Predictors of PTSD 40 years after combat: Findings from the National Vietnam Veterans longitudinal study.

BACKGROUND: Few studies have longitudinally examined predictors of posttraumatic stress disorder (PTSD) in a nationally representative sample of US veterans. We examined predictors of warzone-related PTSD over a 25-year span using data from the National Vietnam Veterans Longitudinal Study (NVVLS). METHODS: The NVVLS is a follow-up study of Vietnam theater veterans (N = 699) previously assessed in the National Vietnam Veterans Readjustment Study (NVVRS), a large national-probability study conducted in the late 1980s. We examined the ability of 22 premilitary, warzone, and postmilitary variables to predict current warzone-related PTSD symptom severity and PTSD symptom change in male theater veterans participating in the NVVLS. Data included a self-report Health Questionnaire survey and a computer-assisted telephone Health Interview Survey. Primary outcomes were self-reported PTSD symptoms assessed by the PTSD Checklist for DSM-5 (PCL 5) and Mississippi PTSD Scale (M-PTSD). RESULTS: Predictors of current PTSD symptoms most robust in hierarchical multivariable models were African-American race, lower education level, negative homecoming reception, lower current social support, and greater past-year stress. PTSD symptoms remained largely stable over time, and symptom exacerbation was predicted by African-American race, lower education level, younger age at entry into Vietnam, greater combat exposure, lower current social support, and greater past-year stressors. CONCLUSIONS: Findings confirm the robustness of a select set of risk factors for warzone-related PTSD, establishing that these factors can predict PTSD symptom severity and symptom change up to 40 years postdeployment.

The influence of different criteria for establishing optimal cutoff scores on performance of two self-report measures for warzone PTSD.

Posttraumatic stress disorder (PTSD) has been regarded as a signature injury of war and elevated to one of the major behavioral health problems faced by military service members and veterans deployed to warzones. In PTSD diagnosis, self-report measures have often been used with a cutoff score to identify those with an elevated likelihood of having PTSD prior to conducting a second-tier diagnostic interview. With an attempt to guide the selection of cutoffs in self-report PTSD measures for various purposes, this study examined how five common criteria for establishing an optimal cutoff influenced the performance of self-report measures for warzone PTSD in relation to the Clinician Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) and whether the influence differed for the PTSD Checklist for DSM-5 and the Mississippi Scale for Combat-Related PTSD. Using a probability sample of Vietnam theater veterans in the National Vietnam Veterans Longitudinal Study, results showed that in both self-report measures, the Youden Index criterion yielded the optimal cutoff that led to better test performance. (PsycINFO Database Record

PTSD and Use of Outpatient General Medical Services Among Veterans of the Vietnam War.

OBJECTIVE: The primary goal of this analysis was to assess whether recent use of outpatient services for general medical concerns by Vietnam veterans varies according to level of posttraumatic stress disorder (PTSD) symptomatology over time. Another goal was to determine whether PTSD symptomatology was associated with veterans' reports of discussing behavioral health issues as part of a general medical visit. METHODS: Self-reported service use data and measures of PTSD were from a nationally representative sample of 848 male and female Vietnam theater veterans (individuals who were deployed to the Vietnam theater of operations) who participated in the National Vietnam Veterans Longitudinal Study, a 25-year follow-up of a cohort of veterans originally interviewed from 1984-1988 as part of the National Vietnam Veterans Readjustment Study. Four categories of PTSD symptomatology course over 25 years were defined, and logistic regression models were used to assess their relationship with recent use of outpatient general medical services. RESULTS: Male and female theater veterans with high or increasing PTSD symptomatology over the period were more likely than those with low symptomatology to report recent VA outpatient visits. Males in the increasing and high categories were also more likely to discuss behavioral health issues at general medical visits. CONCLUSIONS: Vietnam veterans with high and increasing PTSD symptomatology over time were likely to use VA outpatient general health services. Attention to stressors of the aging process and to persistence of PTSD symptoms is important for Vietnam veterans, as is addressing PTSD with other psychiatric and medical comorbidities within the context of outpatient general medical care.

