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1.  Hypervigilance for fear after basolateral amygdala damage in humans 
Translational Psychiatry  2012;2(5):e115-.
Recent rodent research has shown that the basolateral amygdala (BLA) inhibits unconditioned, or innate, fear. It is, however, unknown whether the BLA acts in similar ways in humans. In a group of five subjects with a rare genetic syndrome, that is, Urbach–Wiethe disease (UWD), we used a combination of structural and functional neuroimaging, and established focal, bilateral BLA damage, while other amygdala sub-regions are functionally intact. We tested the translational hypothesis that these BLA-damaged UWD-subjects are hypervigilant to facial expressions of fear, which are prototypical innate threat cues in humans. Our data indeed repeatedly confirm fear hypervigilance in these UWD subjects. They show hypervigilant responses to unconsciously presented fearful faces in a modified Stroop task. They attend longer to the eyes of dynamically displayed fearful faces in an eye-tracked emotion recognition task, and in that task recognize facial fear significantly better than control subjects. These findings provide the first direct evidence in humans in support of an inhibitory function of the BLA on the brain's threat vigilance system, which has important implications for the understanding of the amygdala's role in the disorders of fear and anxiety.
PMCID: PMC3365265  PMID: 22832959
basolateral amygdala; eye tracking; fear vigilance; fMRI; sMRI; urbach–wiethe disease
2.  Functional magnetic resonance imaging during emotion recognition in social anxiety disorder: an activation likelihood meta-analysis 
Background: Social anxiety disorder (SAD) is characterized by abnormal fear and anxiety in social situations. Functional magnetic resonance imaging (fMRI) is a brain imaging technique that can be used to demonstrate neural activation to emotionally salient stimuli. However, no attempt has yet been made to statistically collate fMRI studies of brain activation, using the activation likelihood-estimate (ALE) technique, in response to emotion recognition tasks in individuals with SAD. Methods: A systematic search of fMRI studies of neural responses to socially emotive cues in SAD was undertaken. ALE meta-analysis, a voxel-based meta-analytic technique, was used to estimate the most significant activations during emotional recognition. Results: Seven studies were eligible for inclusion in the meta-analysis, constituting a total of 91 subjects with SAD, and 93 healthy controls. The most significant areas of activation during emotional vs. neutral stimuli in individuals with SAD compared to controls were: bilateral amygdala, left medial temporal lobe encompassing the entorhinal cortex, left medial aspect of the inferior temporal lobe encompassing perirhinal cortex and parahippocampus, right anterior cingulate, right globus pallidus, and distal tip of right postcentral gyrus. Conclusion: The results are consistent with neuroanatomic models of the role of the amygdala in fear conditioning, and the importance of the limbic circuitry in mediating anxiety symptoms.
PMCID: PMC3547329  PMID: 23335892
ALE; social anxiety; generalized social phobia; SAD; meta-analysis; fMRI
3.  Intermittent Explosive Disorder in South Africa: Prevalence, Correlates, and the Role of Traumatic Exposures 
Psychopathology  2009;42(2):92-98.
The epidemiology of DSM-IV intermittent explosive disorder (IED) is not well characterized in developing country settings. In South Africa, given the high rates of violence and trauma, there is particular interest in traumatic exposures as potential risk factors for IED.
We examined the prevalence and predictors of IED in a nationally representative sample of 4351 South African adults. IED and other diagnoses based on DSM-IV criteria were assessed using the World Health Organization Composite International Diagnostic Interview (CIDI). A 28 item scale was constructed to measure exposure to traumatic events.
Overall, 2.0% of participants (95% CI: 0–4.9%) fulfilled criteria for the narrow definition of IED and 9.5% (95% CI: 6.6–12.3%) fulfilled criteria for the broad definition of IED. Individuals with IED experienced high rates of comorbid anxiety, mood, and substance use disorders compared to non-IED participants. In multivariate analysis, a diagnosis of IED was associated with Caucasian and mixed-race ethnicity, psychiatric comorbidity and exposure to multiple traumatic events.
These data suggest a relatively high prevalence of IED in South Africa. By reducing violence and trauma, and by providing appropriate psychological support to trauma survivors, we may be able to reduce rates of IED.
PMCID: PMC3237393  PMID: 19225243
4.  The mental health impact of AIDS-related mortality in South Africa: a national study 
Few data exist on how the HIV/AIDS epidemic may influence population mental health. The associations were examined between knowing someone who died of HIV/AIDS and common mental disorders among South African adults.
Between 2002 and 2004, a nationally representative sample of 4351 adults were interviewed about personally knowing someone who died of HIV/AIDS, and the World Health Organization Composite International Diagnostic Interview was used to generate psychiatric diagnoses for depression, anxiety and substance abuse disorders during the preceding 12 months based on the Diagnostic and Statistical Manual, 4th edition (DSM-IV).
Overall, 42.2% of the sample knew someone who died of HIV/AIDS, and 16.5% met the criteria for at least one DSM-IV diagnosis. Individuals who knew someone who died of HIV/AIDS were significantly more likely to have any DSM-IV defined disorder, including any depressive, anxiety or substance-related disorder (p<0.001 for all associations). In multivariate models adjusted for participant demographic characteristics, life events and socioeconomic status, individual disorders significantly associated with knowing someone who died of HIV/AIDS included generalised anxiety disorder, social phobia and alcohol/drug dependence or abuse. Based on these results, it is estimated that up to 15% of 12-month DSM-IV disorders in the South African adult population may be related to knowing someone who died of HIV/AIDS.
These novel data suggest that AIDS-related mortality may contribute substantially to the burden of mental disorders in settings of high HIV prevalence. While this finding requires further investigation, these data suggest the need to strengthen mental health services in communities where HIV/AIDS is prevalent.
PMCID: PMC3203694  PMID: 19074926
5.  The Epidemiology of Obsessive-Compulsive Disorder in the National Comorbidity Survey Replication 
Molecular psychiatry  2008;15(1):53-63.
Despite significant advances in the study of obsessive-compulsive disorder (OCD), important questions remain about the disorder's public health significance, appropriate diagnostic classification, and clinical heterogeneity. These issues were explored using data from the National Comorbidity Survey Replication (NCS-R), a nationally representative survey of U.S. adults. A subsample of 2073 respondents was assessed for lifetime DSM-IV OCD. More than one-quarter of respondents reported experiencing obsessions or compulsions at some time in their lives. While conditional probability of OCD was strongly associated with the number of obsessions and compulsions reported, only small proportions of respondents met full DSM-IV criteria for lifetime (2.3%) or 12-month (1.2%) OCD. OCD is associated with substantial comorbidity, not only with anxiety and mood disorders but also with impulse-control and substance use disorders. Severity of OCD, assessed by an adapted version of the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), is associated with poor insight, high comorbidity, high role impairment, and high probability of seeking treatment. The high prevalence of subthreshold OCD symptoms may help explain past inconsistencies in prevalence estimates across surveys and suggests that the public health burden of OCD may be greater than its low prevalence implies. Evidence of a preponderance of early-onset cases in males, high comorbidity with a wide range of disorders, and reliable associations between disorder severity and key outcomes may have implications for how OCD is classified in DSM-V.
PMCID: PMC2797569  PMID: 18725912
epidemiology; obsessive behavior; compulsive behavior; obsessive-compulsive behavior; National Comorbidity Survey-Replication
6.  DSM-IV Personality Disorders and Their Axis I Correlates in the South African Population 
Psychopathology  2008;41(6):356-364.
The prevalence of personality disorders (PD) in the South African population is largely unknown. Thus, we undertook to estimate prevalence, demographic correlates, co-morbidity and treatment rates of DSM-IV PD among South Africans.
Sampling and Methods
A three-stage probability sample design was used. Of the 4,433 interviews obtained, based on quality control criteria, 4,315 interviews were retained for analysis. All participants were screened for PD and axis I disorders with the World Health Organisation Composite International Diagnostic Interview. The multiple imputation method was then used to estimate prevalence.
The multiple imputation prevalence estimate in the total sample was 6.8%. All three PD clusters were significantly co-morbid with each other and with other axis I disorders. Male gender was the only significant predictor of PD. Of note was the finding that less than one fifth of participants with a possible PD diagnosis had received treatment for a mental health or substance abuse problem in the previous 12 months.
The high co-morbidity of PD with axis I disorders in South Africa is consistent with previous reports elsewhere. However, more research is indicated to determine the reasons for the higher prevalence of cluster A disorders than of cluster B and C disorders in this population.
PMCID: PMC3949611  PMID: 18765961
Diagnostic and Statistical Manual of Mental Disorders, axis I disorders; Personality disorders, prevalence; South Africa
7.  Twelve-month mental disorders in South Africa: prevalence, service use and demographic correlates in the population-based South African Stress and Health Study 
Psychological medicine  2007;38(2):211-220.
South Africa’s history and current social conditions suggest that mental disorders are likely to be a major contributor to disease burden, but there has been no national study using standardized assessment tools.
