Innate immune inflammatory cell death: PANoptosis and PANoptosomes in host defense and disease

Regulated cell death (RCD) triggered by innate immune activation is an important strategy for host survival during pathogen invasion and perturbations of cellular homeostasis. There are two main categories of RCD, including nonlytic and lytic pathways. Apoptosis is the most well-characterized nonlytic RCD, and the inflammatory pyroptosis and necroptosis pathways are among the best known lytic forms. While these were historically viewed as independent RCD pathways, extensive evidence of cross-talk among their molecular components created a knowledge gap in our mechanistic understanding of RCD and innate immune pathway components, which led to the identification of PANoptosis. PANoptosis is a unique innate immune inflammatory RCD pathway that is regulated by PANoptosome complexes upon sensing pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs) or the cytokines produced downstream. Cytosolic innate immune sensors and regulators, such as ZBP1, AIM2 and RIPK1, promote the assembly of PANoptosomes to drive PANoptosis. In this review, we discuss the molecular components of the known PANoptosomes and highlight the mechanisms of PANoptosome assembly, activation and regulation identified to date. We also discuss how PANoptosomes and mutations in PANoptosome components are linked to diseases. Given the impact of RCD, and PANoptosis specifically, across the disease spectrum, improved understanding of PANoptosomes and their regulation will be critical for identifying new therapeutic targets and strategies.     

Somatic symptoms,pain, catastrophizing and the association with disability among children with heritable connective tissue disorders

The aim of the present study was to investigate the nature and prevalence of nonspecific somatic symptoms, pain and catastrophizing in children with Heritable Connective Tissue Disorders (HCTD), and to determine their association with disability. This observational, multicenter study included 127 children, aged 4–18 years, with Marfan syndrome (MFS) (59%), Loeys-Dietz syndrome (LDS) (8%), Ehlers-Danlos syndromes (EDS) (12%) and hypermobile Ehlers-Danlos syndrome (hEDS) (23%). The assessments included the Children's Somatization Inventory or parent proxy (CSI, PCSI), pain visual-analogue scale (VAS), SUPERKIDZ body diagram, Pain Catastrophizing Scale Child or parent proxy (PCS-C, PCS-P) and Childhood Health Assessment Questionnaire (CHAQ-30). Data from children aged ≥8 years were compared to normative data. In children ≥ 8 years (n = 90), pain was present in 59%, with a median of 4 (IQR = 3–9) pain areas. Compared to normative data, the HCTD group reported significantly higher on the CSI (p ≤ 0.001, d = 0.85), VAS pain intensity (p ≤ 0.001, d = 1.22) and CHAQ-30 (p ≤ 0.001, d = 1.16) and lower on the PCS-C (p = 0.017, d = −0.82) and PCS-P (p ≤ 0.001, d = −0.49). The intensity of nonspecific somatic symptoms and pain explained 45% of the variance in disability (r² = 0.45 F(2,48) = 19.70, p ≤ 0.001). In children ≤ 7 years (n = 37), pain was present in 35% with a median of 5(IQR = 1–13) pain areas. The mean(SD) VAS scores for pain intensity was 1.5(2.9). Functional disability was moderately correlated to the number of pain areas (r = 0.56, p ≤ 0.001), intensity of nonspecific somatic symptoms (r = 0.63, p ≤ 0.001) and pain (r = 0.83, p ≤ 0.001). In conclusion, this study supports the need for comprehensive assessment of nonspecific somatic symptoms, pain, and disability in children with HCTD to allow tailored treatment.     

Associations between reproductive and menstrual factors and postmenopausal sex hormone concentrations.

Reproductive and menstrual characteristics, as well as high circulating estrogen concentrations, are associated with risk of hormone-related cancers in postmenopausal women. To explore possible etiologic relationships between menstrual/reproductive characteristics and risk of hormone-related cancers, we examined associations between menstrual/reproductive factors and serum concentrations of free estradiol, total estradiol, estrone, sex hormone binding globulin (SHBG), and follicle stimulating hormone (FSH). This study was conducted in 173 postmenopausal women using data from the prerandomization visit of an exercise clinical trial. Participants were sedentary, overweight/obese, and not on hormone therapy. Women > or =20 years past menopause had 23% lower total estradiol and 30% lower free estradiol concentrations than women within 4 years of menopause (P for trend = 0.04 and 0.02, respectively). Nulliparous women had 19% higher FSH concentrations than parous women (P = 0.02). Among parous women, parity was positively associated with SHBG and negatively associated with free estradiol concentrations. Women with > or =4 children had 20% lower free estradiol and 38% higher SHBG concentrations compared with women with one birth (P for trend = 0.02 and 0.01, respectively). Total number of months spent breast-feeding was modestly and inversely associated with serum FSH concentrations (P for trend = 0.07). Our results suggest that menstrual/reproductive characteristics may be associated with postmenopausal hormone concentrations; verification of these results in other studies may elucidate how these variables influence risk of hormone-related cancers.     

An Investigation of the Impact of Posttraumatic Stress Disorder on Physical Health

In a large sample of Gulf War veterans (N = 2301) we examined the relations between PTSD symptoms assessed immediately upon returning from the Gulf War and self-reported health problems assessed 18–24 months later. PTSD symptomatology was predictive of self-reported health problems over time for both men and women veterans, even after the effects of combat exposure were removed from the analysis. Female veterans reported significantly more health problems than male veterans, however, there was no interactive effect of gender and PTSD on health problems. These findings provide further support for the theory that psychological response to stressors impacts health outcome.     

