Survivors of war in northern Kosovo (III): The role of anger and hatred in pain and PTSD and their interactive effects on career outcome, quality of sleep and suicide ideation

ABSTRACT: BACKGROUND: The management of chronic debilitating health conditions after trauma remains a challenge in post-conflict settings. The study aimed to expand current understanding of the diagnostic overlap of pain and PTSD and explore their independent and interactive effect on career change, sleep disorder and suicide ideation. The role of anger and hatred as contributing factors to the persistence of pain and PTSD were also examined. METHODS: 125 victims of torture and massive violence identified in a household survey took part in the in-depth assessment. Socio-demographic data and information on trauma, emotional disturbance, injuries and medication history were collected. PTSD was diagnosed according to DSM-IV criteria. Pain was assessed using the McGill Pain Questionnaire and the Margolis Pain Diagram. RESULTS: Nearly 95% participants experienced pain during the last 2 weeks, 47% were diagnosed with PTSD, 50% were taking medication against depression and anxiety. There is substantial overlap of pain, PTSD and emotional disturbance. Injury history, PTSD and negative emotions were related to the pain score and the number of pain locations. Anger, hatred or an inferiority complex particularly amplified pain experience. Headache was constant and especially prevalent in those with recent experience of anger, aggressiveness and hatred. The risk of having chest and abdominal pain within 2 weeks was very high in those who had chest injury and had recently been crying. An increased risk of changing jobs or stopping work or schooling due to depression or injury was observed for those with a higher pain score, and for pain in neck, shoulder and upper limbs. The prevalence of sleep disorders was 80%, that of suicide ideation 70%, and these were found to be associated with greater pain and anger. PTSD was also related to suicide ideation. CONCLUSIONS: The findings provide an overview of pain characteristics in individuals with PTSD and injury and confirm the hypothesized effects on career outcome, sleep disorders and suicide ideation. The study revealed a high level of persistent anger and hatred. The findings suggest the need for new approaches to rehabilitation in a post-war setting, including ways in which to address collective emotional hurt in the society.     

Thermodynamic properties of hyperpolarization-activated current (Ih) in a subgroup of primary sensory neurons

Ih is a poorly selective cation current that activates upon hyperpolarization, present in various types of neurons. Our aim was to perform a detailed thermodynamic analysis of Ih gating kinetics, in order to assess putative structural changes associated with its activation and deactivation. To select dorsal root ganglia neurons that exhibit large Ih, we applied a current signature method by Petruska et al. (J Neurophysiol 84:2365–2379, 2000) and found appropriate neurons in cluster 4. Currents elicited by 3,000-ms hyperpolarizing pulses at 25 and 33°C were fitted with double exponential functions, yielding time constants similar to those of HCN1. The fast activation and deactivation rates showed temperature coefficients (Q ₁₀) of 2.9 and 3.1, respectively, while Q ₁₀ of the absolute conductance was 1.3. Using the Arrhenius–Eyring formalism we computed heights of voltage-independent Gibbs free energy and entropy barriers for each rate. The free energy barriers of the fast rates were just ∼2RT units lower than those of the corresponding slow rates (31.3 vs. 33.2RT for activation, and 24.7 vs. 25.8RT for deactivation, at 25°C). Interestingly, the entropy barriers of the slow rates were negative: −15.2R units for activation and −11.9R units for deactivation, compared to 4.6 and 1.3R units, respectively, for the fast component. The equivalent gating charge (z _g) (3.75 ± 0.32, mean ± SEM, at 25°C) and half-activation potential (V _1/2) (−70.0 ± 1.3 mV at 25°C) did not vary significantly with temperature.     

