The impact of parental acceptance and childhood maltreatment on mental health and physical pain in Burundian survivors of childhood sexual abuse.

BACKGROUND: Parental support has been suggested to mitigate mental and physical consequences following childhood sexual abuse (CSA). However, many CSA survivors experience parental rejection post-CSA. OBJECTIVE: We aimed to understand the impact of abuse-specific parental acceptance on post-traumatic stress disorder (PTSD) and physical pain in Burundian CSA-survivors. We further assessed the significance of parental acceptance among known risk factors for predicting PTSD. METHODS, PARTICIPANTS, AND SETTINGS: Participants (N = 131, 80.9 % female, mean age 16.21 years) were recruited via primary health care centers for survivors of sexual violence which survivors approached post-CSA. Survivors reported on PTSD symptoms, daytime/nighttime pain, and adverse childhood experiences in semi-structured interviews. Parental acceptance levels were categorized (acceptance, no acceptance, no contact) for mothers and fathers separately. Kruskal-Wallis tests assessed group differences. Conditional random forests (CRF) evaluated the significance of parental acceptance in predicting PTSD symptom severity. RESULTS: No significant differences regarding PTSD symptoms and physical pain between levels of maternal acceptance were obtained. Pairwise comparisons revealed significant differences in PTSD symptom severity between paternal acceptance and no acceptance (d = 1.04) and paternal acceptance and no contact (d = 0.81). The CRF identified paternal acceptance as important variable for the prediction of PTSD symptom severity. Even though results were less conclusive, medium effect sizes hint at less pain perception within the paternal acceptance group. CONCLUSIONS: The results highlight paternal acceptance as a potential risk or protective factor regarding psychological and possibly physical well-being in the aftermath of CSA, even in the context of other known risk factors.

Is shame the missing link between traumatic experiences and post-traumatic stress disorder in Burundian children living on the streets?

BACKGROUND: Shame is an emotion reflecting an anticipated social devaluation of the self. It is strongly associated with experiences of humiliation and rejection in early life. Individuals suffering from post-traumatic stress disorder (PTSD) often struggle with shame. However, little is known about how shame contributes to the development and maintenance of PTSD symptoms in children. The present study investigated the ways childhood exposure to human-induced traumatic events promotes a coping mechanism of defeat and withdrawal facilitated by the experience of shame. We tested a dose-response relationship between lifetime experienced traumatic event types and PTSD in children using shame as a mediator. METHODS: We conducted semi-structured interviews with 33 male children who lived and worked on the streets of Bujumbura, the capital of Burundi at the time of data collection. We assessed self-reported PTSD symptom severity, lifetime traumatic event load, violence experienced on the streets and shame intensity. RESULTS: Mediation analyses revealed a significant indirect effect of lifetime traumatic events on PTSD symptom severity through shame intensity and a significant indirect effect of violence experienced on the streets on PTSD symptom severity through shame intensity. CONCLUSION: Our study suggests the mediating role of shame between traumatic experiences as well as violent experiences and PTSD symptom severity in children living on the streets. Shame in children suffering from PTSD seems to play a crucial role in the development and maintenance of PTSD symptoms.

Hypothalamic cellular and molecular plasticity linked to sexual experience in male rats and mice.

Male sexual behavior is subject to learning, resulting in increased efficiency of experienced males compared to naive ones. The improvement in behavioral parameters is underpinned by cellular and molecular changes in the neural circuit controlling sexual behavior, particularly in the hypothalamic medial preoptic area. This review provides an update on the mechanisms related to the sexual experience in male rodents, emphasizing the differences between rats and mice.

Doxycycline is a safe alternative to Hydroxychloroquine + Azithromycin to prevent clinical worsening and hospitalization in mild COVID-19 patients: An open label randomized clinical trial (DOXYCOV)

