Associations between Lifetime Traumatic Events and Subsequent Chronic Physical Conditions: A Cross-National,Cross-Sectional Study

Background

Associations between lifetime traumatic event (LTE) exposures and subsequent physical ill-health are well established but it has remained unclear whether these are explained by PTSD or other mental disorders. This study examined this question and investigated whether associations varied by type and number of LTEs, across physical condition outcomes, or across countries.

Methods

Cross-sectional, face-to-face household surveys of adults (18+) were conducted in 14 countries (n = 38, 051). The Composite International Diagnostic Interview assessed lifetime LTEs and DSM-IV mental disorders. Chronic physical conditions were ascertained by self-report of physician''s diagnosis and year of diagnosis or onset. Survival analyses estimated associations between the number and type of LTEs with the subsequent onset of 11 physical conditions, with and without adjustment for mental disorders.

Findings

A dose-response association was found between increasing number of LTEs and odds of any physical condition onset (OR 1.5 [95% CI: 1.4–1.5] for 1 LTE; 2.1 [2.0–2.3] for 5+ LTEs), independent of all mental disorders. Associations did not vary greatly by type of LTE (except for combat and other war experience), nor across countries. A history of 1 LTE was associated with 7/11 of the physical conditions (ORs 1.3 [1.2–1.5] to 1.7 [1.4–2.0]) and a history of 5+ LTEs was associated with 9/11 physical conditions (ORs 1.8 [1.3–2.4] to 3.6 [2.0–6.5]), the exceptions being cancer and stroke.

Conclusions

Traumatic events are associated with adverse downstream effects on physical health, independent of PTSD and other mental disorders. Although the associations are modest they have public health implications due to the high prevalence of traumatic events and the range of common physical conditions affected. The effects of traumatic stress are a concern for all medical professionals and researchers, not just mental health specialists.     

Stromal progenitors are important for patterning epithelial and mesenchymal cell types in the embryonic kidney

Growth and expansion of the embryonic kidney is driven in large part by continuous branching morphogenesis and nephron induction that occurs in a restricted domain beneath the renal capsule called the nephrogenic zone. Here, new ureteric bud branches and nephron aggregates form surrounded by a layer of cortical stromal cell progenitors. The boundaries and inductive activities of the nephrogenic zone are maintained as the kidney grows. As new ureteric bud branches and nephrogenic aggregates form, older generations of ureteric bud branches, renal vesicles and stromal progenitors are displaced from the nephrogenic zone and undergo further differentiation surrounded by medullary stroma, a different population of stromal cells. Recent studies suggest that cortical and medullary stromal progenitors may be an important source of signals that maintain outer and inner zones of differentiation in the embryonic kidney, and regulate distinct events important for differentiation of nephrons and the collecting duct system.     

Building excitatory and inhibitory synapses: balancing neuroligin partnerships

Processing of neural information is thought to occur by integration of excitatory and inhibitory synaptic inputs. As such, precise control mechanisms must exist to maintain an appropriate balance between each synapse type. Recent findings indicate that neuroligins and their synaptic binding partners modulate the development of both excitatory and inhibitory synapses. Here we highlight these findings and discuss a mechanism potentially involved in controlling the balance between excitation and inhibition.     

Polymorphisms in the trace amine receptor 4 (TRAR4) gene on chromosome 6q23.2 are associated with susceptibility to schizophrenia

Several linkage studies across multiple population groups provide convergent support for a susceptibility locus for schizophrenia--and, more recently, for bipolar disorder--on chromosome 6q13-q26. We genotyped 192 European-ancestry and African American (AA) pedigrees with schizophrenia from samples that previously showed linkage evidence to 6q13-q26, focusing on the MOXD1-STX7-TRARs gene cluster at 6q23.2, which contains a number of prime candidate genes for schizophrenia. Thirty-one screening single-nucleotide polymorphisms (SNPs) were selected, providing a minimum coverage of at least 1 SNP/20 kb. The association observed with rs4305745 (P=.0014) within the TRAR4 (trace amine receptor 4) gene remained significant after correction for multiple testing. Evidence for association was proportionally stronger in the smaller AA sample. We performed database searches and sequenced genomic DNA in a 30-proband subsample to obtain a high-density map of 23 SNPs spanning 21.6 kb of this gene. Single-SNP analyses and also haplotype analyses revealed that rs4305745 and/or two other polymorphisms in perfect linkage disequilibrium (LD) with rs4305745 appear to be the most likely variants underlying the association of the TRAR4 region with schizophrenia. Comparative genomic analyses further revealed that rs4305745 and/or the associated polymorphisms in complete LD with rs4305745 could potentially affect gene expression. Moreover, RT-PCR studies of various human tissues, including brain, confirm that TRAR4 is preferentially expressed in those brain regions that have been implicated in the pathophysiology of schizophrenia. These data provide strong preliminary evidence that TRAR4 is a candidate gene for schizophrenia; replication is currently being attempted in additional clinical samples.     

