Marike Cockeran

The α2C-adrenoceptor antagonist, ORM-10921, has antipsychotic-like effects in social isolation reared rats and bolsters the response to haloperidol.

Early studies suggest that selective α2C-adrenoceptor (AR)-antagonism has anti-psychotic-like and pro-cognitive properties. However, this has not been demonstrated in an animal model of schizophrenia with a neurodevelopmental construct. The beneficial effects of clozapine in refractory schizophrenia and associated cognitive deficits have, among others, been associated with its α2C-AR modulating activity. Altered brain-derived neurotrophic factor (BDNF) has been linked to schizophrenia and cognitive deficits. We investigated whether the α2C-AR antagonist, ORM-10921, could modulate sensorimotor gating and cognitive deficits, as well as alter striatal BDNF levels in the social isolation reared (SIR) model of schizophrenia, comparing its effects to clozapine and the typical antipsychotic, haloperidol, the latter being devoid of α2C-AR-activity. Moreover, the ability of ORM-10921 to augment the effects of haloperidol on the above parameters was also investigated. Animals received subcutaneous injection of either ORM-10921 (0.01mg/kg), clozapine (5mg/kg), haloperidol (0.2mg/kg), haloperidol (0.2mg/kg)+ORM-10921 (0.01mg/kg) or vehicle once daily for 14days, followed by assessment of novel object recognition (NOR), prepulse inhibition (PPI) of startle response and striatal BDNF levels. SIR significantly attenuated NOR memory as well as PPI, and reduced striatal BDNF levels vs. social controls. Clozapine, ORM-10921 and haloperidol+ORM-10921, but not haloperidol alone, significantly improved SIR-associated deficits in PPI and NOR, with ORM-10921 also significantly improving PPI deficits vs. haloperidol-treated SIR animals. Haloperidol+ORM-10921 significantly reversed reduced striatal BDNF levels in SIR rats. α2C-AR-antagonism improves deficits in cognition and sensorimotor gating in a neurodevelopmental animal model of schizophrenia and bolsters the effects of a typical antipsychotic, supporting a therapeutic role for α2C-AR-antagonism in schizophrenia.

The state of the psychological contract and employees' intention to leave : the mediating role of employee well-being

Changes in the work environment can influence employees’ perception of the employment relationship, their psychological contracts, and consequently, their work-related attitudes and behaviour. The study aimed to demonstrate the mechanism through which the state of employees’ psychological contract impacts employees’ intention to leave employment and the role of employee well-being as a mediator. Cross-sectional data were obtained from employees representing various organisations (N = 246). Structural equation modelling demonstrated that employee well-being mediates the relationship between the state of the psychological contract and an employee’s intention to leave the organisation. The study stresses the importance of designing individual-level interventions to enhance well-being in the workplace, which should form part of the retention strategy of any organisation.

The long-term effects of methamphetamine exposure during pre-adolescence on depressive-like behaviour in a genetic animal model of depression.

Methamphetamine (METH) is a psychostimulant and drug of abuse, commonly used early in life, including in childhood and adolescence. Adverse effects include psychosis, anxiety and mood disorders, as well as increased risk of developing a mental disorder later in life. The current study investigated the long-term effects of chronic METH exposure during pre-adolescence in stress-sensitive Flinders Sensitive Line (FSL) rats (genetic model of depression) and control Flinders Resistant Line (FRL) rats. METH or vehicle control was administered twice daily from post-natal day 19 (PostND19) to PostND34, followed by behavioural testing at either PostND35 (early effects) or long-lasting after withdrawal at PostND60 (early adulthood). Animals were evaluated for depressive-like behaviour, locomotor activity, social interaction and object recognition memory. METH reduced depressive-like behaviour in both FSL and FRL rats at PostND35, but enhanced this behaviour at PostND60. METH also reduced locomotor activity on PostND35 in both FSL and FRL rats, but without effect at PostND60. Furthermore, METH significantly lowered social interaction behaviour (staying together) in both FRL and FSL rats at PostND35 and PostND60, whereas self-grooming time was significantly reduced only at PostND35. METH treatment enhanced exploration of the familiar vs. novel object in the novel object recognition test (nORT) in FSL and FRL rats on PostND35 and PostND60, indicative of reduced cognitive performance. Thus, early-life METH exposure induce social and cognitive deficits. Lastly, early-life exposure to METH may result in acute antidepressant-like effects immediately after chronic exposure, whereas long-term effects after withdrawal are depressogenic. Data also supports a role for genetic predisposition as with FSL rats.