ObjectiveWe aimed to compare the safety and efficacy of a doxycycline-based regimen against the national standard guidelines (Hydroxychloroquine plus Azithromycin) for the treatment of mild symptomatic COVID-19. MethodsWe conducted an open-label, randomized, non-inferiority trial, in Cameroon comparing Doxycycline 100mg, twice daily for 7 days versus Hydroxychloroquine, 400 mg daily for 5 days and Azithromycin 500mg at day 1 and 250mg from day 2 through 5, in mild COVID-19 patients. Clinical improvement, biological parameters and adverse events were assessed. The primary outcome was the proportion of clinical cure at day 3, 10 and 30. Non-inferiority was determined by the clinical cure rate between protocols with a 20 percentage points margin. Results194 participants underwent randomization and were treated with Doxycycline (n=97) or Hydroxychloroquine-Azithromycin (n=97). At day 3, 74/92 (80.4%) participants on Doxycycline versus 77/95 (81.1%) on Hydroxychloroquine-Azithromycin -based protocols were asymptomatic (p=0.91). At day 10, 88/92 (95.7%) participants on Doxycycline versus 93/95 (97.9%) on Hydroxychloroquine-Azithromycin were asymptomatic (p=0.44). At day 30 all participants were asymptomatic. SARS-CoV2 PCR was negative at Day 10 in 60/92 (65.2%) participants allocated to Doxycycline and 63/95 (66.3%) participants allocated to Hydroxychloroquine-Azithromycin. None of the participants were admitted for worsening of the disease after treatment initiation. ConclusionDoxycycline 100 mg twice daily for 7 days is as effective and safe as Hydroxychloroquine-Azithromycin, for preventing clinical worsening of mild symptomatic or asymptomatic COVID-19, and achieving virological suppression. Strengths and Limitations[tpltrtarr] This study is one of the first randomized trial, assessing the efficacy and tolerance of Doxycycline to treat COVID-19 [tpltrtarr]It is one of the first to evaluate disease progression and need to hospitalization in mild or asymptomatic COVID-19 [tpltrtarr]Patients will not receive identical treatments [tpltrtarr]Doxycycline has advantages in terms of availability, safety and cost compared to Hydroxychloroquine and Azytromycin [tpltrtarr]Though this study has encounter 7 lost to follow-up, this does not have a major influence on our results [tpltrtarr]These data will assist clinicians in their daily practice, and provide a new tool for the fight against COVID-19

Kinetic modeling of lag times during photo-induced inactivation of E. coli in sunlit surface waters: Unraveling the pathways of exogenous action.

This work presents a kinetic analysis of the exogenous photo-induced disinfection of E. coli in natural waters. Herein, the inactivation of bacteria by light and photo-generated transient species, i.e., hydroxyl radical (HO•), excited triplet states of organic matter (3CDOM*) and singlet oxygen (1O2), was studied. It was found that the exogenous disinfection of E. coli proceeds through a lag time, followed by an exponential phase triggered by photo-generated HO•, 1O2 and 3CDOM*. Also, we report that the concentration increased of transient species (and especially HO•) precursors decreased the lag times of bacteria inactivation. Due to the limitations of the competition kinetics methodology to include the lag phase, an alternative strategy to study the interaction between E. coli and photo-generated transient species was proposed, considering the log-linear pseudo-first order rate constants and lag-times. On this basis and by using APEX software, a full kinetic analysis of exogenous bacterial inactivation, taking into account both lag-time and exponential decay, was developed. This approach provided insights into the conditions that could make exogenous inactivation competitive with the endogenous process for the E. coli inactivation in natural sunlit waters. Hence, this research contributes to the understanding of fundamental kinetic aspects of photoinduced bacterial inactivation, which is the basis for light-assisted processes such as the solar disinfection (SODIS).

Hippocampal expression of a virus-derived protein impairs memory in mice.

The analysis of the biology of neurotropic viruses, notably of their interference with cellular signaling, provides a useful tool to get further insight into the role of specific pathways in the control of behavioral functions. Here, we exploited the natural property of a viral protein identified as a major effector of behavioral disorders during infection. We used the phosphoprotein (P) of Borna disease virus, which acts as a decoy substrate for protein kinase C (PKC) when expressed in neurons and disrupts synaptic plasticity. By a lentiviral-based strategy, we directed the singled-out expression of P in the dentate gyrus of the hippocampus and we examined its impact on mouse behavior. Mice expressing the P protein displayed increased anxiety and impaired long-term memory in contextual and spatial memory tasks. Interestingly, these effects were dependent on P protein phosphorylation by PKC, as expression of a mutant form of P devoid of its PKC phosphorylation sites had no effect on these behaviors. We also revealed features of behavioral impairment induced by P protein expression but that were independent of its phosphorylation by PKC. Altogether, our findings provide insight into the behavioral correlates of viral infection, as well as into the impact of virus-mediated alterations of the PKC pathway on behavioral functions.

Revisiting medial preoptic area plasticity induced in male mice by sexual experience.

