From the Cover: Father's brain is sensitive to childcare experiences

Although contemporary socio-cultural changes dramatically increased fathers'' involvement in childrearing, little is known about the brain basis of human fatherhood, its comparability with the maternal brain, and its sensitivity to caregiving experiences. We measured parental brain response to infant stimuli using functional MRI, oxytocin, and parenting behavior in three groups of parents (n = 89) raising their firstborn infant: heterosexual primary-caregiving mothers (PC-Mothers), heterosexual secondary-caregiving fathers (SC-Fathers), and primary-caregiving homosexual fathers (PC-Fathers) rearing infants without maternal involvement. Results revealed that parenting implemented a global “parental caregiving” neural network, mainly consistent across parents, which integrated functioning of two systems: the emotional processing network including subcortical and paralimbic structures associated with vigilance, salience, reward, and motivation, and mentalizing network involving frontopolar-medial-prefrontal and temporo-parietal circuits implicated in social understanding and cognitive empathy. These networks work in concert to imbue infant care with emotional salience, attune with the infant state, and plan adequate parenting. PC-Mothers showed greater activation in emotion processing structures, correlated with oxytocin and parent-infant synchrony, whereas SC-Fathers displayed greater activation in cortical circuits, associated with oxytocin and parenting. PC-Fathers exhibited high amygdala activation similar to PC-Mothers, alongside high activation of superior temporal sulcus (STS) comparable to SC-Fathers, and functional connectivity between amygdala and STS. Among all fathers, time spent in direct childcare was linked with the degree of amygdala-STS connectivity. Findings underscore the common neural basis of maternal and paternal care, chart brain–hormone–behavior pathways that support parenthood, and specify mechanisms of brain malleability with caregiving experiences in human fathers.Throughout human history and across cultures, women have typically assumed primary caregiving responsibility for infants (1, 2). Although humans are among the few mammalian species where some male parental caregiving is relatively common, father involvement varies considerably within and across cultures, adapting to ecological conditions (1, 3). Involved fathering has been linked with children''s long-term physiological and social development and with increases in mothers'' caregiving-related hormones such as oxytocin and prolactin (3–6). In addition, animal studies demonstrated structural brain alterations in caregiving fathers (7, 8). It has been suggested that, although maternal caregiving is triggered by neurobiological processes related to pregnancy and labor, the human father''s brain, similar to other biparental mammals, adapts to the parental role through active involvement in childcare (1–3). Despite growing childcare involvement of fathers (3, 5, 6), mechanisms for human fathers'' brain adaptation to caregiving experiences remain largely unknown, and no study to our knowledge has examined the brain basis of human fatherhood when fathers assume primary responsibility for infant care.For social species with lengthy periods of dependence, parental caregiving is key to survival and relies on brain structures that maximize survival (2, 9). Animal studies have demonstrated that mammalian mothering is supported by evolutionarily ancient structures implicated in emotional processing, vigilance, motivation, and reward, which are rich in oxytocin receptors, including the amygdala, hypothalamus, nucleus accumbens, and ventral tegmental area (VTA), and that these regions are sensitive to caregiving behavior (9, 10). Imaging studies of human mothers found activation in similar areas, combined with paralimbic insula-cingulate structures that imbue infants with affective salience, ground experience in the present moment and enable maternal simulation of infant states (11–13). These structures implicate a phylogenetically ancient network of emotional processing that rapidly detects motivationally salient and survival-related cues (14) and enables parents to automatically identify and immediately respond to infant distress, thereby maximizing survival. In humans, this emotional processing network is complemented by a cortical mentalizing network of frontopolar-medial-prefrontal-temporo-parietal structures involved in social understanding, theory of mind, and cognitive empathy, including the medial prefrontal cortex (mPFC), frontopolar cortex, superior temporal sulcus (STS), and temporal poles (15). The mentalizing network plays an important role in individuals'' ability to infer mental states from behavior, is already activated during the parents'' first weeks of parenting, and enables parents to cognitively represent infant states, predict infant needs, and plan future caregiving (11–13).The few studies examining the human father''s brain showed activation in similar areas, including the STS, lateral and medial frontal regions, VTA, inferior frontal gyrus (IFG), and orbitofrontal cortex (OFC) (16, 17). Only one study compared maternal and paternal brain response to infant cues, reporting mothers'' greater amygdala activation, fathers'' greater superior-temporal and medial-frontal activation, and maternal and paternal oxytocin''s different associations with amygdala vs. cortical activation (18). Oxytocin, a nine-amino acid neuropeptide that underpins the formation of affiliative bonds (19), supports the development of human parental caregiving (20). Research has shown that maternal and paternal oxytocin levels are associated with parent–infant synchrony, which is the parent''s careful adaptation of caregiving behavior to infant''s social signals (21). However, although oxytocin levels are similar in mothers and fathers, oxytocin is differentially linked with the parent-specific repertoire, for instance, with affectionate contact in mothers and stimulatory play in fathers (5, 20).Ethological perspectives emphasize the importance of studying the neurobiology of parenting in its natural habitat and of using a behavior-based approach to test parents'' brain adaptation to ecological pressures (22). Consistent with findings in other mammals (10), studies on brain–behavior associations in human mothers describe links between mother–infant synchrony and brain activation in the mother''s subcortical regions, including the amygdala, nucleus accumebens, and hippocampus (11, 13). In contrast, the one study testing human fathers'' brain–behavior associations showed correlations with cortical activation (17). Overall, these findings suggest that distinct brain–hormone–behavior pathways may underpin maternal and paternal care; therefore, oxytocin and parenting behavior may be associated with the emotional processing network in mothers but with the socio-cognitive circuit in fathers. Furthermore, animal studies indicate that active caregiving in biparental fathers leads to greater integration of multiple brain networks involved in nurturance, learning, and motivation (7). Hence, active involvement in caregiving may possibly facilitate integration of both parenting-related networks in human fathers, particularly among those who undertake the primary caregiver role.The present study sought to examine the brain basis of human fatherhood by using a “natural experiment,” afforded for the first time in human history, to our knowledge, by contemporary socio-cultural changes. Throughout history, infants without mothers were cared for by other women (2). Current social changes enable the formation of two-father families raising children with no maternal involvement since birth (3). Such a context provides a unique setting to assess changes in the paternal brain on assuming the traditionally maternal role. Moreover, understanding mechanisms of brain adaptation to caregiving experiences in primary-caregiving fathers may shed further light on processes that refine all fathers'' responses to childcare activities.We visited the homes of two-parent families rearing their firstborn child: heterosexual mother-father couples comprising primary-caregiving mothers (PC-Mothers) and secondary-caregiving fathers (SC-Fathers) and homosexual couples comprising two primary-caregiving fathers (PC-Fathers) (SI Materials and Methods). We videotaped parent–infant interaction in the natural habitat, measured parental oxytocin, and used the videotaped parent–child interactions as stimuli for functional MRI (fMRI) to test parental brain response to infant-related cues. Five hypotheses were proposed. First, we expected activation in both subcortical areas involved in vigilance and reward and cortical circuits implicated in social understanding in all parents raising a young infant. Second, we expected greater subcortical activation in mothers, particularly in the amygdala, which has been repeatedly linked with mammalian mothering (23, 24), and greater activation in cortical socio-cognitive circuits in fathers. Third, the brain–hormone–behavior constellation underpinning maternal care was expected to center around the emotional-processing network, whereas the brain–hormone–behavior links in fathers were expected to coalesce with the socio-cognitive network. Fourth, consistent with the context-specific evolution of human fathering (1), we expected greater variability in fathers'' brain response as mediated by actual caregiving experiences. Such variability would be particularly noted among the primary-caregiving fathers raising infants without mothers and may involve functional integration of the subcortical and cortical networks subserving parenting. Finally, we expected that the pathways leading from the parent''s primary caregiving role to greater parent–infant synchrony would be mediated by parental brain activation and oxytocin levels.     

