The Transient Receptor Potential Vanilloid 1 Antagonist Capsazepine Improves the Impaired Lung Mechanics during Endotoxemia

Acute lung injury (ALI) caused by systemic inflammatory response remains a leading cause of morbidity and mortality in critically ill patients. Management of patients with sepsis is largely limited to supportive therapies, reflecting an incomplete understanding of the underlying pathophysiology. Furthermore, there have been limited advances in the treatments for ALI. In this study, lung function and a histological analysis were performed to evaluate the impact of transient receptor potential vanilloid‐1 receptor (TRPV1) antagonist (capsazepine; CPZ) on the lipopolysaccharide (LPS)‐induced lung injury in mice. For this, adult mice pre‐treated with CPZ or vehicle received intraperitoneal injections of LPS or saline and 24 hr after, the mice were anaesthetized, and lung mechanics was evaluated. The LPS‐challenged mice exhibited substantial mechanical impairment, characterized by increases in respiratory system resistance, respiratory system elastance, tissue damping and tissue elastance. The pre‐treatment with CPZ prevented the increase in respiratory system resistance and decreased the increase in tissue damping during endotoxemia. In addition, mice pre‐treated with CPZ had an attenuated lung injury evidenced by reduction on collapsed area of the lung parenchyma induced by LPS. This suggests that the TRPV1 antagonist capsazepine has a protective effect on lung mechanics in ALI during endotoxemia and that it may be a target for enhanced therapeutic efficacy in ALI.     

Abstracts from the Third Symposium of the Spanish Society of Bone and Mineral Research (SEIOMM) Oviedo,Spain 25–27 September 1991

Laboratory Investigations

Abstracts from the Third Symposium of the Spanish Society of Bone and Mineral Research (SEIOMM) Oviedo, Spain 25–27 September 1991     

Detection of Toxoplasma gondii DNA and specific antibodies in high-risk pregnant women

Primary maternal infection with toxoplasmosis during pregnancy is frequently associated with transplacental transmission to the fetus. This study was conducted to test the utility of a polymerase chain reaction (PCR) assay to detect recent infections with Toxoplasma in pregnant women. One hundred forty-eight women with high-risk pregnancies who had abnormal pregnancy outcomes (cases) and 100 with normal pregnancies (controls) were tested for the presence of Toxoplasma DNA in their blood by a nested PCR and specific antibodies to Toxoplasma by an enzyme-linked immunosorbent assay. The IgG results of the cases differed significantly from those of the controls (54% and 12%, respectively; P < 0.02). Four (2.7%) of the cases were IgM positive, but none of the controls were positive. Detection of Toxoplasma DNA in 20 (8.1%) of the IgG-positive cases suggests a recent infection. The risk factors associated with the infection were eating raw meat and contact with soil. The diagnostic serology of recent infection in early pregnancy could be confirmed by a positive Toxoplasma-specific PCR result in blood samples collected in the first half of pregnancy, even in the presence of serologic results difficult to interpret due to the lack of sequential follow-up during pregnancy.     

The phosphorylation state of Ser-129 in human alpha-synuclein determines neurodegeneration in a rat model of Parkinson disease

Studies have shown that alpha-synuclein (alpha-syn) deposited in Lewy bodies in brain tissue from patients with Parkinson disease (PD) is extensively phosphorylated at Ser-129. We used recombinant Adeno-associated virus (rAAV) to overexpress human wild-type (wt) alpha-syn and two human alpha-syn mutants with site-directed replacement of Ser-129 to alanine (S129A) or to aspartate (S129D) in the nigrostriatal tract of the rat to investigate the effect of Ser-129 phosphorylation state on dopaminergic neuron pathology. Rats were injected with rAAV2/5 vectors in the substantia nigra pars compacta (SNc) on one side of the brain; the other side remained as a nontransduced control. The level of human wt or mutant alpha-syn expressed on the injected side was about four times the endogenous rat alpha-syn. There was a significant reduction of dopaminergic neurons in the SNc and dopamine (DA) and tyrosine hydroxylase (TH) levels in the striatum of all S129A-treated rats as early as 4 wk postinjection. Nigral DA pathology occurred more slowly in the wt-injected animals, but by 26 wk the wt alpha-syn group lost nigral TH neurons equivalent to the mutated S129A group at 8 wk. In stark contrast, we did not observe any pathological changes in S129D-treated animals. Therefore, the nonphosphorylated form of S129 exacerbates alpha-syn-induced nigral pathology, whereas Ser-129 phosphorylation eliminates alpha-syn-induced nigrostriatal degeneration. This suggests possible new therapeutic targets for Parkinson Disease.     

