The role of Aß in Alzheimer's Disease as an Evolutionary Outcome of Optimized Innate Immune Defense.

Alzheimer's Disease is a progressive manifestation of aging associated with accumulated Amyloid ß. It remains frustratingly unclear why this protein accumulates and how it contributes to Alzheimer's Disease pathology. In one recent hypothesis, Amyloid ß is suggested to function as an antimicrobial peptide in innate immune defense within the brain, where Amyloid ß gains toxicity when it becomes abundant. This essay proposes an evolutionary explanation for why Amyloid ß expression is regulated at an optimum based on its function as a defense and how this leads to disease. Among its potential physiological functions, Amyloid ß confers benefits to reduce direct pathogen damage while this simultaneously entails cellular cost of defense. Optimal Amyloid ß expression occurs when the gain in fitness from an incremental increase is balanced by the marginal cost of this increase. It proposes that natural selection acting upon the young favored systems to maintain Amyloid ß at an optimal level through mechanisms that induce the defense and repress its expression. With age, the force of natural selection declines and permits mechanisms of negative feedback repression to degenerate. Consequently, Amyloid ß is expressed beyond its optimum. Age also elevates cumulative pathogen exposure, reduces pathogen barriers and reactivates latent pathogens. The net effect is elevated, chronic induction of Amyloid ß in the brain. The model recommends attention to innate immune negative regulation in the brain to discover ways to restore these functions toward a youthful state in the elderly.

Droplet digital PCR as a novel dia-gnostic tool.

BACKGROUND: Nowadays, modern treatment methods for cancer patients are based on targeting specific molecules involved in cellular signaling system associated with tumor initiation and progression. The success of such approach depends on a correctly chosen dia-gnostic test with high sensitivity that identifies the occurrence and level of bio-markers in patients to select those who will respond and benefit from the treatment. The development of new technologies and the upgrades of the known ones contribute to the innovations in molecular characterization of cancer, which allows the detection of patients mutational status with high sensitivity and specificity. PURPOSE: Here, we discuss the utilization of the third-generation type of polymerase chain reaction (PCR), droplet digital PCR (ddPCR), in the molecular dia-gnostics of oncology diseases. According to the studies reported in our review, ddPCR represents a promising tool in genetic profiling of cancer patients. Therefore, the optimization and precise validation may enable gradual implementation of ddPCR into clinical practice in the field of oncology.

Relationship between cough reflex sensitivity and body mass index in children with chronic cough - a pilot study.

Obesity is characterized by chronic, low-grade systemic inflammation. Obesity may also be associated with chronic cough. The aim of this pilot study was to clarify relation of cough reflex sensitivity and body mass index (BMI) in children with chronic cough. Altogether 41 children having symptoms of chronic cough were submitted to cough reflex sensitivity measurement. We assessed the relation of cough reflex sensitivity (CKR) due to BMI. Cough reflex sensitivity was defined as the lowest capsaicin concentration which evoked two (C2) or five (C5) coughs. Capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method (KoKo DigiDoser; nSpire heath Inc, Louisville, CO, USA), modified by the addition of an inspiratory flow regulator valve (RIFR; nSpire heath Inc, Louisville, CO, USA). BMI was calculated. Pulmonary function was within normal range. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Children (22 boys and 19 girls, mean age 6.8 years) cough reflex sensitivity (median, with the Inter-Quartile Range) for C2 was 19.5 (73.4) micromol/l; for C5 it was 78.1 (605.5) micromol/l. We have noticed statistically significant relation of the cough reflex sensitivity (C5) and body mass index (P<0.0001); however, the effect size was small, R2=0.03. Increase of body mass index in one unit is associated with -34.959 micromol/l decrease of C5. We did not find a statistically significant relation between C2 and BMI (P=0.41). The median value of CKR (C2) in boys is not statistically significantly different than the median value of CKR (C2) in girls (P-value 0.5). The median value of CKR (C5) in boys is not statistically significantly different than the median value of CKR (C5) in girls (P-value 0.5). Increase of body mass index in children suffering from chronic cough relates to decrease of cough reflex sensitivity (C5 value).

