Increased HLA-G Expression in Tissue-Infiltrating Cells in Inflammatory Bowel Diseases

Background

Since HLA-G is an immune checkpoint molecule and since Crohn’s disease (CD) and ulcerative colitis (UC) exhibit deregulated immune-mediated mechanisms, we aimed to evaluate intestinal HLA-G expression and soluble HLA-G (sHLA-G) levels in CD/UC patients stratified according to the CD phenotype/localization and UC extension.

Methods

HLA-G tissue expression was assessed by immunohistochemistry in biopsies collected from 151 patients (90 CD, 61 UC) and in surgical resection specimens (28 CD, 12 UC). Surgical material from 24 healthy controls was also assessed. Plasma sHLA-G levels (97 CD, 81 UC, and 120 controls) were evaluated using ELISA.

Results

HLA-G expression was similarly observed in the intestinal epithelial cells of control and CD/UC specimens. However, in biopsies, the plasma cells/lymphocytes infiltrating the lamina propria in CD/UC presented (1) increased HLA-G expression compared to controls (P?<?0.0001), (2) greater cell staining in UC cells than in CD cells irrespective of disease extent (P?=?0.0011), and (3) an increased number of infiltrating cells in the inflammatory CD phenotype compared to that in the stenosing and fistulizing phenotypes (P?=?0.0407). In surgical specimens, CD/UC patients exhibited higher infiltrating cell HLA-G expression in lesion areas than in margins. sHLA-G levels were higher in UC/CD patients (P?<?0.0001) than in controls, but no difference was observed between diseases.

Conclusions

Increased infiltrating cell HLA-G expression associated with increased sHLA-G levels in CD/UC patients may reflect ongoing host strategies to suppress chronic inflammation.

     

Maternal outcomes according to mode of delivery in women with severe preeclampsia: a cohort study

Objective: To determine the association between mode of delivery and maternal complications in patients with severe preeclampsia.

Methods: A prospective cohort study was conducted with 500 pregnant women with severe preeclampsia. The mode of delivery, vaginal or caesarean section, was considered the exposure, while the postpartum maternal complications and severe maternal morbidity were the outcomes. Logistic regression analysis was performed to determine the adjusted risk and 95% confidence intervals (95% CI) of maternal morbidity.

Results: Labour was spontaneous in 22.0% and induced in 28.2%, while 49.8% had an elective caesarean section. Ninety-five (67.4%) of the patients in whom labour was induced delivered vaginally. Total Caesarean rate was 68.2%. The risk of severe maternal morbidity was significantly greater in patients submitted to Caesarean section (54.0% versus 32.7%) irrespective of the presence of labour. Factors that remained associated with severe maternal morbidity following multivariate analysis were a diagnosis of HELLP syndrome after delivery (OR?=?3.73; 95% CI: 1.55–9.88) and having a caesarean (OR?=?1.91; 95% CI: 1.52–4.57).

Conclusions: Caesareans are often performed in patients with severe preeclampsia and are associated with significant postpartum maternal morbidity. Induction of labour should be considered a feasible option in these patients.     

The Collateral Damage of Mass Incarceration: Risk of Psychiatric Morbidity Among Nonincarcerated Residents of High-Incarceration Neighborhoods

Objectives. We examined whether residence in neighborhoods with high levels of incarceration is associated with psychiatric morbidity among nonincarcerated community members.Methods. We linked zip code–linked information on neighborhood prison admissions rates to individual-level data on mental health from the Detroit Neighborhood Health Study (2008–2012), a prospective probability sample of predominantly Black individuals.Results. Controlling for individual- and neighborhood-level risk factors, individuals living in neighborhoods with high prison admission rates were more likely to meet criteria for a current (odds ratio [OR] = 2.9; 95% confidence interval [CI] = 1.7, 5.5) and lifetime (OR = 2.5; 95% CI = 1.4, 4.6) major depressive disorder across the 3 waves of follow-up as well as current (OR = 2.1; 95% CI = 1.0, 4.2) and lifetime (OR = 2.3; 95% CI = 1.2, 4.5) generalized anxiety disorder than were individuals living in neighborhoods with low prison admission rates. These relationships between neighborhood-level incarceration and mental health were comparable for individuals with and without a personal history of incarceration.Conclusions. Incarceration may exert collateral damage on the mental health of individuals living in high-incarceration neighborhoods, suggesting that the public mental health impact of mass incarceration extends beyond those who are incarcerated.The United States leads the world in the percentage of its population that serves time in prison or jail.1,2 As of 2012, nearly 7 million men and women are on probation, parole, or under some other form of community supervision, which means that nearly 3% of the American adult population is currently involved in correctional supervision.3 The burden of incarceration in the United States is not equally distributed in the population. Current estimates from the Bureau of Justice Statistics indicate that 1 of every 3 Black men will serve time in prison in their lifetimes.4 In some communities, these figures are even starker. In Washington, DC, for example, more than 95% of Black men have been in prison in their lifetimes.1 Because of the scope of incarceration within particular subgroups, the current state of the US criminal justice system has been described in such terms as mass imprisonment5 and hyperincarceration.6Research on the health consequences of incarceration falls largely into 2 broad categories. The first, which has received the most empirical attention, has focused on individuals directly involved in the criminal justice system. Individual incarceration exposure is associated with adverse mental7–9 and physical10 health outcomes. A second line of inquiry has evaluated the broader health consequences of incarceration—what has been variously called the “long arm” of corrections,11 the collateral consequences of mass incarceration,5 and “spillover” effects related to incarceration.12 For example, female partners of recently released male prisoners experience depression and anxiety symptoms,13,14 and the children of incarcerated parents are at increased risk for behavioral and mental health problems.15,16 The deleterious health effects of incarceration are not merely confined to the family members of incarcerated individuals, however. Nonincarcerated individuals living in the communities from which inmates are drawn also appear to be at heightened risk for a variety of adverse outcomes, including increased crime rates17 and infectious diseases.18Although this research provides important initial insights into some of the negative consequences of incarceration at the community level, it remains largely unknown whether incarceration influences the mental health of community members who reside in neighborhoods with high-incarceration rates. How might incarceration affect community mental health? High levels of incarceration in neighborhoods can alter the social ecology of communities by eroding social capital and disrupting the kinds of social and family networks and relationships that are necessary for sustaining individuals’ mental health as well as the well-being of communities.1,19–22We examined whether high levels of incarceration in neighborhoods affect the mental health of individuals living in these neighborhoods. We treated incarceration as an ecological or contextual effect, rather than as an individual-level risk factor, which has characterized the majority of research on incarceration and mental health.7,23 That is, rather than examining the mental health consequences of incarceration among those who have themselves been incarcerated or among their family members, we examined the mental health of individuals living in communities that have been exposed to elevated levels of incarceration.     

