathic pain in mice. PSL increased MIP-1α mRNA levels as well as levels of the MIP-1α receptor, CCR1, but not CCR5 in the spinal dorsal horn. PSL-induced tactile allodynia and thermal hyperalgesia were prevented by intrathecal (i.t.) injection of a neutralizing antibody of MIP-1α (2 ng). Recombinant MIP-1α (10 pmol, i.t.) elicited long-lasting tactile allodynia and thermal hyperalgesia in naïve mice. These results suggest that peripheral nerve injury elicits the up-regulation of spinal MIP-1α and CCR1 to participate in neuropathic pain.     

Ectopic discharge in Aβ afferents as a source of neuropathic pain

Ectopic discharge in axotomized dorsal root ganglion neurons is a key driver of neuropathic pain. However, the bulk of this activity is generated and carried centrally in large diameter myelinated Aβ afferents, a cell type that normally signals touch and vibration sense. Evidence is considered suggesting that following axotomy, Aβ afferents undergo a change in their electrical characteristics and also in the neurotransmitter complement that they express. This dual phenotypic switching renders them capable of (1) directly driving postsynaptic pain signaling pathways in the spinal cord, and (2) triggering and maintaining central sensitization.     

Causes of chest pain in primary care – a systematic review and meta-analysis

Aim

To investigate the frequencies of different and relevant underlying etiologies of chest pain in general practice.

Methods

We systematically searched PubMed and EMBASE. Two reviewers independently rated the eligibility of publications and assessed the risk of bias of included studies. We extracted data to calculate the relative frequencies of different underlying conditions and investigated the variation across studies using forest plots, I², tau², and prediction intervals. With respect to unexplained heterogeneity, we provided qualitative syntheses instead of pooled estimates.

Results

We identified 11 eligible studies comprising about 6500 patients. The overall risk of bias was rated as low in 6 studies comprising about 3900 patients. The relative frequencies of different conditions as the underlying etiologies of chest pain reported by these studies ranged from 24.5 to 49.8% (chest wall syndrome), 13.8 to 16.1% (cardiovascular diseases), 6.6 to 11.2% (stable coronary heart disease), 1.5 to 3.6% (acute coronary syndrome/myocardial infarction), 10.3 to 18.2% (respiratory diseases), 9.5 to 18.2% (psychogenic etiologies), 5.6 to 9.7% (gastrointestinal disorders), and 6.0 to 7.1% (esophageal disorders).

Conclusion

This information may be of practical value for general practitioners as it provides the pre-test probabilities for a range of underlying diseases and may be suitable to guide the diagnostic process.Chest pain is a common complaint in all health care settings and can be caused by a wide range of conditions – from diseases with favorable prognosis like musculoskeletal disorders to acute and potentially life-threatening conditions like coronary heart disease (1). Most patients with chest pain are initially seen by their general practitioner (GP) who faces the challenge to triage them. To fulfill this task, GPs need to know the relevant etiologies and their respective frequencies. In an intuitive process of probabilistic reasoning GPs combine the initial likelihood for a given etiology (pre-test probability) with their findings from the patient’s history and the clinical examination in order to reach a final or at least tentative diagnosis (post-test probability) (2,3).Important information is provided by studies of symptoms, which investigate patients presenting with a defined symptom in a health care setting. In particular, they (4) aim to answer three main questions: How often do patients present with the respective symptom? What are the underlying conditions and their respective frequencies? What is the prognosis of these patients? While in the medical literature there are many studies on effects of treatment, causation of disease, or on diagnostic tests, studies of symptoms are not performed as often. As the results of single studies can show large variations, it is desirable to summarize existing information in a systematic review.Therefore, we conducted a systematic review of studies investigating the symptom of chest pain in primary care. Since knowledge of relevant etiologies and their respective frequencies has the highest practical value for clinicians, we confine the current article to the reporting on this research question.     

