Unstable Maternal Environment, Separation Anxiety, and Heightened CO2 Sensitivity Induced by Gene-by-Environment Interplay

Background: In man, many different events implying childhood separation from caregivers/unstable parental environment are associated with heightened risk for panic disorder in adulthood. Twin data show that the occurrence of such events in childhood contributes to explaining the covariation between separation anxiety disorder, panic, and the related psychobiological trait of CO2 hypersensitivity. We hypothesized that early interference with infant-mother interaction could moderate the interspecific trait of response to CO2 through genetic control of sensitivity to the environment. Methodology: Having spent the first 24 hours after birth with their biological mother, outbred NMRI mice were crossfostered to adoptive mothers for the following 4 post-natal days. They were successively compared to normally-reared individuals for: number of ultrasonic vocalizations during isolation, respiratory physiology responses to normal air (20%O2), CO2-enriched air (6% CO2), hypoxic air (10%O2), and avoidance of CO2-enriched environments. Results: Cross-fostered pups showed significantly more ultrasonic vocalizations, more pronounced hyperventilatory responses (larger tidal volume and minute volume increments) to CO2-enriched air and heightened aversion towards CO2- enriched environments, than normally-reared individuals. Enhanced tidal volume increment response to 6%CO2 was present at 16–20, and 75–90 postnatal days, implying the trait’s stability. Quantitative genetic analyses of unrelated individuals, sibs and half-sibs, showed that the genetic variance for tidal volume increment during 6%CO2 breathing was significantly higher (Bartlett x = 8.3, p = 0.004) among the cross-fostered than the normally-reared individuals, yielding heritability of 0.37 and 0.21 respectively. These results support a stress-diathesis model whereby the genetic influences underlying the response to 6%CO2 increase their contribution in the presence of an environmental adversity. Maternal grooming/licking behaviour, and corticosterone basal levels were similar among cross-fostered and normally-reared individuals. Conclusions: A mechanism of gene-by-environment interplay connects this form of early perturbation of infant-mother interaction, heightened CO2 sensitivity and anxiety. Some no

Gene-environment interactions in panic disorder and CO\u2082 sensitivity: Effects of events occurring early in life

Heterogeneous life events (LE) precede the onset of-and potentially increase the susceptibility to-panic disorder (PD). It remains unknown whether LE can act as moderators in the context of gene-by-environment interactions (G 7E) that alter the susceptibility to PD and the related trait of CO\u2082 sensitivity, nor it is known whether such moderation may depend on occurrence of events at different epochs in life. In 712 general population twins we analyzed by Maximum Likelihood analyses of ordinal data whether life (major- and stressful) events moderate the genetic risk for PD and CO\u2082 sensitivity, as indexed by the 35% CO\u2082 /65% O\u2082 challenge. For CO\u2082 sensitivity, best-fitting models encompassed both additive and interactional effects that increased linearly with the cumulative number and severity (SEV) of events in lifetime. By analyzing the moderation effect of cumulative SEV separately for events that had occurred in adulthood (between age 18 and 37) or during childhood-adolescence (before the 18th birthday), we found evidence of G 7E only within the childhood-adolescence window of risk, although twins had rated the childhood-adolescence events as significantly (P\u2009=\u20090.001) less severe than those having occurred during adulthood. For PD, all interactional terms could be dropped without significant worsening of the models' fit. Consistently with a diathesis-stress model, LE appear to act as moderators of the genetic variance for CO\u2082 sensitivity. Childhood-adolescence appears to constitute a sensitive period to the action of events that concur to alter the susceptibility to this panic-related trait

Psychometric Properties of the Social Phobia and Anxiety Inventory for Children (SPAI-C) A Sample of Italian School-Aged Children From the General Population

Reliable and valid self-report questionnaires could be useful as initial screening instruments for social phobia in both clinical settings and general populations. The present study investigates the factor structure and psychometric properties of the Social Phobia and Anxiety Inventory for Children (SPAI-C) in a sample of 228 children from the Italian general population aged 8 to 11. The children were asked to complete the Italian version of the SPAI-C and the Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire. Confirmatory factor analyses revealed that social phobia can be conceptualized as a unitary construct consisting of five distinct but interrelated symptom clusters named Assertiveness, General Conversation, Physical/Cognitive Symptoms, Avoidance, and Public Performance. Internal consistency of the SPAI-C total scores and two subscales was good; correlations between SPAI-C total scores and SCARED total scores/subscales ranged from moderate to high (Generalized Anxiety Disorder, for social phobia), with the SCARED Social Phobia subscale as the best predictor of SPAI-C total scores. The results indicate that the SPAI-C is a reliable and sensitive instrument suitable for identifying Social Phobia in the young Italian general population.Reliable and valid self-report questionnaires could be useful as initial screening instruments for social phobia in both clinical settings and general populations. The present study investigates the factor structure and psychometric properties of the Social Phobia and Anxiety Inventory for Children (SPAI-C) in a sample of 228 children from the Italian general population aged 8 to 11. The children were asked to complete the Italian version of the SPAI-C and the Screen for Child Anxiety Related Emotional Disorders (SCARED) questionnaire. Confirmatory factor analyses revealed that social phobia can be conceptualized as a unitary construct consisting of five distinct but interrelated symptom clusters named Assertiveness, General Conversation, Physical/Cognitive Symptoms, Avoidance, and Public Performance. Internal consistency of the SPAI-C total scores and two subscales was good; correlations between SPAI-C total scores and SCARED total scores/subscales ranged from moderate to high (Generalized Anxiety Disorder, for social phobia), with the SCARED Social Phobia subscale as the best predictor of SPAI-C total scores. The results indicate that the SPAI-C is a reliable and sensitive instrument suitable for identifying Social Phobia in the young Italian general population

Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2\ub75 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46\u201372), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88\ub75% (95% CI 86\ub77\u201390\ub70) with the switch strategy and 89\ub78% (88\ub72\u201391\ub72) with upfront treatment (hazard ratio 0\ub789, 95% CI 0\ub773\u20131\ub708; p=0\ub723). 5-year disease-free survival was 90\ub70% (95% CI 87\ub79\u201391\ub77) with anastrozole (124 events), 88\ub70% (85\ub78\u201389\ub79) with exemestane (148 events), and 89\ub74% (87\ub73 to 91\ub71) with letrozole (129 events; p=0\ub724). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3\u20134 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3\u20134 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency