Mechanisms of actions of guanylin peptides in the kidney

After a salty meal, stimulation of salt excretion via the kidney is a possible mechanism to prevent hypernatremia and hypervolemia. Besides the well known hormonal regulators of salt and water excretion in the distal nephron, arginine vasopressin and aldosterone, guanylin (GN) peptides produced in the intestine were proposed to be intestinal natriuretic peptides. These peptides inhibit Na⁺ absorption in the intestine and induce natriuresis, kaliuresis and diuresis in the kidney. The signaling pathway of GN peptides in the intestine is well known. They activate enterocytes via guanylate cyclase C (GC-C) and increase the cellular concentration of cGMP which leads to secretion of Cl^–, HCO₃^– and water into the intestinal lumen and to inhibition of Na⁺ absorption. Guanylin peptides are filtered in the glomerulus, and additionally synthesized and excreted by tubular cells. They activate receptors located in the luminal membrane of the tubular cells along the nephron. In GC-C deficient mice renal effects of GN peptides are retained. In human, rat, and opossum proximal tubule cells, a cGMP-dependent signaling was demonstrated, but in addition GN peptides apparently also activate a PT-sensitive G-protein coupled receptor. A similar dual signaling pathway is also known for other natriuretic peptides like atrial natriuretic peptide. A cGMP-independent signaling pathway of GN peptides is also shown for principal cells of the human cortical collecting duct where the final hormonal regulation of electrolyte homeostasis takes place. This review will focus on the current knowledge on renal actions of GN peptides and specifically address novel GC-C- and cGMP-independent signaling mechanisms.     

Efficacy of fine‐needle aspiration biopsy in diagnosis of breast cancer: A retrospective study of 303 cases in Bahrain

Breast cancer is a leading cause of death in many countries worldwide and breast lesions remain a common diagnostic dilemma. Fine‐needle aspiration biopsy (FNAB) has been suggested as the most important, first line, minimally invasive measure in the management of patients with breast lesions. The aim of this study is to evaluate the efficacy of FNAB in patients with breast lesions by comparing the diagnostic accuracy of cytology results with that of the definitive histological examination outcome and also to investigate the added value of a single aspirator experience to the overall diagnostic precision and compared with the internationally published results. A retrospective study of 303 breast FNAB samples were carried out by a single experienced cytopathologist with complete comparison records. The prevalence of positive cytologic diagnosis for the breast cancer was determined to be 20.4%. The overall diagnostic accuracy of FNAB was 97.9%, with a specificity and sensitivity of 98.3 and 96.5%, respectively. The overall positive and negative predictive values were determined to be 93.2 and 99.2%, respectively. In addition, the sensitivity was comparable in cases that have been attempted by palpation‐guided sampling compared with those aspirations that were carried out under US guidance. Results from this study confirm that FNAB biopsies performed and reported by a dedicated, single, skilled cytopathologist are highly effective in diagnosis of breast lesions and reliable in differentiating benign and malignant breast lesions with an overall high efficacy in a specialized laboratory‐based FNAB clinic. Diagn. Cytopathol. 2009. © 2009 Wiley‐Liss, Inc.     

Allostatic load associations to acute, 3-year and 6-year prospective depressive symptoms in healthy older adults

Allostatic load represents the strain that chronic stress exerts on interconnected biological systems. Associated algorithms are related to numerous deleterious physical outcomes in older populations, and yet few studies have assessed associations to mental health outcomes like geriatric depression. Using data from the Douglas Hospital Longitudinal Study of Normal and Pathological Aging, we assessed whether using an allostatic load index derived from seven biomarkers could detect self-rated depressive symptoms in 58 healthy older adults followed longitudinally over a 6-year period. Our results revealed that increased allostatic load was associated with increased depressive symptoms on the same year of assessment. After 3 years, AL was prospectively associated with depressive symptoms, but entering age and sex as covariates attenuated this effect to a trend. Only age emerged as a significant predictor of depressive symptoms over 6 years. These findings suggest that increased AL in older age is only associated with depressive symptomatology acutely. Over longer periods of time, however, the physical and psychological sequelae of advanced age may contribute to increased depressive symptoms via pathways otherwise undetectable using allostatic load indices of sub-clinical physiological dysregulations.     

