Brain-heart pathways to blood pressure-related hypoalgesia

OBJECTIVE: High blood pressure (BP) is associated with reduced pain sensitivity, known as BP-related hypoalgesia. The underlying neural mechanisms remain uncertain, yet arterial baroreceptor signaling, occurring at cardiac systole, is implicated. We examined normotensives using functional neuroimaging (fMRI) and pain stimulation during distinct phases of the cardiac cycle to test the hypothesized neural mediation of baroreceptor-induced attenuation of pain. METHODS: Eighteen participants (10 women; 32.7 ± 6.5 years) underwent BP monitoring over one week at home, and individual pain thresholds were determined in the lab. Subsequently, participants were administered unpredictable painful and non-painful electrocutaneous shocks (stimulus type), timed to occur either at systole or diastole (cardiac phase) in an event-related design. After each trial, participants evaluated their subjective experience. RESULTS: Subjective pain was lower for painful stimuli administered at systole compared to diastole, F1, 2283 = 4.82; p = 0.03. Individuals with higher baseline BP demonstrated overall lower pain perception, F1, 2164 = 10.47; p < 0.0001. Within the brain, painful stimulation activated somatosensory areas, prefrontal cortex, cingulate cortex, posterior insula, amygdala, and the thalamus. Stimuli delivered during systole (concurrent with baroreceptor discharge) activated areas associated with heightened parasympathetic drive. No stimulus type x cardiac phase interaction emerged except for a small cluster located in the right parietal cortex. CONCLUSIONS: We confirm the negative associations between BP and pain, highlighting the antinociceptive impact of baroreceptor discharge. Neural substrates associated with baroreceptor/BP-related hypoalgesia include superior parietal lobule, precentral and lingual gyrus, regions typically involved in the cognitive aspects of pain experience

Network abnormalities in generalized anxiety pervade beyond the amygdala-prefrontal cortex circuit: insights from graph theory

Generalized anxiety (GAD) has excessive anxiety and uncontrollable worry as core symptoms. Abnormal cerebral functioning underpins the expression and perhaps pathogenesis of GAD: Studies implicate impaired communication between the amygdala and the pre-frontal cortex (PFC). Our aim was to longitudinally investigate whether such network abnormalities are spatially restricted to this circuit or if the integrity of functional brain networks is globally disrupted in GAD. We acquired resting-state functional magnetic resonance imaging data from 16 GAD patients and 16 matched controls at baseline and after 1 year. Using network modelling and graph-theory, whole-brain connectivity was characterized from local and global perspectives. Overall lower global efficiency, indicating sub-optimal brain-wide organization and integration, was present in patients with GAD compared to controls. The amygdala and midline cortices showed higher betweenness centrality, reflecting functional dominance of these brain structures. Third, lower betweenness centrality and lower degree emerged for PFC, suggesting weakened inhibitory control. Overall, network organization showed impairments consistent with neurobiological models of GAD (involving amygdala, PFC, and cingulate cortex) and further pointed to an involvement of temporal regions. Such impairments tended to progress over time and predict anxiety symptoms. A graph-analytic approach represents a powerful approach to deepen our understanding of GAD

Sindrome della morte improvvisa del lattante (SIDS) in Sicilia: una valutazione dei principali determinanti di accudimento

Aim: to evaluate certain caring behaviors associated with the onset of sudden infant death syndrome (SIDS). Methods: a telephone questionnaire was administered between May and July 2017 to a sample of 1055 Sicilian mothers within 30 days of delivery. A multivariate logistic analysis was conducted considering outcome variables: the sleeping position of the children, exclusive breastfeeding and passive smoking. Results: 62% of the participants place their children in the supine position, 37.9% practice exclusive breastfeeding and 89.0% are not smokers. Being aged &lt; 32 years, having a low level of education and limited economic resources are risk factors for the non-supine positioning of children during sleep. A low level of education, primiparity, non-participation to an antenatal course expose mothers to a greater risk of not practicing exclusive breastfeeding at one month. Postpartum smoking is positively associated with a low level of education. Conclusions: the assessment of the main caring behaviors towards newborns and infants is essential for an effective campaign for reducing the risk of SIDS

The D4Z4 Macrosatellite Repeat Acts as a CTCF and A-Type Lamins-Dependent Insulator in Facio-Scapulo-Humeral Dystrophy

Both genetic and epigenetic alterations contribute to Facio-Scapulo-Humeral Dystrophy (FSHD), which is linked to the shortening of the array of D4Z4 repeats at the 4q35 locus. The consequence of this rearrangement remains enigmatic, but deletion of this 3.3-kb macrosatellite element might affect the expression of the FSHD-associated gene(s) through position effect mechanisms. We investigated this hypothesis by creating a large collection of constructs carrying 1 to >11 D4Z4 repeats integrated into the human genome, either at random sites or proximal to a telomere, mimicking thereby the organization of the 4q35 locus. We show that D4Z4 acts as an insulator that interferes with enhancer–promoter communication and protects transgenes from position effect. This last property depends on both CTCF and A-type Lamins. We further demonstrate that both anti-silencing activity of D4Z4 and CTCF binding are lost upon multimerization of the repeat in cells from FSHD patients compared to control myoblasts from healthy individuals, suggesting that FSHD corresponds to a gain-of-function of CTCF at the residual D4Z4 repeats. We propose that contraction of the D4Z4 array contributes to FSHD physio-pathology by acting as a CTCF-dependent insulator in patients