Results of a Double-Blind,Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as an Adjunctive Therapy in Advanced Cancer Patients with Chronic Uncontrolled Pain

Context

Prior Phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

Sex steroids and odorants modulate gonadotropin-releasing hormone secretion in primary cultures of human olfactory cells

Olfactory neurons and GnRH neurons share a common origin during development. In the nasal epithelia, GnRH neurons persist throughout fetal life and adulthood. The fate and function of these neurons in vivo have remained unknown. In a previous in vitro study, we isolated, cloned, and propagated primary long term cell cultures from the olfactory neuroepithelium of 8- to 12-week-old human fetuses. These cells expressed both neural proteins as well as olfactory genes and were responsive to odorant stimuli. We now report that these human olfactory cells also express the GnRH gene and protein. Combined HPLC and RIA studies have indicated that these cells release authentic GnRH in spent media. The release of GnRH was time dependent and was positively affected by sex steroids and odorants. Immunohistochemical data demonstrated the presence of sex steroid receptors in these cells. The presence of the alpha- and beta-subtypes of the estrogen receptor was also demonstrated by RT-PCR and Western blot analysis. When the cells were stimulated with increasing concentrations of 17beta-estradiol in the presence of a fixed concentration of progesterone (10(-7) mol/L), the combination of the two steroids induced a 3- to 4-fold increase in GnRH secretion. This stimulatory effect was completely blunted by tamoxifen. Neither 17beta-estradiol nor progesterone was effective when tested separately. Treatment with increasing concentrations of the odorant, l-carvone, induced a time- and dose-dependent dramatic increase in GnRH protein release (1000-fold increase) and gene expression. Repeated application of the stimulus resulted in a progressive lower responsiveness of the cells. To our knowledge, this is the first time that primary cell cultures from human fetal olfactory neuroepithelium have been shown to express and release GnRH. Our results also demonstrate that these cultures, which are sensitive to sex steroids and odorants, can be useful models in the study of the complex array of regulatory factors that finely tune GnRH secretion in humans.     

QT-interval prolongation in right precordial leads: an additional electrocardiographic hallmark of Brugada syndrome

OBJECTIVES: The aim of this study was to evaluate whether the occurrence of the Brugada Syndrome typical electrocardiogram (ECG) pattern (i.e., right bundle branch block, coved-type ST-segment elevation, and T-wave inversion in the right precordial leads) is characterized by a concomitant lengthening of QT intervals in the right precordial leads. BACKGROUND: It has been suggested that the typical ECG pattern of Brugada syndrome is due to a decreased net inward current during phase 1 of the action potential, which also leads to its prolongation in the right epicardium. METHODS: Thirty-two subjects (19 males) age 37 +/- 15 years with a suspicious baseline ECG, or who were relatives of Brugada syndrome patients, underwent 12-lead ECG before and after the administration of flecainide. RESULTS: The flecainide test was negative in 14 and positive in 18 subjects. After flecainide administration, the positive ECGs were characterized by a greater QT interval corrected for heart rate (QTc) prolongation in the right precordial leads than that in the negative ECGs (78.2 +/- 35.5 ms vs. 22.0 +/- 28.4 ms in V(1) and 107.1 +/- 43.8 ms vs. 26.7 +/- 30.1 ms in V(2); p < 0.01), whereas there was no difference in the QTc prolongation in the left precordial leads (55.2 +/- 25.3 ms vs. 35.1 +/- 28.1 ms in V(5) and 53.1 +/- 32.8 ms vs. 27.3 +/- 22.4 ms in V(6); p = NS). CONCLUSIONS: In accordance with the electrophysiological background, the typical ECG pattern of Brugada syndrome is also characterized by a considerable prolongation of the QT interval in right precordial leads.