Anti TNF-α in refractory Takayasu's arteritis: cases series and review of the literature

Takayasu arteritis (TA) is a rare large vessels vasculitis. Conventional therapy consists of glucocorticoids which may be associated with other immunosuppressive drugs. However, some patients fail to achieve remission with conventional treatment. The use of anti-tumor necrosis factor-α (TNF-α) in patients with difficult to treat TA could be useful. We report here the main characteristics, treatment and outcome of 84 patients (5 personal cases and 79 patients from the literature) with refractory Takayasu arteritis treated with anti TNF-α. The mean age was 28.5years [median 26.0years, range 7-61years], with 74/83 (89%) of female. All patients, except one, were inadequately controlled with other immunosuppressive regimens before anti TNF-α therapy. First line of anti-TNF-α included infliximab (IFX) in 81% (68/84) and etanercept (ETA) in 19% (16/84). Most patients received IFX at 5mg/kg associated to methotrexate or azathioprine. Thirty one out of 84 (37%) patients achieved a complete remission, and 45 (53.5%) were partial responders. There were 8 (9.5%) non responders at all. Twenty seven out of 84 (32%) patients needed to increase the dose of anti TNF-α because of uncontrolled disease and 15 (18%) needed to change of anti TNF-α. Glucocorticoids have been tapered in 41/79 (52%) [from 20mg (13.1-60) to 2.5mg (0-10) daily, at baseline and after anti-TNF, respectively, p<0.0001] and discontinued in 31/77 (40%). After a median follow-up of 10months [range 3-82], 17 (20%) side effects were recorded leading to discontinuation of anti TNF-α in 8 cases. They included mainly infections, and hypersensitivity reactions. In conclusion, anti-TNF-α are an efficient therapy in refractory TA patients although side effects are observed in 20% of cases. Further studies are warranted to assess the long term efficacy and safety of anti-TNF in TA and to better define if they should be prescribed earlier in the course of TA.     

Does COX2-dependent PGE2 play a role in neuropathic pain?

Neuropathic pain (NeP) is a common chronic pain state with unmet medical needs. Due to poorly defined underlying mechanisms, current therapies for NeP are far from satisfactory. Mounting evidence suggests that long-term plasticity in pain signaling pathways underpins the pathogenesis of NeP. Inflammatory responses in injured nerves have been recognized as important events initially sensitizing nociceptive neurons and subsequently inducing long-term plasticity in the dorsal root ganglion. Inflammatory cells such as invading macrophages and Schwann cells produce a wide array of inflammatory mediators. Cyclooxygenase 2-dependent prostaglandin E2 (COX2/PGE2) is one of the important mediator abundantly produced in injured nerves and involved in the genesis of NeP. In this mini-review, we highlight possible novel mechanisms underlying the role of COX2/PGE2 in injured nerves in the genesis of NeP. Long lasting COX2/PGE2 in injured nerves may induce chronic effects on nociceptors to facilitate the synthesis of pain-related molecules by stimulating 'en passant' injured or spared axons. COX2/PGE2 may also induce chronic effects on local inflammatory cells in injured nerves to facilitate the synthesis of inflammatory mediators via autocrine and paracrine pathways. COX2/PGE2 in injured nerves and downstream PGE2 EP receptor signaling should be considered as therapeutic targets to more effectively treat chronic NeP.     

Therapeutic role of a vaccine targeting RANKL and TNF-α on collagen-induced arthritis

Targeting tumor necrosis factor-α (TNF-α) and activator of NF-κB ligand (RANKL) has been proved highly successful in rheumatoid arthritis (RA) models and patients. This raises a possibility whether a single agent simultaneously targeting TNF-α and RANKL provides a potential therapeutic opportunity. This study aimed to design a dual functional vaccine and evaluate its therapeutic effects in RA mice model. Standard molecular biological techniques were used to generate human RANKL-TNF-like core fusion protein (RTFP-2) vaccine. High titers of antibodies against human TNF-α and RANKL were elicited and the RTFP-2 antiserum decreased TNF-α mediated apoptosis of L929 cells to 41% compared with 90% in positive controls. In addition, the antiserum completely abrogated osteoclastogenesis in?vitro. Immunization with RTFP-2 also reduced the mortality of TNF-α induced cachexia from 56% to 28%. The RANKL-mediated hypercalcemic effects were significantly attenuated in RTFP-2 vaccinated mice. Furthermore, RTFP-2 vaccine significantly mitigated the incidence and severity of CIA via inhibition of inflammation and bone resorption. Our results showed the RTFP-2 vaccine of dual targets ameliorated the symptoms of CIA mice, suggesting the potential possibility to treat inflammatory bone diseases such as RA.     

