Common risk factors associated with acute myocardial infarction: Population-based studies with a focus on gender differences

The overall aim of this thesis was to explore how the risk for AMI, and the associations between several of its risk factors, differs by gender. Information was collected from four Swedish cohorts: one patient cohort from Skara (1992-1993, n=1149) and three population-based cohorts, i.e. from Skara (1993-1994, n=1109), Vara (2001-2004, n=1811), and Skövde (2003-2005, n=1005). Participants were examined and filled out questionnaires regarding lifestyle and health. An interaction between gender and type 2 diabetes was found with regard to the risk of fatal AMI, showing that the impact of type 2 diabetes on AMI is greater in women than in men. Gender differences were also found in several AMI risk factors and in the associations between these risk factors: • Basal salivary cortisol was generally higher in women than in men (and in older subjects in general as compared to younger). • Low morning salivary cortisol and low diurnal variation of cortisol was associated with high waist-hip ratio solely in women. • Leisure time physical activity was negatively associated with insulin resistance and obesity in both men and women. However, the association with regard to insulin resistance and leisure time physical activity was stronger in women than in men. • Occupational physical activity was positively associated with insulin resistance and general and abdominal obesity in women only. • Factor analysis of AMI risk factors yielded three identical clusters in both genders: a “metabolic factor”, a “vitality factor”, and an “addiction factor”. However, these factors partly differed in their association with left ventricular hypertrophy, with significant associations with regard to the metabolic factor in both genders, and to the addiction factor in men. These findings show that gender differences with regard to AMI are present both in the risk of developing the disease and in how different risk factors for the disease interrelate. Thus, this thesis highlights the need for considering and addressing potential gender differences at all stages of preventive and interventional work aiming to reduce the burden of AMI

Long-term psychiatric consequences of exposure to trauma in Cambodia: A regional household survey.

The long-term psychiatric consequences of exposure to war and/or mass conflict continue to be of great concern and particularly in Cambodia. The current cross-sectional study examined the relationship between history of trauma and current psychiatric and functional morbidity in 3200 randomly selected adults aged 18-60 in Cambodia. Structured interviews were conducted from November 2011 until May 2012 in two predominantly rural regions purposively selected for differing duration of exposure to the Khmer Rouge occupation. Information was also collected regarding ongoing daily stressors and intimate partner violence. Despite high prevalence rates of conflict/war-related trauma, current rates of psychiatric disorders (depression, post-traumatic stress disorder) were relatively low, suggesting that the effects of trauma and extreme hardship in civilian populations may be modified by contextual factors and/or the passage of time. Poor to fair physical health was, however, reported by nearly 60% of the sample. Daily stressors were more important for current morbidity levels than history of trauma, especially in the region with shorter Khmer Rouge occupation. The results suggest that a focus exclusively on past trauma may overlook the contribution of adverse daily life circumstances towards current levels of well-being in civilian populations affected by war and/or mass conflict

Blood Pressure and Global Risk Assessment in a Swedish Population

This study investigated the association between SCORE and the 2007 ESH-ESC blood pressure categories and explored achievements of blood pressure goals considering global risk. In 2001–2005, a random sample of inhabitants aged 30–74 years in southwestern Sweden was invited to a survey of cardiovascular risk factors. The study enrolled 2816 participants (participation rate 76%). Blood pressure was categorized according to the 2007 ESH-ESC guidelines. Global risk of 10-year CVD death was estimated using the Swedish SCORE chart also accounting for additional risk from diabetes (SCORE-DM). SCORE-DM increased in both sexes from optimal blood pressure to manifest hypertension but did not differ between the normal blood pressure categories. However, SCORE-DM became significantly higher among those with temporarily high blood pressure (men 3.3 SD (1.7), women 1.1 (1.8)) and hypertension (3.6 (2.0), 2.0 (2.0)), compared to optimal blood pressure (1.6 (2.9), 0.6 (1.9)). In the presence of both hypertension and diabetes, high-risk subjects dominated (men 76%, women 61%), and correspondingly a major proportion of patients with known hypertension were at high risk at a blood pressure ≥160/100 mm Hg. These findings have strong implications on blood pressure evaluation in clinical practice and support the use of SCORE to evaluate global risk