Hyperpulsatile pressure, systemic inflammation and cardiac stress are associated with cardiac wall remodeling in an African male cohort: the SABPA study

Inflammation may contribute to an increase in cardiac wall stress through pathways related to cardiac remodeling. Cardiac remodeling is characterized by myocyte hypertrophy, myocyte death and modifications of the extracellular matrix. We sought to explore associations among cardiac remodeling, inflammation and myocardial cell injury in a bi-ethnic cohort of South African men and women. We included 165 men (76 African and 89 Caucasian) and 174 women (80 African and 94 Caucasian) between 20 and 65 years of age. Inflammatory markers used were C-reactive protein (CRP), interleukin-6 and tumor necrosis factor-alpha (TNF-α), whereas troponin T (Trop T) and the N-terminal of pro B-type natriuretic peptide (NT-proBNP) were used as cardiac markers. The frequency of ischemic events (ST segment depression) and left ventricular strain (left ventricular hypertrophy: LVH) were monitored by a 24-h recording of ambulatory blood pressure (BP), ECG and 12-lead standard ECG. Hypertension diagnosed with ambulatory monitoring was more frequent in Africans (53.85 vs. 24.59%; P<0.001), as was the number of ischemic events (6±15 (1; 5) vs. 3±6 (0; 3)). Inflammatory markers (CRP, IL-6 and TNF-α) and the degree of LVH were all significantly higher in Africans (P<0.05). BP was associated (P<0.05) with Trop T in men across ethnic groups. In African men, cardiac stress (NT-proBNP) was associated with TNF-alpha (P<0.001), Trop T (P<0.001) and pulse pressure (P=0.048; adjusted R2=0.45). The susceptibility for cardiac wall remodeling appears to increase with hyperpulsatile pressure, low-grade systemic inflammation and ventricular stress, and may lead to the development of future cardiovascular events in African men.

The defense response and alcohol intake: A coronary artery disease risk? The SABPA Study

ABSTRACT The behavioral defense coping response (DefS) as a measure of coping with emotional stress may increase alcohol intake (gamma glutamyl transferase (γGT)), the risk for coronary artery disease (CAD) and insulin sensitivity (homeostasis model assessment, HOMA). We assessed associations between coping and cardiometabolic risk markers in a bi-ethnic cohort (N = 390) from South Africa. Ambulatory blood pressure (BP) and ECG, fasting blood and coping scores were obtained. Africans, and mostly when utilizing DefS, showed higher 24h BP, a low-grade inflammatory state, central obesity, increased HOMA [4.07 (3.66, 4.47)] and more ST events compared to their Caucasian counterparts. ROC γ-GT analyses predicting 24-h ambulatory hypertension showed a higher γ-GT cut-point in Africans (55.4 U/l) than in Caucasians (19.5 U/l). Odds ratios (ORs) of γ-GT cut-points predicting 24-h ambulatory hypertension was evident in DefS African men [OR: 7.37 (95% CI: 6.71–8.05), p = 0.003] and in DefS Caucasians, albeit at a lower γ-GT cut-point (19.5 U/l). Higher γ-GT cut-points in DefS Africans or Caucasians were not associated with HOMA > 3. DefS accompanied by alcohol abuse in taxing emotional situations, if no social support is forthcoming, underscores a profile of reduced coronary perfusion. It may enhance vasoconstriction of the coronary arteries, with compensatory increases in BP, and induce a risk for future coronary artery disease.

Defensive coping and renovascular disease risk - Adrenal fatigue in a cohort of Africans and Caucasians: The SABPA study.