Cough reflex sensitivity and fractional exhaled nitric oxide in children with asthma.

Individual studies have suggested the utility of fractional exhaled nitric oxide (FeNO) measurement in detecting cough-variant asthma and eosinophilic bronchitis in patients with chronic cough. The aim of this study was to clarify a correlation of cough reflex sensitivity and fractional exhaled nitric oxide in asthmatic children. 25 children with asthma and 15 controls were submitted to cough reflex sensitivity measurement - capsaicin aerosol in doubling concentrations (from 0.61 to 1250 micromol/l) was inhaled by a single breath method. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Fractional exhaled nitric oxide (FeNO) measurement was included. Asthmatic children' (11 boys and 14 girls, mean age 9+/-1 years) and control group (unconfirmed diagnosis of asthma) (6 boys and 9 girls, mean age 8+/-1 years) were included into the study. FeNO vs. C2 in asthma (Spearman´s rank correlation: -0.146, p=0.49); FENO vs. C5 in asthma (Spearman´s rank correlation: -0.777, p=0.71). We found that there is no correlation between cough reflex sensitivity and fractional exhaled nitric oxide either in children with asthma or in the control group.

Effects of folic acid on testicular toxicity induced by bisphenol-A in male Wistar rats.

We investigated the protective effect of the folic acid (FA) against bisphenol-A (BPA) induced toxicity in rat testis. We used four groups of seven adult male Wistar albino rats. The control group was fed corn oil, the BPA group was given BPA, the FA group was given FA and the FA + BPA group was given FA initially followed by BPA 1 h later. The BPA, FA and corn oil were administered by oral gavage for 14 days. At the end of the experiment, testis sections were examined for histological and histomorphometric characteristics. The TUNEL method was used to detect apoptosis and immunohistochemistry was used to examine the distribution of spermatogonial stem cells. Levels of serum testosterone were measured, and sperm viability and morphology were determined. The histological structure of the testis was normal in the control and FA groups. Although the number of TUNEL positive cells/tubule increased, the seminiferous epithelium height (SEH) at stages VII-VIII decreased in the BPA group compared to the control, FA and FA + BPA groups. The number of TUNEL positive cells/tubule decreased and the SEH at stages VII-VIII increased in the FA + BPA group compared to the BPA group. No significant difference in spermatogonial stem cells was found among groups. The level of serum testosterone and percentage of viable sperm was significantly lower, while the head, midpiece and total sperm abnormalities were significantly higher in the BPA treated group compared to control, FA, FA + BPA groups. It appears that the toxic effects of BPA on testis might be minimized by FA treatment.

Mechanisms of the adenosine A2A receptor-induced sensitization of esophageal C fibers.

Clinical studies indicate that adenosine contributes to esophageal mechanical hypersensitivity in some patients with pain originating in the esophagus. We have previously reported that the esophageal vagal nodose C fibers express the adenosine A2A receptor. Here we addressed the hypothesis that stimulation of the adenosine A2A receptor induces mechanical sensitization of esophageal C fibers by a mechanism involving transient receptor potential A1 (TRPA1). Extracellular single fiber recordings of activity originating in C-fiber terminals were made in the ex vivo vagally innervated guinea pig esophagus. The adenosine A2A receptor-selective agonist CGS21680 induced robust, reversible sensitization of the response to esophageal distention (10-60 mmHg) in a concentration-dependent fashion (1-100 nM). At the half-maximally effective concentration (EC50: ≈3 nM), CGS21680 induced an approximately twofold increase in the mechanical response without causing an overt activation. This sensitization was abolished by the selective A2A antagonist SCH58261. The adenylyl cyclase activator forskolin mimicked while the nonselective protein kinase inhibitor H89 inhibited mechanical sensitization by CGS21680. CGS21680 did not enhance the response to the purinergic P2X receptor agonist α,ß-methylene-ATP, indicating that CGS21680 does not nonspecifically sensitize to all stimuli. Mechanical sensitization by CGS21680 was abolished by pretreatment with two structurally different TRPA1 antagonists AP18 and HC030031. Single cell RT-PCR and whole cell patch-clamp studies in isolated esophagus-specific nodose neurons revealed the expression of TRPA1 in A2A-positive C-fiber neurons and demonstrated that CGS21682 potentiated TRPA1 currents evoked by allylisothiocyanate. We conclude that stimulation of the adenosine A2A receptor induces mechanical sensitization of nodose C fibers by a mechanism sensitive to TRPA1 antagonists indicating the involvement of TRPA1.