c-kit delineates a distinct domain of progenitors in the developing kidney

Early inductive events in mammalian nephrogenesis depend on an interaction between the ureteric bud and the metanephric mesenchyme. However, mounting evidence points towards an involvement of additional cell types--such as stromal cells and angioblasts--in growth and patterning of the nephron. In this study, through analysis of the stem cell factor (SCF)/c-kit ligand receptor pair, we describe an additional distinct cell population in the early developing kidney. While SCF is restricted to the ureteric bud, c-kit-positive cells are located within the renal interstitium, but are negative for Foxd1, an established marker of stromal cells. In fact, the c-kit-positive domain is continuous with a central mesodermal cell mass ventral and lateral to the dorsal aorta, while Foxd1-expressing stromal cells are continuous with a dorsal perisomitic cell population suggesting distinct intraembryonic origins for these cell types. A subset of c-kit-positive cells expresses Flk-1 and podocalyxin, suggesting that this cell population includes angioblasts and their progenitors. c-kit activation is not required for the survival of these cells in vivo, because white spotting (c-kit(W/W)) mice, carrying a natural inactivating mutation of c-kit, display normal intrarenal distribution of the c-kit-positive cells at E13.5. In addition, early kidney development in these mutants is preserved up to the stage when anemia compromises global embryonic development. In contrast, under defined conditions in organ cultures of metanephric kidneys, c-kit-positive cells, including the Flk-1-positive subset, undergo apoptosis after treatment with STI-571, an inhibitor of c-kit tyrosine phosphorylation. This is associated with reductions in ureteric bud branching and nephron number. Conversely, exogenous SCF expands the c-kit-positive population, including Flk-1-positive angioblasts, and accelerates kidney development in vitro. These data suggest that ureteric bud-derived SCF elicits growth-promoting effects in the metanephric kidney by expanding one or more components of the interstitial c-kit-positive progenitor pool.     

Fibrinogen is a co-antioxidant that supplements the vitamin E analog trolox in a model system

Objective: It appears that the atherosclerotic plaque is a prooxidant environment where some molecules that are normally antioxidants, including vitamins C and E, may act as prooxidants that contribute to atherosclerosis by oxidizing LDL. Some molecules can act as co-antioxidants to eliminate this prooxidant effect by recycling or other mechanisms of supplementation. Fibrinogen and other acute phase proteins found in the plaque are antioxidants. We hypothesized that fibrinogen can act as a co-antioxidant to supplement vitamin E thereby eliminating its oxidative effect under prooxidant conditions. We tested a model system for this hypothesis using the vitamin E analogue Trolox in a cell free system.

Methods: LDL was oxidized using 5 umol/l copper. Antioxidant conditions were achieved by adding the antioxidants immediately with LDL, while prooxidant conditions were created by adding antioxidants after a 40 min delay. Oxidation was monitored as the lag phase at 234 nm.

Results: Under antioxidant conditions, the protective effect of fibrinogen and Trolox combined together were about equal to the sum of the anitioxidant effects of each alone (additive), while under prooxidant conditions the combined protection was 54-200% greater (synergistic). These effects were different than those of vitamin C with Trolox in that under antioxidant conditions fibrinogen and Trolox were additive while vitamin C and Trolox showed strong synergistic effects, and in that unlike vitamin C and Trolox fibrinogen showed no prooxidant tendencies under prooxidant reaction conditions.

Conclusions: The data indicated that fibrinogen did act as a co-antioxidant to supplement Trolox and eliminate its prooxidant effect, most probably, by directly quenching the phenoxyl radical, because unlike vitamin C, fibrinogen did not appear to recycle vitamin E. But fibrinogen may act as a universal antioxidant, since unlike Trolox and vitamin C, it showed little tendency toward becoming a prooxidant.