Mental health 15 years after the killings in Rwanda: Imprisoned perpetrators of the genocide against the Tutsi versus a community sample of survivors

Objectives of this study were to compare rates of mental health disorders in Rwandan genocide perpetrators with those of genocide survivors and to investigate potential predictors of symptoms of posttraumatic stress disorder (PTSD) and depression for both groups. We expected high rates of mental disorders in both study groups and hypothesized that symptom severity would be predicted by female gender, older age, lower level of education, higher level of trauma exposure, lower level of agreement to reconciliation, and the participation in killing. Structured clinical interviews were carried out with 269 imprisoned perpetrators (66% men) and 114 survivors (64% women). Significantly more survivors than perpetrators met symptom criteria for PTSD (46% vs. 14%) and suffered from anxiety symptoms (59% vs. 36%). A substantial proportion of both groups suffered from clinically significant depression (46% vs. 41%). PTSD severity in perpetrators was associated with trauma exposure, high levels of agreement to reconciliation, and no participation in killing; the severity of depression was associated with trauma exposure and no participation in killing. In the survivor sample, the severity of PTSD and depression were both correlated with female gender, trauma exposure, and low levels of agreement to reconciliation. Results suggest that both groups exhibit considerable psychiatric morbidity.     

Transcatheter embolization as the new reference standard for endoscopically unmanageable upper gastrointestinal bleeding

Acute nonvariceal upper gastrointestinal bleeding(UGIB) is a major medical emergency problem associated with significant morbidity and mortality.Endoscopy is considered the first method of choice to detect and treat UGIB.Endoscopic therapy usually achieves primary hemostasis,but 10%-30% of these patients have repeat bleeding.In patients in whom hemostasis is not achieved with endoscopic techniques,treatment with transcatheter angiographic embolization(TAE) or surgery is needed.Surgical intervention is usually an expeditious and gratifying endeavor,but it can be associated with high operative mortality rates.A large number of studies support the use of TAE as salvage therapy as an alternative to surgery.However,few studies have compared the results of TAE with that of emergency surgery in terms of efficiency,the frequency of repeat bleeding,and complications.Recently,Ang et al retrospectively compared the outcome of TAE and surgery as salvage therapy of UGIB after failed endoscopic treatment.There were no significant differences in 30 d mortality,complication rates and length of stay although higher rebleeding rates were observed after TAE compared with surgery.In this commentary,we discuss the advantages and drawbacks of these two therapeutic strategies for UGIB.We also attempt to define the exact role of TAE for acute nonvariceal UGIB.     

Bisphosphonates and glucocorticoid osteoporosis in men: results of a randomized controlled trial comparing zoledronic acid with risedronate

Background

We studied 265 men (mean age 56.4 years; range 18-83 years), among patients enrolled in two arms of a double-blind, 1-year study comparing the effects of zoledronic acid (ZOL) with risedronate (RIS) in patients either commencing (prednisolone 7.5 mg/day or equivalent) (prevention arm, n = 88) or continuing glucocorticoid therapy (treatment arm, n = 177).

Methods

Patients received either a single ZOL 5 mg infusion or RIS 5 mg oral daily at randomization, along with calcium (1000 mg) and vitamin D (400-1200 IU). Primary endpoint: difference in percentage change from baseline in bone mineral density (BMD) at the lumbar spine (LS) at 12 months. Secondary endpoints: percentage changes in BMD at total hip (TH) and femoral neck (FN), relative changes in bone turnover markers (β-CTx and P1NP), and overall safety.

Findings

In the treatment subpopulation, ZOL increased LS BMD by 4.7% vs. 3.3% for RIS and at TH the percentage changes were 1.8% vs. 0.2%, respectively. In the prevention subpopulation, bone loss was prevented by both treatments. At LS the percentage changes were 2.5% vs. − 0.2% for ZOL vs. RIS and at TH the percentage changes were 1.1% vs. − 0.4%, respectively. ZOL significantly increased lumbar spine BMD more than RIS at Month 12 in both the prevention population (p = 0.0024) and the treatment subpopulation (p = 0.0232) in men. In the treatment subpopulation, ZOL demonstrated a significantly greater reduction in serum β-CTx and P1NP relative to RIS at all time-points. In the prevention subpopulation, ZOL significantly reduced β-CTx? at all time-points, and P1NP at Month 3 (p = 0.0297) only. Both treatments were well tolerated in men, albeit with a higher incidence of influenza-like illness and pyrexia events post-infusion with ZOL.