Studies on the regulation of transient lower esophageal sphincter relaxations (TLESRs) by acid in the esophagus and stomach.

Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux, but the regulation of TLESR by stimuli in the esophagus is incompletely understood. We have recently reported that acid infusion in the esophagus substantially (by 75%) increased the number of meal-induced TLESR in healthy subjects. We concluded that the TLESR reflex triggered by gastric distention with meal was enhanced by the stimulation of esophageal nerves by acid. However, the possibilities that the acid infused into the esophagus acts after passing though lower esophageal sphincter in stomach to enhance TLESR, or that the acid directly initiates TLESR from the esophagus were not addressed. Here, we evaluated the effect of acid infusion into the proximal stomach on meal-induced TLESR (study 1) and the ability of acid infusion into the esophagus to initiate TLESR without prior meal (study 2). We analyzed TLESRs by using high-resolution manometry in healthy subjects in paired randomized studies. In study 1, we found that acid infusion into the proximal stomach did not affect TLESRs induced by standard meal. The number of meal-induced TLESRs following the acid infusion into the proximal stomach was similar to the number of meal-induced TLESRs following the control infusion. In study 2, we found that acid infusion into the esophagus without prior meal did not initiate TLESRs. We conclude that the increase in the meal-induced TLESRs by acid in the esophagus demonstrated in our previous study is not attributable to the action of acid in the stomach or to direct initiation of TLESR from the esophagus by acid. Our studies are consistent with the concept that the stimuli in the esophagus can influence TLESRs. The enhancement of TLESR by acid in the esophagus may contribute to pathogenesis of gastroesophageal reflux in some patients.

Acid infusion into the esophagus increases the number of meal-induced transient lower esophageal sphincter relaxations (TLESRs) in healthy volunteers.

BACKGROUND: Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of gastroesophageal reflux (GER) but the regulation of TLESR by stimuli in the esophagus is incompletely understood. If stimuli in the esophagus can influence TLESR, then such regulation may perpetuate or limit GER. We addressed the hypothesis that acid in the esophagus enhances TLESRs. METHODS: We evaluated the effect of acid infusion into the distal esophagus on TLESRs evoked by a standard meal in a paired randomized study in healthy subjects. TLESRs were evaluated by using high resolution manometry (HRM). KEY RESULTS: We found that acid in the esophagus enhanced meal-induced TLESRs. Compared to control infusion the number of TLESRs (median [interquartile range]) was increased during 2 h following the acid infusion (11 [9-14] vs 17 [12.5-20], p < 0.01). The average duration of individual TLESRs was not affected. The time-course analysis revealed that a robust increase in TLESRs occurred already in the first hour when the number of TLESRs nearly doubled (6 [5.5-7.5] vs 11 [7.5-12.5], p < 0.05). In contrast to the enhancement of TLESRs, the number of swallows was not changed. CONCLUSIONS & INFERENCES: The acid infusion into the esophagus increases the number of meal-induced TLESRs in healthy subjects. Our results provide evidence for the concept that the stimuli in the esophagus can influence TLESRs. The regulation of TLESR by stimuli in the esophagus may contribute to pathogenesis of GER in some patients.