TNF-α -238, -308, -863 polymorphisms,and brucellosis infection

BackgroundBrucella abortus is an intracellular bacterium that affects humans and domestic animals. Tumor necrosis factor-alpha (TNF-α) has been shown as a key player in the induction of cell-mediated resistance against Brucella infection. We aimed to evaluate the possible influence of the TNF-α promoter polymorphisms (-308 G/A, -238 G/A, and -863 C/A) on the susceptibility of human brucellosis.MethodologyA total of 153 patients with active brucellosis and 128 healthy individuals were recruited. All subjects were genotyped for the polymorphisms in the TNF-α gene by Allele-Specific polymerase chain reaction analysis.ResultsOur results showed that the TNF-α -308 GG genotype was significantly more frequently present in controls than in brucellosis patients (91% vs. 75%), thus was a protective factor against developing brucellosis (OR = 0.313, p = 0.001). In contrast, the -308 GA genotype (OR = 3.026, p = 0.002) and minor allele (A) (OR = 3.058, p = 0.001) as well as AAG haplotype (OR = 4.014, p = 0.001) conferred an increased risk of brucellosis. However, the -238 G/A and -863 C/A polymorphisms were not associated with the risk of brucellosis at both allelic and genotypic levels (p > 0.05).ConclusionOur study revealed that the TNF-α -308 A allele or GA heterozygosity or AAG haplotype were associated with an increased risk of brucellosis in our population.     

Complications of TNF-α antagonists and iron homeostasis

TNF-α is a central regulator of inflammation and its blockade downregulates other pro-inflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficial effect, the use of TNF-α antagonists is associated with an increased risk for infections and neoplasms; the basis for these complications is unclear. This cytokine also participates in iron homeostasis and the sequestration of this metal, mediated by TNF-α, is considered protective. We hypothesize that treatment with TNF-α antagonists predisposes the patient to infections and neoplasms by reversing the sequestration of host iron mediated by the cytokine and increasing available concentrations of this metal. It is recommended that patients who are to receive TNF-α antagonists be tested for iron overload and the use of these agents in those individuals with excess iron should be reconsidered. Furthermore, it is predicted that alternative attempts to treat inflammatory diseases by blocking other pivotal cytokines that also participate in iron homeostasis (e.g. IFN-γ, IL-1, and IL-6) will similarly be associated with infections and neoplastic complications.     

Can topical duloxetine be used for neuropathic pain?

Duloxetine is a serotonin and norepinephrine re-uptake inhibitor with both anti-depressant and pain-relieving properties. Its pain-relieving properties are due to its action on the descending inhibitory pain pathways. However, the fast onset of analgesia may be mediated by mechanisms other than the descending inhibitory pain pathways. This study posits the hypothesis that duloxetine may have pain-relieving property by peripheral analgesic effects. Ways of testing this hypothesis and its potential topical use are discussed.     

Peripheral nerve injury evokes disabilities and sensory dysfunction in a subpopulation of rats: a closer model to human chronic neuropathic pain?

Chronic pain conditions for which treatment is sought are characterized usually by complex behavioural disturbances as well as pain. We review here evidence that although chronic constriction injury (CCI) of the sciatic nerve evokes allodynia and hyperalgesia in all rats, persistent social behavioural and sleep disruption occurs only in a subpopulation of animals. The finding that the 'degree of pain', as defined by allodynia and hyperalgesia, is the same in all animals suggests that the complex behavioural disabilities are independent of the level of sensory dysfunction. An absence of correlation between disability and sensory dysfunction is characteristic also of human neuropathic pain. These findings indicate that: (i). in a subpopulation of rats sciatic injury evokes disabilities characteristic of human neuropathic pain conditions; and (ii). testing for sensory dysfunction alone cannot detect this subpopulation.     