Opposing relationships of childhood threat and deprivation with stria terminalis white matter

While stress may be a potential mechanism by which childhood threat and deprivation influence mental health, few studies have considered specific stress‐related white matter pathways, such as the stria terminalis (ST) and medial forebrain bundle (MFB). Our goal was to examine the relationships between childhood adversity and ST and MFB structural integrity and whether these pathways may provide a link between childhood adversity and affective symptoms and disorders. Participants were young adults (n = 100) with a full distribution of maltreatment history and affective symptom severity. Threat was determined by measures of childhood abuse and repeated traumatic events. Socioeconomic deprivation (SED) was determined by a measure of childhood socioeconomic status (parental education). Participants underwent diffusion spectrum imaging. Human Connectome Project data was used to perform ST and MFB tractography; these tracts were used as ROIs to extract generalized fractional anisotropy (gFA) from each participant. Childhood threat was associated with ST gFA, such that greater threat was associated with less ST gFA. SED was also associated with ST gFA, however, conversely to threat, greater SED was associated with greater ST gFA. Additionally, threat was negatively associated with MFB gFA, and MFB gFA was negatively associated with post‐traumatic stress symptoms. Our results suggest that childhood threat and deprivation have opposing influences on ST structural integrity, providing new evidence that the context of childhood adversity may have an important influence on its neurobiological effects, even on the same structure. Further, the MFB may provide a novel link between childhood threat and affective symptoms.     

Childhood physical abuse predicts stressor-evoked activity within central visceral control regions

Early life experience differentially shapes later stress reactivity, as evidenced by both animal and human studies. However, early experience-related changes in the function of central visceral neural circuits that control stress responses have not been well characterized, particularly in humans. The paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), amygdala (Amyg) and subgenual anterior cingulate cortex (sgACC) form a core visceral stress-responsive circuit. The goal of this study is to examine how childhood emotional and physical abuse relates to adulthood stressor-evoked activity within these visceral brain regions. To evoke acute states of mental stress, participants (n = 155) performed functional magnetic resonance imaging (fMRI)-adapted versions of the multi-source interference task (MSIT) and the Stroop task with simultaneous monitoring of mean arterial pressure (MAP) and heart rate. Regression analyses revealed that childhood physical abuse correlated positively with stressor-evoked changes in MAP, and negatively with unbiased, a priori extractions of fMRI blood-oxygen level-dependent signal change values within the sgACC, BNST, PVN and Amyg (n = 138). Abuse-related changes in the function of visceral neural circuits may reflect neurobiological vulnerability to adverse health outcomes conferred by early adversity.     

Stillbirths and early neonatal mortality in rural Northern Ghana

Objective To calculate perinatal mortality (stillbirth and early neonatal death: END) rates in the Upper East region of Ghana and characterize community‐based stillbirths and END in terms of timing, cause of death, and maternal and infant risk factors. Methods Birth outcomes were obtained from the Navrongo Health and Demographic Surveillance System over a 7‐year period. Results Twenty thousand four hundred and ninty seven pregnant women were registered in the study. The perinatal mortality rate was 39 deaths/1000 deliveries, stillbirth rate 23/1000 deliveries and END rates 16/1000 live births. Most stillbirths were 31 weeks gestation or less. Prematurity, first‐time delivery and multiple gestation all significantly increased the odds of perinatal death. Approximately 70% of END occurred during the first 3 postnatal days, and the most common causes of death were birth asphyxia and injury, infections and prematurity. Conclusion Stillbirths and END remain a significant problem in Navrongo. The main causes of END occur during the first 3 days and may be modifiable with simple targeted perinatal policies.