Serum Insulin and Cognitive Performance in Older Adults: A Longitudinal Study

Purpose

The aim of this study was to examine the association of serum glucose, insulin, and insulin resistance with cognitive functioning 7 years later in a longitudinal population-based study of Finnish older adults.

Paths of causal influence from prenatal inflammation and preterm gestation to childhood asthma symptoms

Introduction: Long-lasting respiratory symptoms have a huge impact on the quality of life in prematurely born children. The aim was to investigate paths of assumed causality leading from foetal inflammatory response syndrome (FIRS) to asthma symptoms in preterms. Methods: Demographic, antenatal, delivery and outcome data were collected from 262 infants with less than 32 completed weeks of gestational age over a 10-year period in a prospective cohort study. The presence of symptoms of asthma beyond the age of 5?years was the primary outcome measure. The causal effect of FIRS on childhood asthma was tested with three different logistic regression models and two structural equation models (SEM). Results: FIRS (OR = 4.7) and subsequent chronic lung disease of prematurity (OR = 7.7) and early childhood wheezing (OR = 9.5) are the most important risk factors for development of asthma symptoms in children born with less than 32?weeks of gestational age. The path analysis showed that FIRS has a large direct (0.59), medium indirect (0.11) and large overall (0.70) effect on CLD; large negative direct effect on ECW (?0.34) and a large positive indirect effect (0.74), mediated by CLD. On the occurrence of asthma symptoms, FIRS has a medium negative direct effect (?0.18) and a medium positive indirect effect (0.26), mediated by CLD and ECW. Conclusion: Prenatal inflammation plays an important role in the development of chronic respiratory disturbances in preterm infants. This influence is mainly related to structural and developmental lung abnormalities initiated in utero as consequences of FIRS, resulting in CLD of prematurity, and overcoming the protective mechanisms of chorioamnionitis.     

HMGB1 released from nociceptors mediates inflammation

Inflammation, the body’s primary defensive response system to injury and infection, is triggered by molecular signatures of microbes and tissue injury. These molecules also stimulate specialized sensory neurons, termed nociceptors. Activation of nociceptors mediates inflammation through antidromic release of neuropeptides into infected or injured tissue, producing neurogenic inflammation. Because HMGB1 is an important inflammatory mediator that is synthesized by neurons, we reasoned nociceptor release of HMGB1 might be a component of the neuroinflammatory response. In support of this possibility, we show here that transgenic nociceptors expressing channelrhodopsin-2 (ChR2) directly release HMGB1 in response to light stimulation. Additionally, HMGB1 expression in neurons was silenced by crossing synapsin-Cre (Syn-Cre) mice with floxed HMGB1 mice (HMGB1^f/f). When these mice undergo sciatic nerve injury to activate neurogenic inflammation, they are protected from the development of cutaneous inflammation and allodynia as compared to wild-type controls. Syn-Cre/HMGB1^fl/fl mice subjected to experimental collagen antibody–induced arthritis, a disease model in which nociceptor-dependent inflammation plays a significant pathological role, are protected from the development of allodynia and joint inflammation. Thus, nociceptor HMGB1 is required to mediate pain and inflammation during sciatic nerve injury and collagen antibody–induced arthritis.