Sexual experience in male rodents, induced by a first exposure to a receptive female, improves efficiency of following copulations. In mice, the mechanisms supporting this improvement are poorly understood. We characterized molecular modifications of the mouse hypothalamic medial preoptic area (mPOA), the main integrative structure for male sexual behaviour, after a single mating event. This paradigm induced long-lasting behavioural improvements and mPOA morphological changes, evidenced by dendritic spine maturation and an increase in the acetylated and tri-methylated forms of histone H3. Ejaculation affected testosterone, progesterone and corticosterone levels in both naive and experienced mice, but sexual experience did not modify basal plasma or hypothalamic levels of steroids. In contrast to studies carried out in rats, no changes were observed, either in the nitrergic system, or in sex steroid receptor levels. However, levels of glutamate- and calcium-associated proteins, including PSD-95, calbindin and the GluN1 subunit of the NMDA receptor, were increased in sexually experienced male mice. The Iba-1 microglial marker was up-regulated in these animals suggesting multicellular interactions induced within the mPOA by sexual experience. In conclusion, plasticity mechanisms induced by sexual experience differ between rat and mouse, even if in both cases they converge to potentiation of the mPOA network.

Phospho-ERK and sex steroids in the mPOA: involvement in male mouse sexual behaviour.

This paper aimed to investigate the mechanisms triggering ERK phosphorylation and its functional role in male sexual behaviour. ERK1/2-phosphorylated form was detected in the medial preoptic area of the hypothalamus (mPOA) during the sexual stimulation of naive and sexually experienced males who were killed 5 min after the first intromission. This mating-induced ERK phosphorylation was increased in sexually experienced males compared to that in naive mice. The functional role of the ERK1/2 pathway activation during sexual behaviour was explored with the administration of a MEK inhibitor, SL-327 (30 mg/kg, i.p.), 45 min before the contact with a receptive female. Inhibition of ERK phosphorylation was found to decrease sexual motivation in both naive and experienced males without altering their copulatory ability. The mechanisms potentially involved in this rapid ERK1/2 pathway activation were specified ex vivo on hypothalamic slices. A thirty-minute incubation with 100 nM of testosterone (T), dihydrotestosterone (DHT) or oestradiol (E2) led to ERK phosphorylation. No changes were observed after incubation with testosterone 3-(O-carboxymethyl)oxime-BSA (T-BSA), an impermeable to the plasma membrane form of testosterone. All these results indicate that ERK phosphorylation within the mPOA could be a key player in the motivational signalling pathway and considered as an index of sexual motivation. They also demonstrate the involvement of oestrogen receptor (ER) and androgen receptor (AR) transduction pathways in steroid-dependent ERK activation.

The combination of dimethoxycurcumin with DNA methylation inhibitor enhances gene re-expression of promoter-methylated genes and antagonizes their cytotoxic effect.

Curcumin and its analogs exhibited antileukemic activity either as single agent or in combination therapy. Dimethoxycurcumin (DMC) is a more metabolically stable curcumin analog that was shown to induce the expression of promoter-methylated genes without reversing DNA methylation. Accordingly, co-treatment with DMC and DNA methyltransferase (DNMT) inhibitors could hypothetically enhance the re-expression of promoter-methylated tumor suppressor genes. In this study, we investigated the cytotoxic effects and epigenetic changes associated with the combination of DMC and the DNMT inhibitor decitabine (DAC) in primary leukemia samples and cell lines. The combination demonstrated antagonistic cytotoxic effects and was minimally cytotoxic to primary leukemia cells. The combination did not affect the metabolic stability of DMC. Although the combination enhanced the downregulation of nuclear DNMT proteins, the hypomethylating activity of the combination was not increased significantly compared to DAC alone. On the other hand, the combination significantly increased H3K27 acetylation (H3K27Ac) compared to the single agents near the promoter region of promoter-methylated genes. Furthermore, sequential chromatin immunoprecipitation (ChIP) and DNA pyrosequencing of the chromatin-enriched H3K27Ac did not show any significant decrease in DNA methylation compared to other regions. Consequently, the enhanced induction of promoter-methylated genes by the combination compared to DAC alone is mediated by a mechanism that involves increased histone acetylation and not through potentiation of the DNA hypomethylating activity of DAC. Collectively, our results provide the mechanistic basis for further characterization of this combination in leukemia animal models and early phase clinical trials.

Hippocampal GSK3ß as a Molecular Link Between Obesity and Depression.