The South African Stress and Health Study was a nationally representative in-person psychiatric epidemiological survey of 4351 adults (aged ≥18 years) that was conducted as part of the WHO World Mental Health (WMH) Survey Initiative between January 2002 and June 2004. Twelve-month prevalence and severity of DSM-IV disorders, treatment, and sociodemographic correlates were assessed with Version 3.0 of the WHO Composite International Diagnostic Interview (CIDI 3.0).
The 12-month prevalence of any DSM-IV/CIDI disorder was 16.5%, with 26.2% of respondents with disorder classified as severe cases and an additional 31.1% as moderately severe cases. The most common disorders were agoraphobia (4.8 %), major depressive disorder (4.9%) and alcohol abuse or dependence (4.5 %). Twenty-eight percent of adults with a severe or moderately severe disorder received treatment compared to 24.4% of mild cases. Some 13.8% of persons with no disorder received treatment. Treatment was mostly provided by the general medical sector with few people receiving treatment from mental health providers.
Psychiatric disorders are much higher in South Africa than in Nigeria and there is a high level of unmet need among persons with severe and moderately severe disorders.
PMCID: PMC2718686  PMID: 17903333
Mental disorders; mental health services; South Africa
8.  Reduced expression of neurofibromin in human meningiomas. 
British Journal of Cancer  1997;76(6):747-756.
Meningiomas are common, mostly benign, tumours arising from leptomeningeal cells of the meninges, which frequently contain mutations in the neurofibromatosis type 2 (NF2) gene. In this study, we analysed a protein product of the neurofibromatosis type 1 (NF1) gene, neurofibromin, in human established leptomeningeal cells LTAg2B, in 17 sporadic meningiomas and in a meningioma from a patient affected by NF2. The expression level of neurofibromin was determined by immunoblotting and immunoprecipitation with anti-neurofibromin antibodies. The functional status of neurofibromin was analysed through its ability to stimulate the intrinsic GTPase activity of p21 ras. In the cytosolic extracts of four sporadic meningiomas and in the NF2-related meningioma, the expression level and the GTPase stimulatory activity of neurofibromin were drastically reduced compared with the level present in the human brain, human established leptomeningeal cells LTAg2B and the remaining 13 meningiomas. Our results suggest that neurofibromin is expressed in leptomeningeal cells LTAg2B and in most meningiomas, i.e. tumours derived from these cells. The reduced expression and GTPase stimulatory activity of neurofibromin was found in about 23% of meningiomas and in the single NF2-related meningioma analysed. These results suggest that decreased levels of neurofibromin in these tumours may contribute to their tumorigenesis.
PMCID: PMC2228040  PMID: 9310240
9.  Steady-state pharmacokinetics of intravenous and oral ciprofloxacin in elderly patients. 
Antimicrobial Agents and Chemotherapy  1989;33(11):1927-1931.
The steady-state pharmacokinetics of ciprofloxacin were evaluated in nine elderly patients with lower respiratory tract infections after an intravenous dosage regimen of 200 mg every 12 h (n = 9) and an oral dosage regimen of 750 mg every 12 h (n = 6). Ciprofloxacin concentrations in serum and urine were measured by high-performance liquid chromatography. The peak concentration in serum, total body clearance (CLs), steady-state volume of distribution (Vss), and terminal elimination half-life after intravenous dosing were 3.5 +/- 0.8 micrograms/ml, 4.38 +/- 1.80 ml/min per kg, 1.6 +/- 0.6 liters/kg, and 5.8 +/- 2.4 h, respectively. The peak concentration in serum, time to peak concentration in serum, absorption lag time, and absolute bioavailability (F) after oral dosing were 7.6 +/- 2.2 micrograms/ml, 1.9 +/- 1.0 h, 0.4 +/- 0.5 h, and 7.7 +/- 24.2%, respectively. The elevated drug concentrations in serum samples from the elderly after oral dosing, compared with data obtained from younger subjects, appear to be a function of reduced CLs, renal clearance, and Vss. The increased F observed in some patients may be due to the effect of concomitant or proximate administration of tube feedings, medications which may alter gastric motility or acidity, or decreased first-pass metabolism. The results demonstrate that factors related to age and declining renal function, rather than infectious disease state, may be primary in determining alterations in pharmacokinetic parameters in the elderly. In elderly patients with normal renal function for their age, no dosage adjustment for intravenous or oral ciprofloxacin is necessary.
PMCID: PMC172789  PMID: 2610503

Results 1-9 (9)