Interpretation

Once-yearly ZOL preserves or increases BMD within 1 year to a greater extent than daily RIS in men receiving glucocorticoid therapy.     

Serum IgE clearance is facilitated by human FcεRI internalization

The high-affinity IgE receptor FcεRI is constitutively expressed in mast cells and basophils and is required for transmitting stimulatory signals upon engagement of IgE-bound allergens. FcεRI is also constitutively expressed in dendritic cells (DCs) and monocytes in humans; however, the specific functions of the FcεRI expressed by these cells are not completely understood. Here, we found that FcεRI expressed by human blood DC antigen 1–positive (BDCA1⁺) DCs and monocytes, but not basophils, traffics to endolysosomal compartments under steady-state conditions. Furthermore, IgE bound to FcεRI on BDCA1⁺ DCs was rapidly endocytosed, transported to the lysosomes, and degraded in vitro. IgE injected into mice expressing human FcεRIα (FCER1A-Tg mice) was endocytosed by conventional DCs and monocytes, and endocytosis was associated with rapid clearance of circulating IgE from these mice. Importantly, this rapid IgE clearance was dependent on monocytes or DCs but not basophils. These findings strongly suggest that constitutive internalization of human FcεRI by DCs and monocytes distinctively contributes to serum IgE clearance.     

Association between sensitisation and pain-related behaviours in an experimental canine model of osteoarthritis

Evaluation of nociceptive sensitisation in canine osteoarthritis studies has been poorly reported, or even related to other clinical symptoms. In 16 dogs, peak vertical force (PVF), subjective pain assessment using 3 scales, sympathetic stress response with electrodermal activity (EDA) measurement, and behavioural changes with video analysis and telemetered motor activity were quantified at baseline (D-7), and 28 and 56 days post transection of the cranial cruciate ligament. As markers of central sensitisation, selected spinal cord biomarkers (substance P and transthyretin) were quantified at D56. Electrical withdrawal thresholds on the stifle and the tail were measured as indicative of peripheral and central quantitative sensory testing (QST) sensitisation, respectively. The effects of vehicle administration (n = 8) were compared with tiludronate (2 mg/kg subcutaneously, q2week, starting at D0) administration. Generalized estimated equations tested the association between the behavioural and physiological methods and QST sensitisation, and therefore the sensitivity of the methods for detecting treatment efficacy. Compared to tiludronate, at D56, vehicle-treated dogs had increased spinal substance P (P = 0.01), concomitant decreased transthyretin (P = 0.02), and (compared to baseline) demonstrated peripheral and central QST sensitisation, which was not present for tiludronate. Only PVF, the spontaneous behaviour “walking with full weight-bearing,” and EDA were associated with occurrence of QST sensitisation and indicated significant tiludronate analgesic efficacy after inclusion of central QST sensitisation as a predictor variable in the statistical model. This study establishes the strong interest to implement QST as a predictor of canine osteoarthritis pain symptoms explained by pain sensitisation.     

Effects of intravenous administration of pentoxifylline in pancreatic ischaemia–reperfusion injury

Background

Therapeutic strategies to reduce the occurrence of pancreatic ischaemia–reperfusion (I–R) injury might improve outcomes in human pancreas and kidney transplantation. In addition to its haemorrheologic effects, pentoxifylline has an anti-inflammatory effect by inhibiting NF-κB activation. This group has previously demonstrated that pentoxifylline induces an anti-inflammatory response in acute pancreatitis and liver I–R models. This led to the hypothesis that pentoxifylline might reduce pancreatic and renal lesions and the systemic inflammatory response in pancreatic I–R injury. The aim of this experimental study was to evaluate the effect of pentoxifylline administration in a rat model of pancreatic I–R injury.

Methods

Pancreatic I–R was performed in Wistar rats over 1 h by clamping the splenic vessels. The animals submitted to I–R were divided into two groups: Group 1 (n = 20, control) rats received saline solution administered i.v. at 45 min after ischaemia, and Group 2 (n = 20) rats received pentoxifylline (25 mg/kg) administered i.v. at 45 min after ischaemia. Blood samples were collected to enable the determination of amylase, creatinine, tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-10. Pancreatic malondialdehyde (MDA) content, pancreas histology and pulmonary myeloperoxidase (MPO) were also assessed.

