AIP variant causing familial prolactinoma.

Pathogenic variants in the aryl hydrocarbon receptor-interacting protein (AIP) gene are increasingly recognised as a cause of familial isolated pituitary adenoma. AIP-associated tumours are most commonly growth hormone (GH) producing. In our cohort of 175 AIP mutation positive patients representing 93 kindreds, 139 (79%) have GH excess, 19 have prolactinoma (17 familial and 2 sporadic cases) and out of the 17 clinically non-functioning tumours 4 were subsequently operated and found to be GH or GH & prolactin immunopositive adenoma. Here we report a family with an AIP variant, in which multiple family members are affected by prolactinoma, but none with GH excess. To our knowledge this is the first reported family with an AIP pathogenic variant to be affected solely by prolactinoma. These data suggest that prolactinoma families represent a small subset of AIP mutation positive kindreds, and similar to young-onset sporadic prolactinomas, AIP screening would be indicated.

Significant Benefits of AIP Testing and Clinical Screening in Familial Isolated and Young-onset Pituitary Tumors.

CONTEXT: Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). OBJECTIVE: To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. DESIGN: 12-year prospective, observational study. PARTICIPANTS & SETTING: We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. INTERVENTIONS & OUTCOME: AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). RESULTS: Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). CONCLUSIONS: Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Correction: How Do People Become W.E.I.R.D.? Migration Reveals the Cultural Transmission Mechanisms Underlying Variation in Psychological Processes.

[This corrects the article DOI: 10.1371/journal.pone.0147162.].

Author Correction: Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant men.

In the version of this Article originally published, the units for the 'Weight' column in Table 1 were incorrect; they should have been kg. This has now been corrected.

Childhood ecology influences salivary testosterone, pubertal age and stature of Bangladeshi UK migrant men.

Male reproductive investment is energetically costly, and measures of human reproductive steroid hormones (testosterone), developmental tempo (pubertal timing) and growth (stature) correlate with local ecologies at the population level. It is unclear whether male reproductive investment in later life is 'set' during childhood development, mediated through adulthood, or varies by ethnicity. Applying a life-course model to Bangladeshi migrants to the United Kingdom, here we investigate plasticity in human male reproductive function resulting from childhood developmental conditions. We hypothesized that childhood ecology shapes adult trade-offs between reproductive investment and/or other fitness-related traits. We predicted correspondence between these traits and developmental timing of exposure to ecological constraints (Bangladesh) or conditions of surplus (United Kingdom). We compared: Bangladesh sedentees (n = 107); Bangladeshi men who migrated in childhood to the United Kingdom (n = 59); migrants who arrived in adulthood (n = 75); second-generation UK-born and raised children of Bangladeshi migrants (n = 56); and UK-born ethnic Europeans (n = 62). Migration before puberty predicted higher testosterone and an earlier recalled pubertal age compared with Bangladeshi sedentees or adult migrants, with more pronounced differences in men who arrived before the age of eight. Second-generation Bangladeshis were taller, with higher testosterone than sedentees and adult migrants, and higher waking testosterone than Europeans. Age-related testosterone profiles varied by group, declining in UK migrants, increasing in sedentees, and having no significant relationship within UK-born groups. We conclude that male reproductive function apparently remains plastic late into childhood, is independent of Bengali or European ethnicity, and shapes physiological trade-offs later in life.

Cortisol awakening response is elevated in acute coronary syndrome patients with type-D personality.

OBJECTIVE: Type-D or "distressed" personality and depression following admission for acute coronary syndrome (ACS) have been associated with poor clinical outcome. The biological pathways underpinning this relationship may include disruption of the hypothalamic-pituitary-adrenocortical (HPA) axis. We therefore assessed cortisol output in patients who had recently suffered from ACS. METHOD: Salivary cortisol was assessed eight times over a 24-h period in 72 patients within 5 days of admission for ACS. Depressive symptoms were measured with the Beck Depression Inventory (BDI), and type-D personality was measured with the Type-D Scale-16. Particular attention was given to cortisol awakening response (CAR), which was measured as the difference in cortisol between waking and peak responses 15-30 min later. RESULTS: Cortisol showed a typical diurnal pattern, with low levels in the evening, high levels early in the day, and CAR averaging 7.58+/-10.0 nmol/l. Cortisol was not related to the severity of ACS or underlying coronary artery disease or to BDI scores. The CAR was positively associated with type-D personality independently of age, gender, and body mass (P=.007). Linear regression showed that type-D personality accounted for 7.9% of the variance in CAR after age, sex, body mass, BDI, cortisol level on waking, and fatigue had been taken into account (P=.008). CONCLUSIONS: Type-D personality may be associated with disruption of HPA axis function in survivors of acute cardiac events and may contribute to heightened inflammatory responses influencing future cardiac morbidity.