Warty dyskeratoma/focal acantholytic dyskeratosis--an update on a rare oral lesion

J Oral Pathol Med (2012) 41 : 261–267 Background: Warty dyskeratoma (WD) is an uncommon lesion of the skin that is considered to be associated with the pilosebaceous apparatus. Histologically similar lesions have been described in the oral region mainly by case reports and under the terms ‘WD’ or ‘focal acantholytic dyskeratosis (FAD)’. Owing to the paucity of reports, many aspects of the oral lesions remain unclear. The purpose of this study is to report a new case in an extremely rare location, the buccal mucosa, and to present a comprehensive updated review and analysis of the literature. Methods: We reviewed all cases of oral lesions that were diagnosed as WD and FAD and analyzed them according to their clinical and pathologic features. Results: The search yielded only 41 cases. The lesions usually appeared as asymptomatic, solitary, white nodules, papules, or patches on bone‐bound mucosa. They occasionally had a rough surface and depressed center. The lesions were most common in the fifth to seventh decades. Use of tobacco appeared to be the most prevalent predisposing factor. The histopathological differential diagnosis of the lesion included acantholytic squamous cell carcinoma, keratoacanthoma, and Darier’s disease. Conclusion: Warty dyskeratoma/FAD are uncommon oral lesions which are not encountered in the daily practice of oral pathologists. The absence of an association of oral lesions with the pilosebaceous apparatus suggests that they are probably distinctly different from cutaneous ones. As such, we suggest the histologic term isolated FAD for oral lesions, rather than WD.     

The increased risk for pneumocystis pneumonia in patients receiving rituximab-CHOP-14 can be prevented by the administration of trimethoprim/sulfamethoxazole: a single-center experience

Recent studies suggest an increased risk for Pneumocystis jirovecii pneumonia (PJP) in adults receiving short-interval rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) therapy for diffuse large cell B cell lymphoma (DLBCL). This retrospective study evaluates precise PJP incidence and the efficacy of anti-PJP prophylaxis in DLBCL. Patients with DLBCL, aged ≥18 years and treated between December 2004 and December 2010, were included. Details of treatment-related respiratory infections, focusing on PJP incidence, risk factors and prophylaxis, were assessed. A total of 132 patients were analyzed; 47 were treated with rituximab-CHOP therapy every 21 days (R-CHOP-21) and 85 were treated every 14 days (R-CHOP-14). The incidence of treatment-related respiratory infections was higher in patients receiving R-CHOP-14. PJP was diagnosed in 5 patients: 4 in the R-CHOP-14 (6.6%) and 1 in the R-CHOP-21 cohort (2.6%), using triplex polymerase chain reaction (PCR) for PJ in bronchoalveolar fluid. None of the patients receiving P.jirovecii prophylaxis (n = 33) developed PJP, compared with 6.6% of those treated with R-CHOP-14 without such prophylaxis. An older age and R-CHOP administered every 14 rather than every 21 days increased the PJP risk. Trimethoprim/sulfamethoxazole prophylaxis is found to be highly efficient in preventing this life-threatening complication and, therefore, should be recommended for patients receiving the R-CHOP-14 regimen.     

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia: Risk stratified approach with a long-term follow-up

The use of allogeneic stem cell transplantation (SCT) for chronic myeloid leukemia (CML) was almost abandoned in recent years for very effective targeted therapy with tyrosine kinase inhibitors (TKIs). However, approximately one third of patients still need another treatment including SCT. 38 consecutive CML patients were treated (most in preimatinib era) with allogeneic SCT, using partial T cell depletion (TCD) and preemptive donor lymphocyte infusion (DLI), without post‐transplant graft‐versus‐host disease (GvHD) prophylaxis. Conditioning included busulfan, cyclophosphamide, antithymocytic globulin, and fludarabine followed by donor stem cell transfusion. With a median follow up of 90.5 months (1–134), 32 patients are alive. 97% engrafted. 5‐year leukemia free survival (LFS) and overall survival (OS) were 78.95% and 84.2%, respectively. All patients are in major molecular remission and 78% in complete molecular remission. Transplant‐related mortality (TRM) was 13%. Twenty‐four patients received DLI for residual disease. Acute GvHD, mostly Grades I‐II, occurred in 18% of patients post‐transplant and in 24% of patients receiving DLI. In conclusion, the risk‐adapted approach using only partial TCD and preemptive escalated dose of DLI precluded the need for immunosuppressive medications and reduced the risk of significant GvHD without compromising engraftment and long‐term disease control. Am. J. Hematol. 2012. © 2012 Wiley Periodicals, Inc.     