Results

Significant reductions in serum TNF-α, IL-6 and IL-10 were observed in Group 2 compared with Group 1 (P < 0.05). No differences in pancreatic MDA content or serum amylase levels were observed between the two groups. The histologic score was significantly lower in pentoxifylline-treated animals, denoting less severe pancreatic histologic damage.

Conclusions

Pentoxifylline administration reduced the systemic inflammatory response, the pancreatic histological lesion and renal dysfunction in pancreatic I–R injury and may be a useful tool in pancreas and kidney transplantation.     

Procalcitonin biomarker kinetics fails to predict treatment response in perioperative abdominal infection with septic shock

Introduction

Procalcitonin (PCT) biomarker is suggested to tailor antibiotic therapy in the medical intensive care unit (ICU) but studies in perioperative medicine are scarce. The aim of this study was to determine whether PCT reported thresholds are associated with the initial treatment response in perioperative septic shock secondary to intra-abdominal infection.

Methods

This single ICU, observational study included patients with perioperative septic shocks secondary to intra-abdominal infection. Demographics, PCT at days 0, 1, 3, 5, treatment response and outcome were collected. Treatment failure included death related to the initial infection, second source control treatment or a new onset intra-abdominal infection. The primary endpoint was to assess whether PCT thresholds (0.5 ng/ml or a drop from the peak of at least 80%) predict the initial treatment response.

Results

We included 101 consecutive cases. Initial treatment failed in 36 patients with a subsequent mortality of 75%. Upon admission, PCT was doubled when treatment ultimately failed (21.7 ng/ml ± 38.7 vs. 41.7 ng/ml ± 75.7; P = 0.04). Although 95% of the patients in whom PCT dropped down below 0.5 ng/ml responded to treatment, 50% of the patients in whom PCT remained above 0.5 ng/ml also responded successfully to treatment. Moreover, despite a PCT drop of at least 80%, 40% of patients had treatment failure.

Conclusions

In perioperative intra-abdominal infections with shock, PCT decrease to 0.5 ng/ml lacked sensitivity to predict treatment response and its decrease of at least 80% from its peak failed to accurately predict treatment response. Studies in perioperative severe infections are needed before using PCT to tailor antibiotic use in this population.     

Neandertals made the first specialized bone tools in Europe

Modern humans replaced Neandertals ∼40,000 y ago. Close to the time of replacement, Neandertals show behaviors similar to those of the modern humans arriving into Europe, including the use of specialized bone tools, body ornaments, and small blades. It is highly debated whether these modern behaviors developed before or as a result of contact with modern humans. Here we report the identification of a type of specialized bone tool, lissoir, previously only associated with modern humans. The microwear preserved on one of these lissoir is consistent with the use of lissoir in modern times to obtain supple, lustrous, and more impermeable hides. These tools are from a Neandertal context proceeding the replacement period and are the oldest specialized bone tools in Europe. As such, they are either a demonstration of independent invention by Neandertals or an indication that modern humans started influencing European Neandertals much earlier than previously believed. Because these finds clearly predate the oldest known age for the use of similar objects in Europe by anatomically modern humans, they could also be evidence for cultural diffusion from Neandertals to modern humans.     