Experimental priming of independent and interdependent activity does not affect culturally variable psychological processes.

Cultural psychologists have shown that people from Western countries exhibit more independent self-construal and analytic (rule-based) cognition than people from East Asia, who exhibit more interdependent self-construal and holistic (relationship-based) cognition. One explanation for this cross-cultural variation is the ecocultural hypothesis, which links contemporary psychological differences to ancestral differences in subsistence and societal cohesion: Western thinking formed in response to solitary herding, which fostered independence, while East Asian thinking emerged in response to communal rice farming, which fostered interdependence. Here, we report two experiments that tested the ecocultural hypothesis in the laboratory. In both, participants played one of two tasks designed to recreate the key factors of working alone and working together. Before and after each task, participants completed psychological measures of independent-interdependent self-construal and analytic-holistic cognition. We found no convincing evidence that either solitary or collective tasks affected any of the measures in the predicted directions. This fails to support the ecocultural hypothesis. However, it may also be that our priming tasks are inappropriate or inadequate for simulating subsistence-related behavioural practices, or that these measures are fixed early in development and therefore not experimentally primable, despite many previous studies that have purported to find such priming effects.

How Do People Become W.E.I.R.D.? Migration Reveals the Cultural Transmission Mechanisms Underlying Variation in Psychological Processes.

Cultural psychologists have shown that people from Western, Educated, Industrialised, Rich, Democratic (WEIRD) countries often exhibit different psychological processing to people from less-WEIRD countries. The former exhibit more individualistic and less collectivistic social orientation, and more analytic and less holistic cognition, than non-Westerners. Yet the mechanisms responsible for maintaining this cultural variation are unclear. Immigration is an ideal 'natural experiment' for uncovering such mechanisms. We used a battery of psychological measures previously shown to vary cross-culturally to compare the social orientation and cognitive style of 286 residents of East London from three cultural backgrounds: (i) 1st-generation British Bangladeshi immigrants; (ii) 2nd-generation British Bangladeshis raised in the UK to Bangladeshi-raised parents; and (iii) non-migrants whose parents were born and raised in the UK. Model comparison revealed that individualism and dispositional attribution, typical of Western societies, are driven primarily by horizontal cultural transmission (e.g. via mass media), with parents and other family members having little or no effect, while collectivism, social closeness and situational attribution were driven by a mix of vertical/oblique cultural transmission (e.g. via family contact) and horizontal cultural transmission. These individual-level transmission dynamics can explain hitherto puzzling population-level phenomena, such as the partial acculturation of 2nd-generation immigrants on measures such as collectivism (due to the mix of vertical and horizontal cultural transmission), or the observation in several countries of increasing individualism (which is transmitted horizontally and therefore rapidly) despite little corresponding change in collectivism (which is transmitted partly vertically and therefore more slowly). Further consideration of cultural transmission mechanisms, in conjunction with the study of migrant communities and model comparison statistics, can shed light on the persistence of, and changes in, culturally-variable psychological processes.

The impact of time of waking and concurrent subjective stress on the cortisol response to awakening.

