The mast cell - neurofibromatosis connection.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder affecting 1/3000 individuals worldwide. It results from germline mutations of the neurofibromin gene and it is fully penetrant by the age of 5. Neurofibromin is a 2818 amino acid protein that is produced in many cell types, but its levels are especially high in the nervous system.

Time to look past TNF and thalidomide for cachexia - could mast cells and flavonoids be the answer?

Cachexia is a wasting condition associated with late stages of many chronic illnesses and may be present in up to 80% of patients with advanced cancers. Cachexia is a metabolic derangement resulting in a disturbance to the homeostasis of muscle breakdown and synthesis, favoring catabolism and muscle loss. Despite making strides in treating cancer itself, there have been no major advances in the treatment of cachexia pharmacologically or nutritionally. Clinical trials using anti-TNF biologics and thalidomide have largely failed. A new approach may be to focus on other possible waste-inducing mediators, possibly derived from mast cells, and the beneficial action of select natural flavonoids.

Atopic diseases and inflammation of the brain in the pathogenesis of autism spectrum disorders.

Autism spectrum disorders (ASDs) affect as many as 1 in 45 children and are characterized by deficits in sociability and communication, as well as stereotypic movements. Many children also show severe anxiety. The lack of distinct pathogenesis and reliable biomarkers hampers the development of effective treatments. As a result, most children with ASD are prescribed psychopharmacologic agents that do not address the core symptoms of ASD. Autoantibodies against brain epitopes in mothers of children with ASD and many such children strongly correlate with allergic symptoms and indicate an aberrant immune response, as well as disruption of the blood-brain barrier (BBB). Recent epidemiological studies have shown a strong statistical correlation between risk for ASD and either maternal or infantile atopic diseases, such as asthma, eczema, food allergies and food intolerance, all of which involve activation of mast cells (MCs). These unique tissue immune cells are located perivascularly in all tissues, including the thalamus and hypothalamus, which regulate emotions. MC-derived inflammatory and vasoactive mediators increase BBB permeability. Expression of the inflammatory molecules interleukin (IL-1ß), IL-6, 1 L-17 and tumor necrosis factor (TNF) is increased in the brain, cerebrospinal fluid and serum of some patients with ASD, while NF-kB is activated in brain samples and stimulated peripheral blood immune cells of other patients; however, these molecules are not specific. Instead the peptide neurotensin is uniquely elevated in the serum of children with ASD, as is corticotropin-releasing hormone, secreted from the hypothalamus under stress. Both peptides trigger MC to release IL-6 and TNF, which in turn, stimulate microglia proliferation and activation, leading to disruption of neuronal connectivity. MC-derived IL-6 and TGFß induce maturation of Th17 cells and MCs also secrete IL-17, which is increased in ASD. Serum IL-6 and TNF may define an ASD subgroup that benefits most from treatment with the natural flavonoid luteolin. Atopic diseases may create a phenotype susceptible to ASD and formulations targeting focal inflammation of the brain could have great promise in the treatment of ASD.

Children with autism spectrum disorders, who improved with a luteolin-containing dietary formulation, show reduced serum levels of TNF and IL-6.

Autism spectrum disorders (ASDs) have been associated with brain inflammation as indicated by microglia activation, as well as brain expression and increased plasma levels of interleukin-6 (IL-6) and tumor necrosis factor (TNF). Here we report that serum levels of IL-6 and TNF were elevated (61.95 ± 94.76 pg ml(-1) and 313.8 ± 444.3 pg ml(-1), respectively) in the same cohort of patients with elevated serum levels of corticotropin-releasing hormone (CRH) and neurotensin (NT), while IL-9, IL-31 and IL-33 were not different from controls. The elevated CRH and NT levels did not change after treatment with a luteolin-containing dietary formulation. However, the mean serum IL-6 and TNF levels decreased significantly (P=0.036 and P=0.015, respectively) at the end of the treatment period (26 weeks) as compared with levels at the beginning; these decreases were strongly associated with children whose behavior improved the most after luteolin formulation treatment. Our results indicate that there are distinct subgroups of children within the ASDs that may be identifiable through serum levels of IL-6 and TNF and that these cytokines may constitute distinct prognostic markers for at least the beneficial effect of luteolin formulation.

Elevated serum neurotensin and CRH levels in children with autistic spectrum disorders and tail-chasing Bull Terriers with a phenotype similar to autism.

Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by defects in communication and social interactions, as well as stereotypic behaviors. Symptoms typically worsen with anxiety and stress. ASD occur in early childhood, often present with regression and have a prevalence of 1 out of 68 children. The lack of distinct pathogenesis or any objective biomarkers or reliable animal models hampers our understanding and treatment of ASD. Neurotensin (NT) and corticotropin-releasing hormone (CRH) are secreted under stress in various tissues, and have proinflammatory actions. We had previously shown that NT augments the ability of CRH to increase mast cell (MC)-dependent skin vascular permeability in rodents. CRH also induced NT receptor gene and protein expression in MCs, which have been implicated in ASD. Here we report that serum of ASD children (4-10 years old) has significantly higher NT and CRH levels as compared with normotypic controls. Moreover, there is a statistically significant correlation between the number of children with gastrointestinal symptoms and high serum NT levels. In Bull Terriers that exhibit a behavioral phenotype similar to the clinical presentation of ASD, NT and CRH levels are also significantly elevated, as compared with unaffected dogs of the same breed. Further investigation of serum NT and CRH, as well as characterization of this putative canine breed could provide useful insights into the pathogenesis, diagnosis and treatment of ASD.

Hyaluronic acid levels are increased in complicated parapneumonic pleural effusions.

BACKGROUND AND AIM: Hyaluronic acid (HA) is a component of extracellular matrix and may play a role in the pleural inflammation which is implicated in parapneumonic effusions.The aim of the current study was to investigate HA levels in serum and pleura in patients with parapneumonic effusions. METHODS: We prospectively studied pleural and serum levels of HA in 58 patients with pleural effusions due to infection (complicated and uncomplicated parapneumonic effusions), malignant effusions and transudative effusions due to congestive heart failure. In addition to HA, TNF-alpha and IL-beta levels were determined in pleural fluid and serum by ELISA. RESULTS: The median +/- SD HA levels (pg/ml) in pleural fluid of patients with complicated effusions (39.058 +/- 11.208) were significantly increased (p < 0.005), compared to those with uncomplicated parapneumonic effusions (11.230 +/- 1.969), malignant effusions (10.837 +/- 4.803) or congestive heart failure (5.392 +/- 3.133). There was no correlation between pleural fluid and serum HA values. Pleural fluid TNF-alpha levels (146 +/- 127 pg/mL) and IL-1beta levels (133.4 +/- 156 pg/mL) were significantly higher in patients with complicated parapneumonic effusions compared to patients with other types of effusion (p < 0.05). No significant association between HA and TNF-alpha or IL-1beta was found. CONCLUSIONS. HA may play a significant role in the inflammatory process which characterises exudative infectious pleuritis. Further investigation might reveal whether HA is a useful marker in the management of parapneumonic effusions.

The acute effect of smoking in healthy and asthmatic smokers.

BACKGROUND: Acute exposure to cigarette smoke is related to airway and systemic inflammation and oxidative stress. Little is known about the acute effect of cigarette smoking in smoking asthmatics. The aim of this study was to evaluate the acute effect of smoking in airway and systemic inflammation and oxidative stress in normal smokers and patients with properly treated well-controlled persistent asthma. MATERIALS AND METHODS: Ten normal smokers and 10 smokers with moderate persistent asthma controlled with LABA and ICS were recruited. Subjects refrained from smoking for at least 12 h prior to their inclusion. We compared the effects of smoking of two cigarettes on airway obstruction, airway inflammation and oxidative stress [by measuring fraction of exhaled nitric oxide (FeNO), plus pH and 8-isoprostane in exhaled breath condensate (EBC)] before and 30, 90 and 180 min after smoking. Furthermore, we evaluated systemic oxidative stress, C-reactive protein (CRP) and serum amyloid A (SAA) and urine leukotriene E(4) (LTE(4)) before and 180 min after smoking. RESULTS: No differences were observed in EBC pH and 8-isoprostane, FeNO and systemic oxidative stress between the groups at baseline. In asthmatics, EBC pH decreased 30 min and EBC 8-isoprostane increased 90 min after smoking (P = 0.039 and P = 0.029 respectively), which was not evident in smoking controls. Serum oxidative stress increased only in asthmatic smokers at 180 min (P = 0.001). No differences were observed in SAA, CRP and urine LTE(4) levels before and after smoking. CONCLUSION: Acute smoking has more deleterious effects in well-controlled properly treated asthmatic smokers compared with matched normal smokers.