Course of Posttraumatic Stress Disorder 40 Years After the Vietnam War: Findings From the National Vietnam Veterans Longitudinal Study.

IMPORTANCE: The long-term course of readjustment problems in military personnel has not been evaluated in a nationally representative sample. The National Vietnam Veterans Longitudinal Study (NVVLS) is a congressionally mandated assessment of Vietnam veterans who underwent previous assessment in the National Vietnam Veterans Readjustment Study (NVVRS). OBJECTIVE: To determine the prevalence, course, and comorbidities of war-zone posttraumatic stress disorder (PTSD) across a 25-year interval. DESIGN, SETTING, AND PARTICIPANTS: The NVVLS survey consisted of a self-report health questionnaire (n = 1409), a computer-assisted telephone survey health interview (n = 1279), and a telephone clinical interview (n = 400) in a representative national sample of veterans who served in the Vietnam theater of operations (theater veterans) from July 3, 2012, through May 17, 2013. Of 2348 NVVRS participants, 1920 were alive at the outset of the NVVLS, and 81 died during recruitment; 1450 of the remaining 1839 (78.8%) participated in at least 1 NVVLS study phase. Data analysis was performed from May 18, 2013, through January 9, 2015, with further analyses continued through April 13, 2015. MAIN OUTCOMES AND MEASURES: Study instruments included the Mississippi Scale for Combat-Related PTSD, PTSD Checklist for DSM-IV supplemented with PTSD Checklist for DSM-5 items (PCL-5+), Clinician-Administered PTSD Scale for DSM-5 (CAPS-5), and Structured Clinical Interview for DSM-IV, Nonpatient Version. RESULTS: Among male theater veterans, we estimated a prevalence (95% CI) of 4.5% (1.7%-7.3%) based on CAPS-5 criteria for a current PTSD diagnosis; 10.8% (6.5%-15.1%) based on CAPS-5 full plus subthreshold PTSD; and 11.2% (8.3%-14.2%) based on PCL-5+ criteria for current war-zone PTSD. Among female veterans, estimates were 6.1% (1.8%-10.3%), 8.7% (3.8%-13.6%), and 6.6% (3.5%-9.6%), respectively. The PCL-5+ prevalence (95% CI) of current non-war-zone PTSD was 4.6% (2.6%-6.6%) in male and 5.1% (2.3%-8.0%) in female theater veterans. Comorbid major depression occurred in 36.7% (95% CI, 6.2%-67.2%) of veterans with current war-zone PTSD. With regard to the course of PTSD, 16.0% of theater veterans reported an increase and 7.6% reported a decrease of greater than 20 points in Mississippi Scale for Combat-Related PTSD symptoms. The prevalence (95% CI) of current PCL-5+-derived PTSD in study respondents was 1.2% (0.0%-3.0%) for male and 3.9% (0.0%-8.1%) for female Vietnam veterans. CONCLUSIONS AND RELEVANCE: Approximately 271,000 Vietnam theater veterans have current full PTSD plus subthreshold war-zone PTSD, one-third of whom have current major depressive disorder, 40 or more years after the war. These findings underscore the need for mental health services for many decades for veterans with PTSD symptoms.

Ecto-nucleoside triphosphate diphosphohydrolase 2 modulates local ATP-induced calcium signaling in human HaCaT keratinocytes.