Both time of awakening and stress are thought to influence the magnitude of the cortisol awakening response (CAR), but the relative importance of these factors is unclear. This study assessed these influences in a combined within- and between-subject design. Data were collected from 32 men and women working as station staff in the London underground railway system in three conditions: early-shift days, day-shift days, and control days. Saliva samples were obtained on waking, 30 and 60 min later, together with measures of concurrent subjective stress, sleep quality the night before, and accumulated stress at the end of the day. Participants woke up more than 3.5h earlier on average on early-shift than day-shift or control days, and cortisol levels on waking were lower in the early-shift condition. The CAR (assessed both with increases from waking to 30 min and with area under the curve measures) was greater on early-shift days. However, respondents were more stressed over the hour after waking and reported more sleep disturbance on early-shift days; when these factors were taken into account, the difference in CAR related to experimental condition was no longer significant. Comparisons were also made between individuals who started their day-shifts in the morning and afternoon. The morning shift group woke an average of 2h earlier than did the afternoon shift group, but did not differ on stress, sleep quality, or CAR. Stress assessed retrospectively at the end of the day was not associated with the CAR. We conclude that early waking, stress early in the day, and sleep disturbance often coincide, but need to be distinguished in order accurately to interpret differences in CAR magnitude.

The influence of psychological stress and socioeconomic status on platelet activation in men.

OBJECTIVE: Circulating monocyte- and neutrophil-platelet aggregates are sensitive markers of in vivo platelet activation. Socioeconomic status is inversely associated with risk of coronary heart disease. We assessed the impact of psychological stress on leukocyte-platelet aggregates in men from higher and lower socioeconomic status groups. METHODS: Participants were 37 healthy non-smoking men aged 30-59 years, divided by occupation into higher and lower social status groups. Blood was drawn at baseline, immediately following stressful behavioural tasks, and at 30 and 75 min post-stress, and aggregates were analysed using flow cytometry. Cardiovascular and subjective stress responses were also monitored. RESULTS: There were significant increases following stress in monocyte-, neutrophil-, lymphocyte- and total leukocyte-platelet aggregates (all P<0.05). The largest responses were in monocyte-platelet (21% increase) and neutrophil-platelet (16.7% increase) aggregates. Lower socioeconomic status men had greater numbers of leukocyte-platelet aggregates throughout, but the magnitude of stress responses did not vary with social status. The increase in monocyte- and leukocyte-platelet aggregates was associated with systolic blood pressure stress responsivity. CONCLUSIONS: Psychological stress induces platelet activation as indexed by leukocyte-platelet aggregates, and correlations with cardiovascular stress reactions suggest that sympathoadrenal responses may be responsible. Platelet activation may be a mechanism through which social position influences cardiovascular disease risk.

Exaggerated platelet and hemodynamic reactivity to mental stress in men with coronary artery disease.

OBJECTIVE: This study compared the effects of acute mental stress on cardiovascular and subjective responses and platelet activation in male patients with established coronary artery disease (CAD) and age-matched controls. METHODS: We assessed 17 male CAD patients aged 44 to 59 years and 22 healthy male controls. Blood pressure, heart rate, and hemodynamics were assessed before, during, and up to 2 hours after administration of color/word and mirror tracing tasks. Blood was sampled at baseline, after tasks, and at 30 and 75 minutes after stress, and platelet activation was assessed by measuring platelet-leukocyte aggregates (PLAs) using flow cytometry. RESULTS: CAD patients showed significantly greater systolic blood pressure stress responses than controls (mean increases of 43.9 and 28.3 mm Hg, adjusted for income, body mass index, waist/hip ratio, and medication), together with larger increases in heart rate (14.1 and 4.7 bpm) and cardiac index. Total peripheral resistance increased during the poststress recovery period in CAD patients but not in controls. PLAs increased with stress in both groups, but remained elevated at 75 minutes in CAD patients, returning to baseline in controls. Heart rate and cardiac index responses were correlated with increases in subjective stress and with depression ratings, whereas PLA responses were associated with ratings of task difficulty. CONCLUSION: Acute mental stress stimulated heightened cardiovascular responses in CAD patients, coupled with more prolonged platelet activation. These factors may contribute to plaque rupture and thrombogenesis, and partly mediate stress-induced triggering of acute coronary syndromes.

Platelets, coronary heart disease, and stress.