Interleukin-4, interleukin-10, and interleukin-1-receptor antagonist but not transforming growth factor-beta induce ramification and reduce adhesion molecule expression of rat microglial cells

The activity of microglial cells is strictly controlled in order to maintain central nervous system (CNS) immune privilege. We hypothesized that several immunomodulatory factors present in the CNS parenchyma, i.e., the Th2-derived cytokines interleukin (IL)-4 and IL-10, interleukin-1-receptor-antagonist (IL-1-ra), or transforming growth factor (TGF)-beta can modulate microglial morphology and functions. Microglial cells were incubated with IL-4, IL-10, IL-1-ra, TGF-beta, or with astrocyte conditioned media (ACM) and were analyzed for morphological changes, expression of intercellular adhesion molecule (ICAM)-1, and secretion of IL-1beta or tumor necrosis factor (TNF)-alpha. Whereas untreated controls showed an amoeboid morphology both Th2-derived cytokines, IL-1-ra, and ACM induced a morphological transformation to the ramified phenotype. In contrast, TGF-beta-treated microglial cells showed an amoeboid morphology. Even combined with the neutralizing antibodies against IL-4, IL-10, or TGF-beta ACM induced microglial ramification. Furthermore, ACM did not contain relevant amounts of IL-4 and IL-10, as measured by enzyme-linked immunosorbent assay (ELISA). Flow cytometry showed that lipopolysaccharide (LPS)-induced ICAM-1-expression on microglial cells was strongly suppressed by ACM, significantly modulated by IL-4, IL-10, or IL-1-ra, but not influenced by TGF-beta. The LPS-induced secretion of IL-1beta and TNF-alpha was only reduced after application of ACM, whereas IL-4 or IL-10 did not inhibit IL-1beta- or TNF-alpha secretion. TGF-beta enhanced IL-1beta- but not TNF-alpha secretion. In summary, we demonstrate that IL-4, IL-10, and IL-1-ra induce microglial ramification and reduce ICAM-1-expression, whereas the secretion of proinflammatory cytokines is not prevented. TGF-beta has no modulating effects. Importantly, unidentified astrocytic factors that are not identical with IL-4, IL-10, or TGF-beta possess strong immunomodulatory properties.     

Acute renal failure in newborn. Case presentation

Acute renal failure in newborn occurs in 6-8%. Using a systematic approach, physicians can determine the cause of acute renal failure in most patients. Renal cortical necrosis is an uncommon cause of acute renal failure, secondary to perinatal asphyxia or severe anemia. We report our first experience in peritoneal dialysis for a newborn with renal injury due to severe bleeding through the umbilical cord.     

The immunosuppressant mycophenolate mofetil attenuates neuronal damage after excitotoxic injury in hippocampal slice cultures

In this study we investigated whether treatment with the immunosuppressant mycophenolate mofetil (MMF) has beneficial effects on neuronal damage after excitotoxic injury. Organotypic hippocampal slice culture (OHSC), lesioned by the application of N-methyl-d-aspartate (NMDA) after 6 days in vitro, showed an improved preservation of the hippocampal cytoarchitecture after continuous treatment with MMF for 3 further days (10 or 100 micro g/mL). Treatment with NMDA and MMF (100 microg/mL) reduced the number of damaged propidium iodide (PI)+ neurons by 50.7% and the number of microglial cells by 52%. Continuous treatment of lesioned OHSCs with MMF for 3 days almost abrogated the glial proliferative response, reflected by the 91.5% reduction in the number of bromo-desoxy-uridine (BrdU)-labelled microglial cells and astrocytes. Microglial cells in MMF-treated OHSCs contained fragmented nuclei, indicating apoptotic cell death, an effect which was also found in isolated microglial cells treated with MMF. The beneficial effect of MMF on neuronal survival apparently does not reflect a direct antiexcitotoxic effect, as short-term treatment of OHSCs with NMDA and MMF for 4 h did not reduce the number of PI+ neurons. In conclusion, MMF inhibits proliferation and activation of microglia and astrocytes and protects neurons after excitotoxic injury.     

Mycotoxin fumonisin B1 alters the cytokine profile and decreases the vaccinal antibody titer in pigs.