Different environmental variables predict distribution and cover of the introduced red seaweed Eucheuma denticulatum in two geographical locations

In this study we examined abiotic and biotic factors that could potentially influence the presence of a non-indigenous seaweed, Eucheuma denticulatum, in two locations, one outside (Kane'ohe Bay, Hawai'i, USA) and one within (Mafia Island, Tanzania) its natural geographical range. We hypothesized that the availability of hard substrate and the amount of wave exposure would explain distribution patterns, and that higher abundance of herbivorous fishes in Tanzania would exert stronger top-down control than in Hawai'i. To address these hypotheses, we surveyed E. denticulatum in sites subjected to different environmental conditions and used generalized linear mixed models (GLMM) to identify predictors of E. denticulatum presence. We also estimated grazing intensity on E. denticulatum by surveying the type and the amount of grazing scars. Finally, we used molecular tools to distinguish between indigenous and non-indigenous strains of E. denticulatum on Mafia Island. In Kane'ohe Bay, the likelihood of finding E. denticulatum increased with wave exposure, whereas on Mafia Island, the likelihood increased with cover of coral rubble, and decreased with distance from areas of introduction (AOI), but this decrease was less pronounced in the presence of coral rubble. Grazing intensity was higher in Kane'ohe Bay than on Mafia Island. However, we still suggest that efforts to reduce non-indigenous E. denticulatum should include protection of important herbivores in both sites because of the high levels of grazing close to AOI. Moreover, we recommend that areas with hard substrate and high structural complexity should be avoided when farming non-indigenous strains of E. denticulatum

Identification of PDL-1 as a novel biomarker of sensitizer exposure in dendritic-like cells

The development of novel in vitro methods to assess risks of allergic sensitization are essential in reducing animal testing whilst maintaining consumer safety. The main research objectives of this study were to identify novel biomarkers to assess the sensitization predictability of chemicals. Phenotypic and cytokine responses of moDCs and MUTZ-3 cells were investigated following application of contact sensitizers; dinitrochlorobenzene (DNCB), cinnamaldehyde (Cin), eugenol (E), isoeugenol (IE), P-phenylenediamine (PPD) and non-sensitizers; salicyclic acid (SA) and sodium lauryl sulphate (SLS). CD86 was up-regulated on MUTZ-3 cells in response to DNCB, Cin and PPD, however, moDCs only modulated CD86 in response to DNCB and E. PDL-1 (Programmed death receptor ligand-1) proved a promising sensitization biomarker in MUTZ-3 cells where up-regulation occurred in response to DNCB, Cin, IE and PPD. Additionally, moDC-expressed PDL-1 was modulated in response to Cin, IE and E thus demonstrating improved sensitizer predictability when compared with CD86. MCP-1 and RANTES were identified as biomarkers of DNCB exposure but MCP-1 did not show any change in expression above controls for the other sensitizers investigated. However, RANTES was increased in MUTZ-3 cells by both DNCB and Cin. Our findings highlight novel biomarkers which, in MUTZ-3 cells, could be taken forward within a multiple biomarker in vitro assay ensuring strong and reliable predictability. © 2010 Elsevier Ltd

Subjective embodiment during the rubber hand illusion predicts severity of premonitory sensations and tics in Tourette Syndrome

In Tourette Syndrome, the expression of tics and commonly preceding premonitory sensations is associated with perturbed subjective feelings of self-control and agency. We compared responses to the Rubber Hand Illusion in 23 adults with TS and 22 controls. Both TS and control participants reported equivalent subjective embodiment of the artificial hand: feelings of ownership, location, and agency were greater during synchronous visuo-tactile stimulation, compared to asynchronous. However, individuals with TS did not manifest greater proprioceptive drift, an objective marker of embodiment observed in controls. An 'embodiment prediction error' index of the difference between subjective embodiment and objective proprioceptive drift correlated with severity of premonitory sensations. Feelings of ownership also correlated with premonitory sensation severity, and feelings of agency with tic severity. These findings suggest that subjective bodily ownership, as measured by the rubber hand illusion, contributes to susceptibility to the premonitory sensations that may be a precipitating factor in tics