Coronary heart disease is the leading cause of death in Western society, and its development is associated with chronic stress and other psychosocial factors. Atherosclerosis, the disorder underlying this disease, is an inflammatory process in which leukocytes interact with structurally intact but dysfunctional endothelium of the arteries. Platelets play a key role in this process by binding to leukocytes and promoting their recruitment to the endothelium. Platelet-leukocyte interactions also stimulate the release of pro-inflammatory and pro-thrombotic factors which promote atherosclerosis. Elevated circulating levels of platelet-leukocyte aggregates have been reported in cardiac patients and in individuals of low socioeconomic status, a factor associated with chronic psychological stress. Increased platelet activation has also been observed in individuals prone to depression or hostility, and in people subject to high levels of work stress. Acute psychological stress increases circulating platelet-leukocyte aggregates in healthy individuals and this effect is prolonged in cardiac patients. Platelet activation may be a mechanism linking psychosocial stress with increased coronary risk, and may also play a role in the emotional triggering of acute coronary syndromes in patients with advanced coronary disease.

Pathophysiological processes underlying emotional triggering of acute cardiac events.

Acute negative emotional states may act as triggers of acute coronary syndrome (ACS), but the biological mechanisms involved are not known. Heightened platelet activation and hemodynamic shear stress provoked by acute stress may contribute. Here we investigated whether patients whose ACS had been preceded by acute anger, stress, or depression would show heightened hemodynamic and platelet activation in response to psychophysiological stress testing. We studied 34 male patients an average of 15 months after they had survived a documented ACS. According to an interview conducted within 5 days of hospital admission, 14 men had experienced acute negative emotion in the 2 h before symptom onset, and 20 men had not experienced any negative emotion. Hemodynamic variables and platelet activation were monitored during performance of challenging color-word interference and public speaking tasks and over a 2-h poststress recovery period. The emotion trigger group showed significantly greater increases in monocyte-platelet, leukocyte-platelet, and neutrophil-platelet aggregate responses to stress than the nontrigger group, after adjusting for age, body mass, smoking status, and medication. Monocyte-platelet aggregates remained elevated for 30 min after stress in the emotion trigger group. The emotion trigger group also showed poststress delayed recovery of systolic pressure and cardiac output compared with the nontrigger group. These results suggest that some patients with coronary artery disease may be particularly susceptible to emotional triggering of ACS because of heightened platelet activation in response to psychological stress, coupled with impaired hemodynamic poststress recovery.

The effect of oxidative stress on endothelium-dependent and nitric oxide donor-induced relaxation: implications for nitrate tolerance.

Increased inactivation of nitric oxide (NO) by superoxide has been implicated in nitrate tolerance. Here, we set out to compare the inhibitory effect of superoxide on endothelium-dependent, acetylcholine (ACh)-mediated vascular relaxation with that on the endothelium-independent effects of glyceryl trinitrate (GTN) and another NO donor drug, S-nitrosoglutathione (GSNO). Rings of thoracic aorta from adult male Wistar rats (350-450 g) were precontracted with phenylephrine (approximately EC(90)) prior to cumulative additions (10 nM/L-10 microM/L) of GTN, GSNO, or ACh. Rings were then treated with the superoxide generator pyrogallol (300 micromol/L) alone or following pretreatment with the Cu/Zn superoxide dismutase inhibitor diethyldithiocarbamate (DETCA; 100 micromol/L), and cumulative additions of the vasodilators were repeated. All experiments were conducted in the presence of catalase (3000 U/ml) to prevent accumulation of hydrogen peroxide. Relaxation to ACh was abolished by pyrogallol-derived superoxide. Relaxation to GSNO was significantly inhibited by superoxide (P < 0.05, n = 8) and was more pronounced at lower GSNO concentrations. However, GTN was relatively resistant to inhibition by superoxide with modest inhibition only occurring in rings pretreated with DETCA prior to pyrogallol (P < 0.05; n = 8). In contrast to GSNO, the inhibitory effect was more pronounced with high concentrations of GTN, suggesting that the mechanism underlying superoxide-mediated inhibition is different for the two NO donor drugs. Further experiments showed that vascular responses to ACh were not inhibited (P > 0.05, n = 6) in aortic rings made tolerant to GTN (10 micromol/L, 2-h incubation) and that treatment of vessels with the antioxidant vitamin C (1 mmol/L) successfully prevented the development of tolerance. Taken together, these results suggest that superoxide is not a major factor in tolerance in vitro and imply that the protective actions of vitamin C are unrelated to its antioxidant activity in this setting.