Suicide risk and mental health indicators: Do they differ by abuse and HIV status?

PURPOSE: This study examines the association between women's HIV serostatus, intimate partner violence (IPV) experience, and risk of suicide and other mental health indicators. Using data from Project WAVE (Women, AIDS, and the Violence Epidemic), we 1) describe the rates of suicidal thoughts and attempts, anxiety, and depression; 2) examine whether and to what extent these outcomes differ by women's HIV and IPV status. METHODS: A one-time interview was conducted with a sample 611 women living in an urban area, one-half of whom were HIV-positive. RESULTS: Having thought about suicide was reported by 31% of the sample and 16% reported having attempted suicide. Among HIV-positive women, thoughts of suicide occurred more frequently among those who were recently diagnosed. One-half of the sample reported problems with depression, and 26% reported problems with anxiety; of women reporting these problems, 56% received mental health treatment. Rates varied significantly by HIV and IPV status, with women who were both HIV-positive and abused consistently faring worse. Relative to HIV-negative non-abused women, HIV-positive abused women were 7.0 times as likely to report problems with depression, 4.9 times as likely to report problems with anxiety, 3.6 times as likely to have thought about suicide, and 12.5 times as likely to have ever attempted suicide. Our findings that abused HIV-negative women were also at significantly elevated risk for all of these outcomes lends support to the conclusion that it is the experience of abuse that is associated with the negative outcomes. CONCLUSIONS: Health care and service providers interacting with women who may be HIV-positive and/or in abusive relationships should routinely assess for mental health status, especially suicide risk, which may need crisis intervention.     

Reorganizing the system of care surrounding laparoscopic surgery: a cost-effectiveness analysis using discrete-event simulation.

PURPOSE: To determine the cost-effectiveness of a proposed reorganization of surgical and anesthesia care to balance patient volume and safety. METHODS: Discrete-event simulation methods were used to compare current surgical practice with a new modular system in which patient care is handed off between 2 anesthesiologists. A health care system's perspective, using hospital and professional costs, was chosen for the cost-effectiveness analysis. Outcomes were patient throughput, flow time, wait time, and resource use. Sensitivity analyses were performed on staffing levels, mortality rates, process times, and scheduled patient volume. RESULTS: The new strategy was more effective (average 4.41 patients/d [median = 5] v. 4.29 [median = 4]) and had similar costs (average cost/ patient/d = 5327 dollars v. 5289 dollars) to the current strategy with an incremental cost-effectiveness of 318 dollars/additional patient treated/d. Surgical mortality rate must be >4% or hand-off delay >15 min before the new strategy is no longer more effective. CONCLUSION: The proposed system is more cost-effective relative to current practice over a wide range of mortality rates, hand-off times, and scheduled patient volumes.     

Alcohol use and abuse by adolescents: the impact of living in a border community.

PURPOSE: To determine the rates of alcohol consumption and alcohol-related risk behaviors among a sample of high school students living on the U.S.-Mexico border, as well as to investigate factors associated with alcohol use among this population. METHODS: A self-administered anonymous questionnaire was administered to students in grades 9-12 during Fall and Spring semesters of 2001 (n = 1366; 639 males and 722 females) in 16 high schools in a community along the U.S.-Mexico border. The questionnaire addressed demographic factors, alcohol consumption, and alcohol-related behaviors. Surveys were completed by Chi-square tests for homogeneity of the odds ratio and logistic regression models were used to identify factors significantly associated with the outcome variables. RESULTS: Rates of binge drinking (45%), drinking and driving (19%), and riding with a driver who had been drinking (46%) were higher for our study population when compared with state and national rates. Students who consumed alcohol were more likely to report alcohol-related problems and lower academic grades. Drinking while in Mexico was significantly associated with binge drinking (OR = 6.44), drinking and driving (OR = 5.39), and riding with a driver who has been drinking (OR = 3.12). CONCLUSIONS: The high rates of alcohol risk behaviors among students living on the U.S.-Mexico border underscore the need to develop and implement culturally appropriate prevention programs that address alcohol consumption in Mexico, particularly in terms of students driving back home.     

Maternal mortality: a twenty-year survey at the King Faisal University Hospital, Al-Khobar, Eastern Saudi Arabia.

This was an institutional study of all maternal deaths that occurred among 56422 total births at the King Faisal University Hospital, Al-Khobar, Saudi Arabia, between 1983 and 2002. The underlying cause of each maternal death and potentially avoidable factors were analysed. There were 16 maternal deaths in the hospital during the study period, giving a maternal mortality rate of 28.4/100,000 births. The leading cause of death was haemorrhage in seven (43.75%) patients, followed by pulmonary embolism in four (25%) and general anaesthesia in two (12.5%) mothers. The risk factors noted were maternal age 35 years and parity 5 coupled with iron deficiency anaemia. The main avoidable factors were failure of the patients to seek timely medical care and to follow medical advice. More than half the number of direct obstetrical causes of death was thought to be preventable. A rapidly changing attitude of women towards childbirth is occurring through progressively increasing female education and community health programmes in the region. Further reduction of maternal mortality rates in the community is envisaged through greater patient acceptance of medical advice, family spacing and proficient obstetric services.