A subset of CD8+ T cells acquiring selective suppressive properties may play a role in GvHD management

Difficulty in segregating graft-versus-tumor effect (GvT) from graft-versus-host disease (GvHD) remains a major limitation of allogeneic stem cell transplantation (Allo SCT). Naturally occurring regulatory T cells have been suggested to suppress alloreactive T cells involved in GvHD; however, their non-selective suppressive effect raises concern regarding probable attenuation of the GvT effect. Recent studies suggested inducible CD8 (iCD8) cells to be useful in suppressing autoimmune reactions, although their function in the Allo SCT setting has not been fully explored. The current study assessed in-vitro the properties of iCD8 T cells, generated in response to allogeneic dendritic cells (DCs), imitating the Allo SCT conditions. CD25^? peripheral blood mononuclear cells (PBMCs) were stimulated with allogeneic DCs in mixed lymphocyte culture (MLC). The resultant iCD8⁺CD25⁺ population was isolated and assessed for phenotypic markers, cytokine expression profile, cell proliferation, inhibitory capacity and anti-viral response. The generated CD8⁺CD25⁺FOXP3⁺ T cells selectively inhibited the primary allogeneic response, without attenuating T cell response against other stimuli, such as mitogens or a cytomegalovirus (CMV) recall antigen. In conclusion, iCD8⁺CD25⁺ cells suppress allogeneic stimulation, while maintaining the capacity to respond to infectious pathogens. These cells could be potentially efficient in the Allo SCT setting, where GvHD prevention is required.     

Changes in interpersonal conflicts among adolescents during psychodynamic therapy

Abstract

The core conflictual relationship theme (CCRT) method was used in psychodynamic therapy with 10 adolescents to study change in interpersonal conflicts in the course of treatment. Relationship anecdote paradigm interviews were conducted at the beginning of therapy and before termination 8 to 9 months later. Adolescents were asked to describe 4 relationship episodes for each of the following significant others: parents, peers, and therapist. The CCRTs for the 3 relationships were different: The main wishes toward the parents were to be close and to be given independence; toward friends, to be close and to be open; and toward the therapist, to be helped and to be understood. The responses of other and self toward parents were significantly more negative than responses in other relationships. Responses of self and other in the therapeutic relationship were significantly more positive. At the end of therapy the interactions with parents were more positive, whereas those with the therapist grew more ambivalent.     

Marek's disease viruses circulating in commercial poultry in Italy in the years 2015–2018 are closely related by their meq gene phylogeny

Marek's disease (MD) is a lymphoproliferative disease important to the poultry industry worldwide; it is caused by Gallid alphaherpesvirus 2 (GaHV‐2). The virulence of GaHV‐2 isolates has shifted over the years from mild to virulent, very virulent and very virulent +. Nowadays the disease is controlled by vaccination, but field strains of increased virulence are emerging worldwide. Economic losses due to MD are mostly associated with its acute form, characterized by visceral lymphomas. The present study aimed to molecularly classify a group of 13 GaHV‐2 strains detected in vaccinated Italian commercial chicken flocks during acute MD outbreaks, and to scrutinize the ability of predicting GaHV‐2 virulence, according to the meq gene sequence. The full‐length meq genes were amplified, and the obtained amino acid (aa) sequences were analysed, focusing mainly on the number of stretches of four proline molecules (PPPP) within the transactivation domain. Phylogenetic analysis was carried out with the Maximum Likelihood method using the obtained aa sequences, and the sequences of Italian strains detected in backyard flocks and of selected strains retrieved from GenBank. All the analysed strains showed 100% sequence identity in the meq gene, which encodes a Meq protein of 339 aa. The Meq protein includes four PPPP motifs in the transactivation domain and an interruption of a PPPP motif due to a proline‐to‐serine substitution at position 218. These features are typically encountered in highly virulent isolates. Phylogenetic analysis revealed that the analysed strains belonged to a cluster that includes high‐virulence GaHV‐2 strains detected in Italian backyard flocks and a hypervirulent Polish strain. Our results support the hypothesis that the virulence of field isolates can be suggested by meq aa sequence analysis.     