Keratinocytes are the major building blocks of the human epidermis. In many physiological and pathophysiological conditions, keratinocytes release adenosine triphosphate (ATP) as an autocrine/paracrine mediator that regulates cell proliferation, differentiation, and migration. ATP receptors have been identified in various epidermal cell types; therefore, extracellular ATP homeostasis likely determines its long-term, trophic effects on skin health. We investigated the possibility that human keratinocytes express surface-located enzymes that modulate ATP concentration, as well as the corresponding receptor activation, in the pericellular microenvironment. We observed that the human keratinocyte cell line HaCaT released ATP and hydrolyzed extracellular ATP. Interestingly, ATP hydrolysis resulted in adenosine diphosphate (ADP) accumulation in the extracellular space. Pharmacological inhibition by ARL 67156 or gene silencing of the endogenous ecto-nucleoside triphosphate diphosphohydrolase (NTPDase) isoform 2 resulted in a 25% reduction in both ATP hydrolysis and ADP formation. Using intracellular calcium as a reporter, we found that although NTPDase2 hydrolyzed ATP and generated sustainable ADP levels, only ATP contributed to increased intracellular calcium via P2Y2 receptor activation. Furthermore, knocking down NTPDase2 potentiated the nanomolar ATP-induced intracellular calcium increase, suggesting that NTPDase2 globally attenuates nucleotide concentration in the pericellular microenvironment as well as locally shields receptors in the vicinity from being activated by extracellular ATP. Our findings reveal an important role of human keratinocyte NTPDase2 in modulating nucleotide signaling in the extracellular milieu of human epidermis.

Costars, a Dictyostelium protein similar to the C-terminal domain of STARS, regulates the actin cytoskeleton and motility.

Through analysis of a chemotaxis mutant obtained from a genetic screen in Dictyostelium discoideum, we have identified a new gene involved in regulating cell migration and have named it costars (cosA). The 82 amino acid Costars protein sequence appears highly conserved among diverse species, and significantly resembles the C-terminal region of the striated muscle activator of Rho signaling (STARS), a mammalian protein that regulates the serum response factor transcriptional activity through actin binding and Rho GTPase activation. The cosA-null (cosA(-)) cells formed smooth plaques on bacterial lawns, produced abnormally small fruiting bodies when developed on the non-nutrient agar and displayed reduced migration towards the cAMP source in chemotactic assays. Analysis of cell motion in cAMP gradients revealed decreased speed but wild-type-like directional persistence of cosA(-) cells, suggesting a defect in the cellular machinery for motility rather than for chemotactic orientation. Consistent with this notion, cosA(-) cells exhibited changes in the actin cytoskeleton, showing aberrant distribution of F-actin in fluorescence cell staining and an increased amount of cytoskeleton-associated actin. Excessive pseudopod formation was also noted in cosA(-) cells facing chemoattractant gradients. Expressing cosA or its human counterpart mCostars eliminated abnormalities of cosA(-) cells. Together, our results highlight a role for Costars in modulating actin dynamics and cell motility.

Locomotion guidance by extracellular matrix is adaptive and can be restored by a transient change in Ca2+ level.

Navigation of cell locomotion by gradients of soluble factors can be desensitized if the concentration of the chemo-attractant stays unchanged. It remains obscure if the guidance by immobilized extracellular matrix (ECM) as the substrate is also adaptive and if so, how can the desensitized ECM guidance be resensitized. When first interacting with a substrate containing micron-scale fibronectin (FBN) trails, highly motile fish keratocytes selectively adhere and migrate along the FBN paths. However, such guided motion become adaptive after about 10 min and the cells start to migrate out of the ECM trails. We found that a burst increase of intracellular calcium created by an uncaging technique immediately halts the undirected migration by disrupting the ECM-cytoskeleton coupling, as evidenced by the appearance of retrograde F-actin flow. When the motility later resumes, the activated integrin receptors render the cell selectively binding to the FBN path and reinitiates signaling events, including tyrosine phosphorylation of paxillin, that couple retrograde F-actin flow to the substrate. Thus, the calcium-resensitized cell can undergo a period of ECM-navigated movement, which later becomes desensitized. Our results also suggest that endogenous calcium transients as occur during spontaneous calcium oscillations may exert a cycling resensitization-desensitization control over cell's sensing of substrate guiding cues.

Structural and catalytic studies of lithium complexes bearing pendant aminophenolate ligands.