Obesity is considered as a risk factor for mood disorders including depression. Nevertheless, the mechanisms underlying this association are not clearly understood. To address this issue, we investigated the impact of high-fat (HF)-diet-induced obesity on depressive-like behavior and on serotonin (5-HT)-dependent Akt/glycogen synthase kinase 3ß (GSK3ß) signaling in the dentate gyrus (DG) of the hippocampus, which has been associated with mood regulation. We first showed that a HF diet induced significant overweight and hyperglycemia as well as a depressive-like behavior in adult Wistar rats. By using an ex vivo approach on brain slices, we demonstrated that 5-HT activates the Akt/GSK3ß cascade in the DG of control chow (C) diet-fed animals and that a 16-week HF diet feeding abolishes this activation, concurrently with a desensitization of leptin and insulin signaling in the same region. Furthermore, depressive-like behavior inversely correlated with 5-HT-induced phosphorylation of GSK3ß in the subgranular neurons of the DG. Interestingly, a substitution of HF with C diet for 6 weeks induced a total loss of depressive symptoms, whereas body weight and glycemia remained significantly higher compared to control rats. In addition, food restoration led to a recovery of the Akt/GSK3ß signaling pathway activation in the DG. In parallel, we observed a negative correlation between body weight and cell proliferation in the subgranular zone of the DG. To conclude, we provide evidence for a desensitization of 5-HT-induced Akt/GSK3ß signaling and an impaired cell proliferation in the DG by HF diet, suggesting novel molecular mechanisms linking obesity to depression.

Attenuated Levels of Hippocampal Connexin 43 and its Phosphorylation Correlate with Antidepressant- and Anxiolytic-Like Activities in Mice.

Clinical and preclinical studies have implicated glial anomalies in major depression. Conversely, evidence suggests that the activity of antidepressant drugs is based, at least in part, on their ability to stimulate density and/or activity of astrocytes, a major glial cell population. Despite this recent evidence, little is known about the mechanism(s) by which astrocytes regulate emotionality. Glial cells communicate with each other through gap junction channels (GJCs), while they can also directly interact with neurons by releasing gliotransmitters in the extracellular compartment via an hemichannels (HCs)-dependent process. Both GJCs and HCs are formed by two main protein subunits: connexins (Cx) 30 and 43 (Cx30 and Cx43). Here we investigate the role of hippocampal Cx43 in the regulation of depression-like symptoms using genetic and pharmacological approaches. The first aim of this study was to evaluate the impact of the constitutive knock-down of Cx43 on a set of behaviors known to be affected in depression. Conversely, the expression of Cx43 was assessed in the hippocampus of mice subjected to prolonged corticosterone (CORT) exposure, given either alone or in combination with an antidepressant drug, the selective serotonin reuptake inhibitor fluoxetine. Our results indicate that the constitutive deficiency of Cx43 resulted in the expression of some characteristic hallmarks of antidepressant-/anxiolytic-like behavioral activities along with an improvement of cognitive performances. Moreover, in a new cohort of wild-type mice, we showed that CORT exposure elicited anxiety and depression-like abnormalities that were reversed by chronic administration of fluoxetine. Remarkably, CORT also increased hippocampal amounts of phosphorylated form of Cx43 whereas fluoxetine treatment normalized this parameter. From these results, we envision that antidepressant drugs may exert their therapeutic activity by decreasing the expression and/or activity of Cx43 resulting from a lower level of phosphorylation in the hippocampus.

Combination of cellular population data and CytoDiff analyses for the diagnosis of lymphocytosis.

BACKGROUND: Differentials with moderate lymphocytosis are common in hematology laboratories and it is important in these cases to discriminate monoclonal from reactive lymphocytosis (RL). Blood smear reflex examination is dependent of the expertise of a cytologist, time-consuming and not always informative. Therefore, rapid and easy orientation parameters are clearly needed to discriminate malignant from RL. METHODS: The differential performed by the Beckman-Coulter analyzers is based on the determination of three parameters (volume, conductivity and scatter of the cell subpopulations) called cellular population data (CPD). This study evaluated CPD in 332 patients with a typical B-chronic lymphocytic leukemia (B-CLL), 90 patients with other B-lymphoproliferative diseases (OLPD) and 55 patients with a proven RL, and established a discriminating protocol to identify these pathologies. Secondly, this approach was evaluated in a prospective study including 102 patients with lymphocyte counts above 3.5 × 10(9)/L and in each case the diagnosis suggested by CPD was compared with conventional flow cytometry (FC) analysis and that obtained using CytoDiff reagent, a combination of six antibodies/five colors which performs a rapid WBC differential by FC. RESULTS: Lymphocyte anisocytosis was observed for malignant and RL. A low lymphocyte volume identifies monoclonal B-cell lymphocytosis and classical B-CLL. CytoDiff analysis is helpful when lymphocyte volume is in the normal range. A ratio B-Ly/total Ly count >0.32 is suggestive of a B-malignancy, whereas a non-cytotoxic T-lymphocyte count above 2.43 × 10(9)/L suggests RL. CONCLUSIONS: The analysis of CPD in combination with CytoDiff analysis shows promise for the rapid and accurate identification of lymphocyte pathologies in routine practice.