Fumonisin B1 (FB1), a mycotoxin produced by Fusarium verticillioides, may contaminate feed and food. In the present study, we investigated the effect of FB1 on the modulation of the cytokine profile and on the establishment of a vaccinal antibody response. In vitro investigations on pig peripheral blood mononuclear cells (PBMC) indicate that FB1 decreased interleukin-4 (IL-4) and increased interferon-gamma (IFN-gamma) synthesis at both the protein and mRNA levels. A short in vivo exposure (7 days) of weanling piglets to 1.5 mg/kg body weight of purified FB1 altered the cytokine balance in mesenteric lymph nodes and spleen similarly to the in vitro PBMC results. We also investigated the effect of FB1 on the antibody response during a vaccination process. A prolonged in vivo exposure (28 days) of weanling piglets to feed contaminated with 8 mg FB1/kg significantly decreased the expression of IL-4 mRNA by porcine whole blood cells and diminished the specific antibody titer after vaccination against Mycoplasma agalactiae. By contrast, ingestion of the contaminated feed had no effect on the serum concentration of the immunoglobulin subset (IgG, IgA, and IgM). Taken together, our data suggest that FB1 alters the cytokine profile and decreases the specific antibody response built during a vaccination protocol. These results may have implications for humans or animals eating contaminated food or feed.     

Effects of caffeine and phosphodiesterase inhibitors on activation of neonatal T lymphocytes

Caffeine and selective PDE inhibitors are widely used in clinical management of preterm and term neonates. However, little is known about how these compounds interact with the neonatal adaptive immune system. We aimed to describe the effects of caffeine, milrinone and sildenafil on the activation and cytokine production of T cells from umbilical cord blood (UCB) compared to adult peripheral blood (APB).We isolated mononuclear cells from 10 APB and 6 UCB samples. We assessed intracellular cytokine production (IFN-γ, IL-2, IL-4, IL-6, IL-17) of stimulated CD4 cells and parameters of calcium influx and ROS production following treatment with caffeine, milrinone, sildenafil, dbcAMP or a specific A2A receptor antagonist, ZM241385 using flow cytometry.In ABP, only ZM241385 caused a 1.14-fold increase in calcium influx, while all compounds increased calcium influx in UCB. This effect was more pronounced in case of caffeine (1.41-fold) and dbcAMP (1.3-fold) compared to milrinone (1.22-fold), sildenafil (1.23-fold) or ZM241385 (1.23-fold). Intracellular levels of the studied cytokines were unaffected by the applied compounds in both APB and UCB samples.Caffeine increases calcium influx upon activation in neonatal T lymphocytes to a larger extent than milrinone or sildenafil. This effect appears to be mediated primarily via increased cAMP levels rather than A2A receptor inhibition. Overall, the application of caffeine, sildenafil or milrinone does not appear to have immunosuppressive effects on neonatal T cells.     

Torque teno virus for risk stratification of graft rejection and infection in kidney transplant recipients—A prospective observational trial

The nonpathogenic and ubiquitous torque teno virus (TTV) is associated with immunosuppression in solid organ transplant recipients. Studies in kidney transplant patients proposed TTV quantification for risk stratification of graft rejection and infection. In this prospective trial (DRKS00012335) 386 consecutive kidney transplant recipients were subjected to longitudinal per‐protocol monitoring of plasma TTV load by polymerase chain reaction for 12 months posttransplant. TTV load peaked at the end of month 3 posttransplant and reached steady state thereafter. TTV load after the end of month 3 was analyzed in the context of subsequent rejection diagnosed by indication biopsy and infection within the first year posttransplant, respectively. Each log increase in TTV load decreased the odds for rejection by 22% (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.62‐0.97; P = .027) and increased the odds for infection by 11% (OR 1.11, 95% CI 1.06‐1.15; P < .001). TTV was quantified at a median of 14 days before rejection was diagnosed and 27 days before onset of infection, respectively. We defined a TTV load between 1 × 10⁶ and 1 × 10⁸ copies/mL as optimal range to minimize the risk for rejection and infection. These data support the initiation of an interventional trial assessing the efficacy of TTV‐guided immunosuppression to reduce infection and graft rejection in kidney transplant recipients.     

Induced abortion among women veterans: data from the ECUUN study

Objective

We compared rates of induced abortion among women veterans receiving Veterans Affairs (VA) healthcare to rates in the general US population, as current policy prohibits VA provision of abortion counseling or services even when pregnancy endangers a veteran's life.