Noncanonical GPCR signaling arising from a PTH receptor–arrestin–Gβγ complex

G protein-coupled receptors (GPCRs) participate in ubiquitous transmembrane signal transduction processes by activating heterotrimeric G proteins. In the current “canonical” model of GPCR signaling, arrestins terminate receptor signaling by impairing receptor–G-protein coupling and promoting receptor internalization. However, parathyroid hormone receptor type 1 (PTHR), an essential GPCR involved in bone and mineral metabolism, does not follow this conventional desensitization paradigm. β-Arrestins prolong G protein (G_S)-mediated cAMP generation triggered by PTH, a process that correlates with the persistence of arrestin–PTHR complexes on endosomes and which is thought to be associated with prolonged physiological calcemic and phosphate responses. This presents an inescapable paradox for the current model of arrestin-mediated receptor–G-protein decoupling. Here we show that PTHR forms a ternary complex that includes arrestin and the Gβγ dimer in response to PTH stimulation, which in turn causes an accelerated rate of G_S activation and increases the steady-state levels of activated G_S, leading to prolonged generation of cAMP. This work provides the mechanistic basis for an alternative model of GPCR signaling in which arrestins contribute to sustaining the effect of an agonist hormone on the receptor.According to the current model for activation and signaling of G protein-coupled receptors (GPCRs), receptor (R) signaling begins when the binding of an agonist ligand (L) stabilizes the active form of the receptor (R*), allowing its coupling to heterotrimeric G proteins (Gαβγ) through a diffusion-controlled process (1–3). The L–R*–G complex catalyzes GDP–GTP exchange on the Gα subunit, promoting the dissociation of the activated G protein into GTP-bound Gα (Gα-GTP) and Gβγ dimers from the receptor. Dissociated Gα-GTP and Gβγ proteins in turn activate specific downstream effectors, such as adenylyl cyclases in the case of Gα_S (Fig. 1A). Activated adenylyl cyclases catalyze a few rounds of cAMP production, the number of which is determined by the rate of GTP hydrolysis of the Gα_S-bound GTP. In order for subsequent rounds of adenylyl cyclase activation to occur, inactive GDP-bound Gα must encounter a Gβγ dimer and then reform an L–R*–G complex (Fig. 1A). In this classical model, arrestin plays a dual role: On one hand, it desensitizes the receptor by preventing further rounds of L–R* and G coupling; on the other, it promotes receptor endocytosis, thus reducing receptor availability on the cell surface. In either case, the classical model predicts that arrestin negatively regulates the levels of the L–R*–G complex, providing the main mechanism by which the signal of a GPCR system is turned off (4, 5). This model, primarily derived from the analysis of the behavior of the β₂-adrenergic receptor (β₂-AR) (4, 5) and many other class 1 GPCRs (6–12), is taken to be universal for GPCR biology (13). Recent findings have challenged this view. We recently showed that parathyroid hormone receptor type 1 (PTHR)–arrestin complexes contribute to prolonging cAMP signaling mediated by PTH or its fully functional N-terminal synthetic analog, PTH(1–34), in cells as diverse as human embryonic kidney (HEK)293 cells expressing recombinant receptor and osteoblastic ROS17/2.8 cells (2, 14) that natively express PTHR. PTH rapidly recruits β-arrestin 1 or β-arrestin 2 to PTHR and stabilizes a persistent ternary PTH–PTHR–arrestin complex that continues signaling via adenylyl cyclases for a considerable time (>30 min) after exposure to a short “pulse” of agonist ligand (14). Because prolonged PTH-induced signaling requires persistent activation of G_S by coupling with PTHR in its L–R* state, this raises the intriguing question of how G_S can bind and be activated by a PTHR that is already associated with arrestin. We reasoned that a long-lived PTH–PTHR–arrestin complex could contribute to sustained cAMP signaling by stabilizing an interaction with the active state of G_S (Fig. 1B, model 1). Alternatively, complexes formed through interactions between β-arrestins and the Gβγ dimer, known to scaffold some signaling complexes (15–17), could promote sustained PTH-induced cAMP signaling by maintaining multiple rounds of Gα_S association with and dissociation from a PTHR–arrestin–Gβγ complex that generates a high level of active Gα_S (Fig. 1B, model 2). Here we tested these hypotheses by using a series of diverse biochemical and biophysical approaches.Open in a separate windowFig. 1.Signaling models of GPCR. (A) Classical model. A ligand binds the inactive state of a GPCR and stabilizes its active form, which then couples with heterotrimeric G proteins (Gαβγ) through a diffusion-controlled process (step 1). The L–R*–G complex in turn catalyzes GDP–GTP exchange on Gα, leading to dissociation of the GTP-bound Gα (Gα-GTP) along with the Gβγ dimer from the receptor (step 2). In the case of G_S, Gα-GTP activates specific effectors such as adenylyl cyclases (AC), which catalyze the synthesis of cAMP from ATP (step 3). The hydrolysis of GTP to GDP causes the dissociation of Gα_S from adenylyl cyclases, shutting down cAMP production and its reassociation to Gβγ subunits (step 4). In this model, the recruitment of β-arrestin mediates desensitization of G-protein signaling. (B) Noncanonical model. (1) A long-lived PTH–PTHR–arrestin complex could contribute to sustained cAMP signaling by stabilizing an interaction with the active state of G_S. (2) Alternatively, the interaction between the activated PTHR and G_S is stabilized by β-arrestins. After the first round of activation, step 1 is bypassed, such that free Gα-GDP directly reassociates with PTHR–Gβγ complexes to initiate a new cycle of G-protein activation. Arrestin stabilizes the G-protein cycle, resulting in prolonged cAMP production.