Perseverative cognition alters the functionality of positive valence systems: an investigation with a multimodal approach

Growing evidence suggests that perseverative cognition (PC), a form of cognition characterized by repetitive, intrusive and uncontrollable thoughts, is a transdiagnostic risk factor for different psychiatric disorders. Although PC characterizes both hypo-motivational (e.g., depression) and hyper-motivational (e.g., addiction) disorders, it has been almost exclusively studied within the context of the negative valence systems and only anecdotal evidence exists about its effects on reward processing. The present study combined laboratory-based, computational and ecological assessments with the aim to fill this gap. Psychiatrically healthy individuals performed the Probabilistic Reward Task (PRT) before and after the experimental induction of PC (n = 22) or a waiting period (n = 24). The effects of PC on reward sensitivity and learning rate were dissociated by means of computational modeling. All participants then underwent a one-week Ecological Momentary Assessment of everyday occurrence of PC, as well as anticipatory and consummatory reward-related behavior. Increased response bias on the PRT appeared in response to the induction of PC (versus waiting), likely due to an increase in learning rate but not in reward sensitivity, as suggested by computational modeling. Daily episodes of PC increased the discrepancy between expected and obtained reward (reward prediction error). The current converging experimental and ecological evidence advises toward the value of investigating neurobiological alterations underpinning reward processing dysfunctions during PC as well as toward the implementation of ad hoc interventions to normalize positive valence systems dysfunctionality

A new MAGE-4 antigenic peptide recognized by cytolytic T lymphocytes on HLA-A24 carcinoma cells.

"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in other normal tissues. They encode tumor specific antigens that are used in cancer immunotherapy trials. MAGE-4 antigens represent promising targets for cancer immunotherapy because gene MAGE-4 is expressed in more than 50% of carcinomas of the esophagus, lung, bladder, and head and neck. To identify new MAGE-4 antigenic peptides, we have folded HLA-A*2402 soluble molecules with candidate peptide NYKRCFPVI, which corresponds to amino acids 143 to151 of the MAGE-4 protein. A24/MAGE-4 multimers were used to isolate a cytolytic T cell clone that recognized the MAGE-4 peptide from the blood cells of a donor without cancer. This clone lysed specifically A24 carcinoma cells expressing MAGE-4. The antigenic peptide is processed more efficiently in tumor cells pre-treated with IFN-gamma. This MAGE-4 peptide could represent an interesting target for immunotherapy because it is presented by HLA-A24 molecules, which are widely expressed in different ethnic groups

A MAGE-1 antigenic peptide recognized by human cytolytic T lymphocytes on HLA-A2 tumor cells.

"Cancer-germline" genes such as those of the MAGE family are expressed in many tumors and in male germline cells, but are silent in normal tissues. They encode shared tumor-specific antigens that have been used in therapeutic vaccination trials of cancer patients. It was previously demonstrated that MAGE-1 peptide KVLEYVIKV was presented by HLA-A 0201 molecules on the surface of a human breast carcinoma cell line, but no human specific CTL had been isolated so far. Here, we have used HLA-A2/MAGE-1 fluorescent multimers to isolate from blood cells three human CTL clones that recognized the MAGE-1 peptide. These clones killed efficiently HLA-A2 tumor cells expressing MAGE-1, whether or not they were treated with IFN-gamma, suggesting that the MAGE-1 antigen is processed efficiently by both the standard proteasome and the immunoproteasome. These results indicate that the MAGE-1.A2 peptide can be used for antitumoral vaccination

Can't get it off my brain: meta-analysis of neuroimaging studies on perseverative cognition

Perseverative cognition (i.e. rumination and worry) describes intrusive, uncontrollable, repetitive thoughts. These negative affective experiences are accompanied by physiological arousal, as if the individual were facing an external stressor. Perseverative cognition is a transdiagnostic symptom, yet studies of neural mechanisms are largely restricted to specific clinical populations (e.g. patients with major depression). The present study applied activation likelihood estimation (ALE) meta-analyses to 43 functional neuroimaging studies of perseverative cognition to elucidate the neurobiological substrates across individuals with and without psychopathological conditions. Task-related and resting state functional connectivity studies were examined in separate meta-analyses. Across task-based studies, perseverative cognition engaged medial frontal gyrus, cingulate gyrus, insula, and posterior cingulate cortex. Resting state functional connectivity studies similarly implicated posterior cingulate cortex together with thalamus and anterior cingulate cortex (ACC), yet the involvement of ACC distinguished between perseverative cognition in healthy controls (HC) and clinical groups. Perseverative cognition is accompanied by the engagement of prefrontal, insula and cingulate regions, whose interaction may support the characteristic conjunction of self-referential and affective processing with (aberrant) cognitive control and embodied (autonomic) arousal. Within this context, ACC engagement appears critical for the pathological expression of rumination and worry