Inactivation of TGFβ receptors in stem cells drives cutaneous squamous cell carcinoma

Melanoma patients treated with oncogenic BRAF inhibitors can develop cutaneous squamous cell carcinoma (cSCC) within weeks of treatment, driven by paradoxical RAS/RAF MAPK pathway activation. Here, we identify frequent TGFBR1 and TGFBR2 mutations in human vemurafenib-induced skin lesions and in sporadic cSCC. Functional analysis reveals these mutations ablate canonical TGFb Smad signaling which is localised to bulge stem cells in both normal human and murine skin. MAPK pathway hyperactivation (through BRafV600E or KRASG12D knockin) and TGFb signaling ablation (through Tgfbr1 deletion) in Lgr5+ve stem cells enables rapid cSCC development in the mouse. Mutation of TP53 (which is commonly mutated in sporadic cSCC) coupled with TGFbR1 deletion in Lgr5+ve cells also results in cSCC development. These findings indicate that Lgr5+ve stem cells can act as a cell of origin for cSCC and that RAS-RAF-MAPK pathway hyperactivation or TP53 mutation, coupled with loss of TGFb signaling, are driving events of skin tumorigenesis

Amplified engagement of prefrontal cortex during control of voluntary action in Tourette syndrome

Tourette syndrome is characterized by ‘unvoluntary’ tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. Although tic suppression in Tourette syndrome also engages the inferior frontal gyrus, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during functional MRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withhold responses to NoGo cues, and decide whether to press or withhold to ‘Choose’ cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus, thalamus and primary motor cortex. In Tourette syndrome, activity was elevated in the inferior frontal gyrus, insula and basal ganglia, most notably within the right inferior frontal gyrus during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this inferior frontal gyrus hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the pre-supplementary motor area to the caudate nucleus, globus pallidus and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater inferior frontal gyrus engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia

The Asp298 allele of endothelial nitric oxide synthase is a risk factor for myocardial infarction among patients with type 2 diabetes mellitus

Background: Endothelial dysfunction plays a central role in atherosclerotic progression and cardiovascular complications of type 2 diabetes mellitus (T2DM). Given the role of nitric oxide in the vascular system, we aimed to test hypotheses of synergy between the common endothelial nitric oxide synthase (eNOS) Asp(298) allele and T2DM in predisposing to acute myocardial infarction (AMI). Methods: In a population-based patient survey with 403 persons with T2DM and 799 healthy subjects from the population without diabetes or hypertension, we analysed the relation between T2DM, sex and the eNOS Asp(298) allele versus the risk for AMI. Results: In an overall analysis, T2DM was a significant independent risk factor for AMI. In patients with T2DM, homozygosity for the eNOS Asp(298) allele was a significant risk factor (HR 3.12 [1.49-6.56], p = 0.003), but not in subjects without diabetes or hypertension. Compared to wild-type non-diabetic subjects, all patients with T2DM had a significantly increased risk of AMI regardless of genotype. This risk was however markedly higher in patients with T2DM homozygous for the Asp(298) allele (HR 7.20 [3.01-17.20], p < 0.001), independent of sex, BMI, systolic blood pressure, serum triglycerides, HDL -cholesterol, current smoking, and leisure time physical activity. The pattern seemed stronger in women than in men. Conclusion: We show here a strong independent association between eNOS genotype and AMI in patients with T2DM. This suggests a synergistic effect of the eNOS Asp(298) allele and diabetes, and confirms the role of eNOS as an important pathological bottleneck for cardiovascular disease in patients with T2DM