BACKGROUND Defensive coping is an established cardiovascular risk factor in Africans. Additionally, chronic, excessive or inadequate hypothalamic-pituitary-adrenal axis (HPAA) stress responses could either increase or decrease cortisol responses, which may relate to renal impairment. We scrutinised the relationship between urinary cortisol levels and renovascular disease risk in Africans and Caucasians utilising defensive coping. METHODS Africans (n=168) and Caucasians (n=207) from the SABPA (Sympathetic activity and Ambulatory Blood Pressure in Africans) study were included in our analyses, excluding HIV positive, diabetic, renal impairment, and cortisone users. The Coping Strategy Indicator questionnaire assessed preferred coping responses. Ambulatory blood pressure was recorded together with 8h fasting blood and urine sampling. Renovascular disease risk markers included the albumin-to-creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR). RESULTS The main findings revealed that Caucasians with high cortisol showed augmented renovascular disease risk. Conversely, Africans revealed low cortisol levels whilst 21.84% reported experience of severe stress, possibly depicting HPAA hypoactivity. Additionally, these Africans with low cortisol revealed increased ACR and decreased eGFR, which was further enhanced by defensive coping. CONCLUSIONS Defensive coping enhanced renovascular risk in Africans, especially in those with lower cortisol, which may be due to HPAA dysfunction and/or adrenal fatigue.

Troponin T release is associated with silent myocardial ischaemia in black men: the SABPA study

Background High sensitivity cardiac troponin T (hs-cTnT) is a validated marker of myocardial damage and may reflect the degree of silent myocardial ischaemia (SMI) and ventricular strain. Our aim was to compare hs-cTnT levels in black and white South Africans taking SMI into consideration. We further explored the capability of hs-cTnT to predict the presence of compensatory systolic hypertension in this South African cohort. Methods A bi-ethnic sex cohort (n = 404) with similar socioeconomic status (198 black participants and 206 white participants, aged 20–65 years) participated in this target population study where 24 h ambulatory blood pressure, electrocardiogram and overnight fasting cardiometabolic variables were measured. Results Hypertension, higher glycated haemoglobin levels and more frequent and longer SMI events were observed more often in the black participants. Multivariate linear regression analysis showed positive associations between SMI events [Adj. R2 = 0.19; β 0.35 (0.08–0.62); p < 0.01], SMI event maximum duration [Adj. R2 = 0.17, β 0.43 (0.16–0.70), p < 0.01], SMI total duration [Adj. R2 = 0.12; β 0.37 (0.10; 0.65), p = 0.05] and hs-cTnT in black males only.] A lower hs-cTnT cut-point ≥4.2 pg/ml for 24 h systolic hypertension was predicted in the black participants compared with ≥5.6 pg/ml in the white participants (area under the curve 0.66–67 (95% CI: 0.57–0.75), p < 0.001) with a respective sensitivity/specificity of 64/68% and 61/71%. Conclusions hs-cTnT may be a potential marker of SMI in the prediction of systolic blood pressure increases, as well as clusters of risk factors for cardiovascular disease. Ethnic- and possibly sex-specific references values for hs-cTnT should be considered for risk stratification.

Medicine possession ratio as proxy for adherence to antiepileptic drugs: prevalence, associations, and cost implications

Objective To determine the adherence status to antiepileptic drugs (AEDs) among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168), who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm) was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent) if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low) or >110% (unacceptably high) was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208) but were independent of sex (P<0.182; Cramer’s V=0.009). Age group (P<0.0001; Cramer’s V=0.067), active ingredient (P<0.0001; Cramer’s V=0.071), and number of comor-bidities (P<0.0001; Cramer’s V=0.050) were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US

Ethnic disparity in defensive coping endothelial responses: The SABPA study

736,376.23) of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US

Investigation of the coexistence of CKD and non-communicable chronic diseases in a PBM company in South Africa

3,227,894.85 (16.38%). Conclusion Nonadherence to antiepileptic treatment is a major problem, encompassing ~20% of cost in our study. Adherence, however, is likely to improve with the treatment period. Further research is needed to determine the factors influencing epileptic patients’ prescription refill adherence.