Lithium complexes bearing mono-anionic aminophenolate ligands are described. Reactions of ligand precursors HON(Me)Ph(OMe), HON(Me)Ph(SMe), HON(Me)C(OMe) or HON(Me)C(NMe2) [HON(Me)Ph(OMe) = (2-OMeC6H4CH2)N(Me)(CH2-2-HO-3,5-C6H2((t)Bu)2); HON(Me)Ph(SMe)= (2-SMe-C6H4CH2)N(Me)(CH2-2-HO-3,5-C6H2((t)Bu)2); HON(Me)C(OMe) = (MeOCH(2)CH2)N(Me)(CH2-2-HO-3,5-C6H2((t)Bu)2); HON(Me)C(NMe2) = (Me2NCH2CH2)N(Me)(CH2-2-HO-3,5-C6H2((t)Bu)2)] with 1.1-1.3 molar equivalents of (n)BuLi in diethyl ether solution afford (LiON(Me)Ph(OMe))(2) (3), (LiON(Me)Ph(SMe))2 (4), (LiON(Me)C(OMe))2 (5) and (LiON(Me)C(NMe2))2 (6) as dinuclear lithium complexes. The BnOH adduct of , (BnOH)(LiON(Me)C(OMe)) (7), was prepared from the reaction of and BnOH in diethyl ether solution. The molecular structures are reported for ligand precursor HON(Me)Ph(SMe) and compounds 3-5 and 7. These dinuclear lithium complexes show excellent catalytic activities toward the ring-opening polymerization of L-lactide in the presence of benzyl alcohol.

High-resolution simultaneous three-photon fluorescence and third-harmonic-generation microscopy.

In recent years, nonlinear laser scanning microscopy has gained much attention due to its unique ability of deep optical sectioning. Based on our previous studies, a 1,200-1,300-nm femtosecond laser can provide superior penetration capability with minimized photodamage possibility. However, with the longer wavelength excitation, three-photon-fluorescence (3PF) would be necessary for efficient use of intrinsic and extrinsic visible fluorophores. The three-photon process can provide much better spatial resolution than two-photon-fluorescence due to the cubic power dependency. On the other hand, third-harmonic-generation (THG), another intrinsic three-photon process, is interface-sensitive and can be used as a general structural imaging modality to show the exact location of cellular membranes. The virtual-transition characteristic of THG prevents any excess energy from releasing in bio-tissues and, thus, THG acts as a truly noninvasive imaging tool. Here we demonstrated the first combined 3PF and THG microscopy, which can provide three-dimensional high-resolution images with both functional molecule specificity and sub-micrometer structural mapping capability. The simultaneously acquired 3PF and THG images based on a 1,230-nm Cr:forsterite femtosecond laser are shown with a Hoechst-labeled hepatic cell sample. Strong 3PF around 450 nm from DNA-bounded Hoechst-33258 can be observed inside each nucleus while THG reveals the location of plasma membranes and other membrane-based organelles such as mitochondria. Considering that the maximum-allowable laser power in common nonlinear laser microscopy is less than 10 mW at 800 nm, it is remarkable that even with a 100-mW 1,230-nm incident power, there is no observable photo damage on the cells, demonstrating the noninvasiveness of this novel microscopy technique.

Intercellular calcium waves mediate preferential cell growth toward the wound edge in polarized hepatic cells.

During liver regeneration, hepatocytes sense the damage and initiate proliferation of the quiescent cells through poorly understood mechanisms. Here, we have used cultured hepatic cells to study the roles played by intercellular calcium in mediating wound-healing processes. Well-differentiated and polarized Hep-G2 cells repaired an experimentally induced wound by induction of cell divisions. The resulting cellular growth did not occur evenly across the healing cell lawn; instead, proliferations were three times more active within 150-200 microm from the wound edge than further away; this periwound preferential cell growth was not observed in the poorly differentiated and/or nonpolarized cells. We have provided experimental evidence demonstrating that the wounding procedure itself could elicit a propagating calcium wave, and interestingly, blocking this injury-associated intercellular calcium communication could effectively inhibit the biased cell growth along the margin of the wound. A photolithography-based patterned cell culture system was employed to help delineate the mechanisms underlying this type of calcium signaling. In conclusion, our results suggested that intercellular communications via propagating calcium waves coordinate regenerative cell proliferations in response to hepatic tissue losses.