Cannabinoid Receptor Activation Prevents the Effects of Chronic Mild Stress on Emotional Learning and LTP in a Rat Model of Depression

Most psychiatric disorders are characterized by emotional memory or learning disturbances. Chronic mild stress (CMS) is a common animal model for stress-induced depression. Here we examined whether 3 days of treatment using the CB1/2 receptor agonist WIN55,212-2 could ameliorate the effects of CMS on emotional learning (ie, conditioned avoidance and extinction), long-term potentiation (LTP) in the hippocampal-accumbens pathway, and depression-like symptoms (ie, coping with stress behavior, anhedonia, and weight changes). We also examined whether the ameliorating effects of WIN55,212-2 on behavior and physiology after CMS are mediated by CB1 and glucocorticoid receptors (GRs). Rats were exposed to CMS or handled on days 1–21. The agonist WIN55,212-2 or vehicle were administered on days 19–21 (IP; 0.5 mg/kg) and behavioral and electrophysiological measures were taken on days 23 and 28. The CB1 receptor antagonist AM251 (IP; 0.3 mg/kg) or the GR antagonist RU-38486 (IP; 10 mg/kg) were co-administered with WIN55,212-2. Our results show that CMS significantly modified physiological and behavioral reactions, as observed by the impairment in avoidance extinction and LTP in the hippocampal-accumbens pathway, and the alterations in depression-like symptoms, such as coping with stress behavior, weight gain, and sucrose consumption. The most significant effect observed in this study was that 3 days of WIN55,212-2 administration prevented the CMS-induced alterations in emotional memory (ie, extinction) and plasticity. This effect was mediated by CB1 receptors as the CB1 receptor antagonist AM251 prevented the ameliorating effects of WIN55,212-2 on extinction and LTP. The GR antagonist RU-38486 also prevented the CMS-induced alterations in extinction and plasticity, and when co-administered with WIN55,212-2, the preventive effects after CMS were maintained. The findings suggest that enhancing cannabinoid signaling could represent a novel approach to the treatment of cognitive deficits that accompany stress-related depression.     

Israeli Rousettus aegyptiacus Pox Virus (IsrRAPXV) Infection in Juvenile Egyptian Fruit Bat (Rousettus aegyptiacus): Clinical Findings and Molecular Detection

During 2019, five carcasses of juvenile Egyptian fruit bats (Rousettus aegyptiacus) were submitted to the Kimron Veterinary Institute. These bats exhibited typical poxvirus like lesion plaques of different sizes on the skin, abdomen and the ventral side of the wings. Clinical and histopathological findings suggested a poxvirus infection. Infectious virus was isolated from skin swabs, skin tissue and tongue of the dead bats and was further confirmed to be a Poxvirus by molecular diagnosis using PCR with pan-chordopoxviruses primers. All the dead bats were found positive for two Poxvirus genes encoding a metalloproteinase and DNA dependent DNA polymerase. In this study, a novel real time quantitative PCR (qPCR) assay was established to further confirmed the presence of specific poxvirus viral DNA in all pathologically tested tissues. Moreover, according to sequence analysis, the virus was found to be highly similar to the recently discovered Israeli Rousettus aegyptiacus Pox Virus (IsrRAPXV).