Morphine Stimulates Mesangial Cell TNF-α and Nitrite Production

Background: Intravenous opiate abusers are susceptible to develop heroin and HIV-associated nephropathies; however, the role of opiates in the development of these kidney lesions is not clear. Patients with opiate addiction are prone to recurrent infections. Methods: The effect of morphine was studied on the generation of TNF- with or without LPS (lipopolysaccharide) by cultured mouse mesangial cells. In addition, the effect of morphine was evaluated on mesangial cell nitrite production. To evaluate the role of opiate receptors, we studied the effect of naloxone and naltrexone on mesangial cell TNF- and nitrite production. To determine the role of TNF- on mesangial cell nitrite production, we examined the effect of anti-TNF- antibody on morphine-induced nitrite production. Assay of TNF- and nitrite production was carried by ELISA and Griess method respectively. Results: Morphine alone did not enhance the generation of TNF- by mesangial cells, however, an enhanced (P < 0.001) TNF- production was observed when mesangial cells were first treated with morphine for 18 h and then activated further with LPS. Maximum release of TNF- was seen at a concentration of 10^–12 M of morphine. Opiate receptor antagonists (naloxone and naltrexone) inhibited the effect of morphine. Morphine also amplified (P < 0.0002) the effect of LPS on mesangial cell nitrite production. Anti-TNF- antibody attenuated morphine induced nitrite generation. Conclusion: We conclude that morphine stimulates the generation of TNF- by LPS-activated mesangial cells. This effect of morphine seems to be opiate receptor mediated and has a downstream effect in the form of mesangial cell nitrite generation. The present in vitro study provides the basis for a hypothesis that morphine may be playing a role in the development of heroin and HIV-associated nephropathies.     

TNF-α and sICAM-1 in intracranial aneurismal rupture

Introduction  Subarachnoidal hemorrhage (SAH) occurring after aneurismal rupture produces an inflammatory response in the cerebral circulation. Tumor necrosis factor (TNF)-α is a major cytokine in this process. Adhesion molecules provide information on inflammatory reactions taking place in the walls of blood vessels. Clinical evidence suggests a role of soluble intercellular adhesion molecule (sICAM)-1 in early hemorrhagic events. This study aimed to evaluate the implementation of early TNF-α and sICAM-1 serum measurement for the prognosis of patient outcome after intracranial aneurismal rupture. Materials and Methods  The study consisted of 27 patients with a diagnosis of intracranial aneurysm. SAH was evaluated on admission according to the Fisher scale, patients’ consciousness with the Glasgow Coma Scale, clinical grading with the Hunt and Hess scale, and clinical outcome with the Glasgow Outcome Scale (GOS). Blood samples were drawn within 72 h after arrival at the emergency room. Serum concentrations of TNF-α and sICAM-1 were assayed with the ELISA method. Results  The initial serum TNF-α concentration in the aneurismal patients was low and did not correlate with radiological and clinical scores. The serum sICAM-1 level positively correlated with the severity of bleeding assessed by the Fisher scale and negatively with the patient’s scoring in the GOS. Conclusions  This study demonstrated the absence of a systemic TNF-α-mediated inflammatory response at the onset of subarachnoid hemorrhage. Early measurement of serum sICAM-1 levels offers a potential prognostic value in the assessment of patients’ outcome after brain aneurismal rupture.     