The dual threat of infection and injury exerted a significant influence on the evolution of the mammalian immune and nervous systems. The nervous system detects changes in the environment, generates reflexive responses to those changes, and integrates these responses across space and time to establish adaptive memories of events (1, 2). Sensory neurons, termed nociceptors, innervate tissues subjected to infection and injury and are activated by the molecular products of microbes and tissue injury (3–6). Nociceptor signaling stimulates reflexive neural circuits to coordinate defensive behavior, including inflammation (3–9). Reflex neural signaling arising in the brain and spinal cord is capable of integrating divergent stimulating and inhibitory inputs, because neural signaling circuits act in opposition (10, 11). This balance of opposing signals enables fine tuning of physiological responses by smoothing gradients of corrective action in response to a changing environment (12). Evolutionary pressure from infection and injury also molded the mammalian immune system to detect changes in the environment, mobilize coordinated defensive reactions, and establish memory (13). The acute onset of infection and injury produces inflammation, defined by pain, edema, heat, redness, and loss of function mediated by immune cells producing cytokines and other inflammatory mediators (6, 14). Because uninhibited inflammation also causes dangerous shock and lethal tissue injury, homeostatic mechanisms at the intersection of the nervous system and immune system have a fundamental role in health by inhibiting inflammation (15–17).The nervous system inhibits inflammation by transmitting antiinflammatory signals in the vagus nerve, which arises in the brainstem and sends efferent projections to the organs (15–18). In the inflammatory reflex, signals descend from the brain to the abdominal celiac mesenteric ganglia, the origin of the splenic nerve (19, 20). In the spleen, splenic nerve signals stimulate a subset of T lymphocytes to secrete acetylcholine, which interacts with alpha 7 nicotinic acetylcholine receptors to inhibit macrophage production of TNF and other inflammatory mediators (21–23). Detailed mechanistic insight into the neuroscience, functional immunology, and molecular mechanisms of the inflammatory reflex enabled therapeutic trials using vagus nerve stimulation to inhibit inflammation in humans. This strategy to stimulate the inflammatory reflex inhibits cytokine release and suppresses inflammation in patients with inflammatory bowel disease and rheumatoid arthritis (24–26). Since evolution selects for reflexively controlled homeostatic systems acting antagonistically, here we reasoned it likely also selected for neural reflex circuits which stimulate inflammation and enhance immunity.High mobility group box 1 protein (HMGB1), a ubiquitous nuclear protein conserved across evolution from archaea to mammals, is a necessary and sufficient mediator of sterile injury- and infection-elicited inflammation and immunity (27, 28). It is passively released by cells undergoing necrosis and secreted by innate immune cells activated by inflammation (27, 29). HMGB1 stimulates inflammation by activating the receptor for advanced glycation end products (RAGE) and Toll-like receptor 2, 4, and 9 (TLR 2, 4, and 9) expressed by many different cell types (30–32). Signal transduction via these receptors culminates in increased expression of cytokines, and in recruiting and stimulating monocytes, lymphocytes, and neutrophils. HMGB1 also stimulates dendritic cell maturation and enhances antibody responses to antigen, an important early stage in memory formation (33, 34). Administration of HMGB1 antagonists significantly attenuates the severity of inflammation in preclinical models of sepsis, inflammatory bowel disease, arthritis, and neuroinflammation (31, 32, 35, 36).HMGB1 is expressed in the nervous system in cortical neurons and in nociceptors (37–40). In preclinical models of nerve injury, HMGB1 levels are increased in the cell bodies of nociceptors residing in the dorsal root ganglia (DRG) (39, 40). In brain neurons, HMGB1 translocates into the cytoplasm and is released during ischemia (38, 41). Exposure of cortical neurons to ethanol activates HMGB1 release via a mechanism dependent upon NOX2/NLRP1 inflammasome (42). Neuronal HMGB1 expression is also significantly enhanced during nerve injury (39, 43, 44). Because HMGB1 stimulates inflammation, and is expressed by nociceptors, and since nociceptors provide a ubiquitous network of nervous system connectivity to peripheral tissues, we reasoned HMGB1 released by nociceptors is a mechanism of neurogenic inflammation. Here, utilizing neuronal-specific ablation of HMGB1 (Syn-Cre/HMGB1^fl/fl mice), we discovered a specific role for neuron-derived HMGB1 in inflammation. Genetic silencing of HMGB1 in neurons attenuates inflammation after sciatic nerve injury and in collagen antibody–induced polyarthritis revealing a previously unexpected, but essential, mechanistic role for neuronal HMGB1 in inflammation.     

Chorioamnionitis and chronic lung disease of prematurity: a path analysis of causality

Current evidence suggests that additional pathogenetic factors could play a role in the development of chronic lung disease of prematurity, other than mechanical ventilation and free radical injury. The introduction of the concept of "fetal inflammatory response syndrome" offers a new perspective on the pathogenesis of chronic lung disease of prematurity. New statistical approaches could be useful tools in evaluating causal relationships in the development of chronic morbidity in preterm infants. The aim of this study was to test a new statistical framework incorporating path analysis to evaluate causality between exposure to chorioamnionitis and fetal inflammatory response syndrome and the development of chronic lung disease of prematurity. We designed a prospective cohort study that included consecutively born premature infants less than 32 weeks of gestation whose placentas were collected for histological analysis. Histological chorioamnionitis, clinical data, and neonatal outcomes were related to chronic lung disease. Along with standard statistical methods, a path analysis was performed to test the relationship between histological chorioamnionitis, gestational age, mechanical ventilation, and development of chronic lung disease of prematurity. Among the newborns enrolled in the study, 69/189 (36%) had histological chorioamnionitis. Of those with histological chorioamnionitis, 28/69 (37%) were classified as having fetal inflammatory response syndrome, according to the presence of severe chorioamnionitis and funisitis. Histological chorioamnionitis was associated with a lower birth weight, shorter gestation, higher frequency of patent ductus arteriosus, greater use of surfactant, and higher frequency of chronic lung disease of prematurity. Severe chorioamnionitis and funisitis were significantly associated with lower birth weight, lower gestational age, lower Apgar score at 5 minutes, more frequent use of mechanical ventilatory support and surfactant, as well as higher frequency of patent ductus arteriosus and chronic lung disease. The results of the path analysis showed that fetal inflammatory response syndrome has a significant direct (0.66), indirect (0.11), and overall (0.77) effect on chronic lung disease. This study demonstrated a strong positive correlation between exposure of the fetus to a severe inflammatory response and the development of chronic lung disease of prematurity.     

Entecavir treatment of children 2–16 years of age with chronic hepatitis B infection

Background and study aimsChildhood acquired chronic hepatitis B is associated with a significant lifetime risk of developing cirrhosis or hepatocellular carcinoma. Our objective in this study was to report retrospectively the response to treatment with Entecavir in 8 children with chronic hepatitis B followed at the King Abdulaziz University Hospital, Jeddah, Saudi Arabia.Patients and methodsThis study is an observational hospital based chart review of children and adolescents with chronic hepatitis B treated with entecavir at the King Abdulaziz University Hospital, Jeddah, Saudi Arabia in the period between June 2007 and July 2011.ResultsHalf of the studied group was males, and the median age at the time of treatment was 4.8 years (range, 2.6–15). All subjects displayed infection with HBV genotype D and all were HBeAg positive. Half of the patients had been previously treated with lamivudine, while the remaining half was treatment naïve patients. The mean ALT ± SD was 84.9 ± 34.7 IU/L (range, 46–133) and the mean HBV DNA was 5.01 × 10⁸ ± 5.7 × 10⁸ IU/mL (range, 5.5 × 10⁷–1.3 × 10⁹). Patients were treated with a daily oral dose of 0.5 mg entecavir, and the mean duration of treatment was 23.8 ± 11.9 months, (range 14.9–44.7 months). HBV DNA suppression of more than 2 log₁₀ was achieved in all patients. HBV DNA was undetected in 37.5%, with ALT normalization in 87.5% and lastly HBeAg seroconversion and loss occurred in 37.5%. No adverse side effects were observed during the treatment with entecavir.ConclusionWe conclude from this limited data that 37.5% of children treated with entecavir achieved HBeAg loss and seroconversion with no side effects observed during treatment period, however long term safety and efficacy in children should be demonstrated through a multicenter study, enrolling large number of patients.