Role of genetic polymorphisms in ACE and TNF-α gene in sarcoidosis: a meta-analysis

A great number of association studies have been performed to identify the genes involved in the etiology and prognosis of sarcoidosis. We performed a systematic review of case-control studies through the PubMed database and evaluated them for a possible inclusion into a meta-analysis in order to assess whether the reported genetic polymorphisms are the risk factors of sarcoidosis. Case-control studies with clear diagnostic criteria and interventions were included. Only investigations of a single polymorphism/gene involvement in sarcoidosis reported more than five times were selected. Aggregating data from 12 studies on ID/ACE polymorphisms, the odds ratio (OR) for sarcoidosis, if the polymorphism was considered under the dominant genetic model, was not significantly increased: 1.19 (95% CI 0.98–1.43); OR under the recessive model was 1.20 (95% CI 0.98–1.46). In seven case-control studies on −308/TNF-α polymorphism, the OR for sarcoidosis if the polymorphism considered under the dominant genetic model was significantly increased at 1.47 (95% CI 1.03–2.08); the OR under the recessive model was 1.39 (95% CI 0.67–2.90). In conclusion, the results showed that the TNF-α genotype could be a significant risk factor for sarcoidosis, whereas the risk of sarcoidosis due to the ACE genotype was not substantially elevated.     

Association of -308G/A and -238G/A polymorphisms of TNF-α and osteosarcoma risk

Objective: As a proinflammatory cytokine, TNF-α is associated with increased risk of osteosarcoma (OS). Our study aimed to explore the association of TNF-α polymorphisms and OS susceptibility in the Han Chinese population. Methods: 80 OS patients and 99 healthy people, matched on the age and sex, participated in the study. Genotyping was conducted by the method of polymerase chain reaction-restricted fragment length polymorphisms (PCR-RFLP). Then logistic regression was used to evaluate the effects of TNF-α polymorphisms (-308G/A and -238G/A) on the pathology of OS. Results: The frequency of AA genotype in -308G/A locus in the cases was significantly higher than that of the healthy group (20.0% vs. 6.1%). Patients with OS were more likely to possess AA genotype of -308G/A locus (OR=4.00, 95% CI=1.41-11.38). For the patients with A allele, the risk for OS increased 0.62 fold (OR=1.62, 95% CI=1.04-2.50). There was no remarkable relationship of -238G/A polymorphisms and OS susceptibility. In addition, we found that patients with G-A and A-A haplotypes was much higher in the cases than that of control group (68.0% and 25.0%, 53.0% and 38.9%, respectively). A-G haplotype appeared to increase the risk for OS (OR=1.93, 95% CI=1.13-2.94). Conclusion: The AA genotype of -308G/A locus of TNF-α gene was a risk factor for OS, however there was no correlation between -238G/A of TNF-α and OS.     

TNF-α signalling and inflammation: interactions between old acquaintances

Introduction

Inflammation is a very important part of innate immunity and is regulated in many steps. One such regulating step is the cytokine network, where tumor necrosis factor α (TNF-α) plays one of the most important roles.

Methods

A PubMed and Web of Science databases search was performed for studies providing evidences on the role of TNF-α in inflammation, apoptosis, and cancer.

Results and Conclusion

This review concisely summarizes the role of this pro-inflammatory cytokine during inflammation. It is focused mainly on TNF-α intracellular signaling and its influence on the typical inflammatory features in the organism. Being one of the most important pro-inflammatory cytokines, TNF-α participates in vasodilatation and edema formation, and leukocyte adhesion to epithelium through expression of adhesion molecules; it regulates blood coagulation, contributes to oxidative stress in sites of inflammation, and indirectly induces fever. The connection between TNF-α and cancer is mentioned as well.     

Drug induced autoimmune hepatitis and TNF-α blocking agents: Is there a real relationship?

Hepatotoxicity is an expected side effect of tumour necrosis factor-α (anti-TNF-α) blocking agents including, infliximab, etanercept and adalimumab. Although mild to moderate elevations of liver enzymes have been recognised after the use of these agents, severe hepatitis is rarely reported. Reactivation of viral hepatitis and drug induced liver injury is two main causes of liver dysfunction in these patients. A broad spectrum, ranging from minor immunological alterations to systemic autoimmune disease, has been reported during treatment with anti-TNF-α. Therefore, in recent studies TNF-α blocking agents have been considered a potential cause of drug induced autoimmune hepatitis. Taking into account the advances in the field of hepatology, this review summarizes the general characteristics of anti-TNF-α induced liver injury and autoimmune hepatitis.