Sentinel seroprevalence of SARS-CoV-2 in Gauteng Province, South Africa, August - October 2020.

BACKGROUND: Estimates of prevalence of anti-SARS-CoV-2 antibody positivity (seroprevalence) for tracking the COVID-19 epidemic are lacking for most African countries. OBJECTIVES: To determine the prevalence of antibodies against SARS-CoV-2 in a sentinel cohort of patient samples received for routine testing at tertiary laboratories in Johannesburg, South Africa. METHODS: This sentinel study was conducted using remnant serum samples received at three National Health Laboratory Service laboratories in the City of Johannesburg (CoJ) district. Collection was from 1 August to 31 October 2020. We extracted accompanying laboratory results for glycated haemoglobin (HbA1c), creatinine, HIV, viral load and CD4 T-cell count. An anti-SARS-CoV-2 targeting the nucleocapsid (N) protein of the coronavirus with higher affinity for IgM and IgG antibodies was used. We reported crude as well as population-weighted and test-adjusted seroprevalence. Multivariate logistic regression analysis was used to determine whether age, sex, HIV and diabetic status were associated with increased risk for seropositivity. RESULTS: A total of 6 477 samples were analysed, the majority (n=5 290) from the CoJ region. After excluding samples with no age or sex stated, the model population-weighted and test-adjusted seroprevalence for the CoJ (n=4 393) was 27.0% (95% confidence interval (CI) 25.4 - 28.6). Seroprevalence was highest in those aged 45 - 49 years (29.8%; 95% CI 25.5 - 35.0) and in those from the most densely populated areas of the CoJ. Risk for seropositivity was highest in those aged 18 - 49 years (adjusted odds ratio (aOR) 1.52; 95% CI 1.13 - 2.13; p=0.0005) and in samples from diabetics (aOR 1.36; 95% CI 1.13 - 1.63; p=0.001). CONCLUSIONS: Our study conducted between the first and second waves of the pandemic shows high levels of current infection among patients attending public health facilities in Gauteng Province.

Longitudinal changes in vitamin D and its metabolites in pregnant South Africans.

BACKGROUND: Vitamin D deficiency (VDD) has been associated with adverse maternal and foetal outcomes and is determined by measuring 25 hydroxyvitamin D (25(OH)D). The 25(OH)D is catabolized to 24, 25-(OH) 2D and the ratio of 25(OH) D to 24, 25-(OH)2D, the vitamin D metabolite ratio (VMR), is thought to be a superior marker of VDD, being elevated in such states. The aims of this study were to assess the longitudinal vitamin D status of pregnant women by measuring cholecalciferol, 25(OH)D, 24, 25-(OH)2D and VMR at two time points and also to determine any association of vitamin D and metabolites with gestational age at birth, birth length and weight. METHODS: We recruited 400 pregnant black African women in their first trimester (V1) and measured weights and heights. Ultrasound scans were performed for gestational age. Blood was drawn at V1 and at about 26 weeks (V2) of gestation for cholecalciferol, 25(OH)D, 24, 25-(OH)2D, VMR and parathyroid hormone (PTH). An OGTT was performed at V2 where fasting glucose, insulin and 30-minute glucose were measured. At birth, we measured birth weight, length and gestational age. Maternal insulin, PTH and vitamin D binding protein (VDBP) were measured by immunoassay. Maternal albumin was measured colorimetrically. Maternal cholecalciferol, 25(OH)D and 24, 25-(OH)2D, were measured by mass spectrometry and free and bioavailable vitamin D were calculated. Initial gestation was determined by ultrasound. We compared analytes by visit as well as by 25(OH)D status. Vitamin D deficiency (<30 nmol/L) was defined according to the National Academy of Medicine guidelines. Linear regression analysis was used to determine associations of vitamin D molecules with maternal blood pressure, fasting and 30-minute insulin and blood glucose and neonatal parameters. RESULTS: Results are presented for participants for whom we had complete data (n = 330-346 depending on variable). The prevalence of vitamin D deficiency (VDD) was 35.8 % at V1 and 32.4 % at V2. Levels of 25(OH)D did not change significantly between visits. Levels of 24, 25(OH)2D dropped from the first to the second visit (17.64 ± 12.64 to 9.39 ± 9.07 nmol/L; p < 0.0001) while VMR increased ((3.15 (1.31; 7.67) to 7.90 (2.44; 25.98); p < 0.0001). The proportion of women with the lowest cholecalciferol concentrations increased at V2 compared to the V1 (36.1-42.8 %; p = 0.02). In multivariable regression models 25(OH)D was negatively associated with 30-minute glucose concentrations (p = 0.038) whilst 24, 25-(OH)2D was positively associated with fasting insulin (p = 0.017) and HOM A-I R (p = 0.023). There was no correlation of 25(OH)D or metabolites with infant birth weight, birth length or gestational age. CONCLUSIONS: Maternal VDD is common in pregnant black South African women. Decreased VMR suggest that catabolism of 25(OH)D is reduced in pregnancy to maintain adequate free vitamin D levels.

Multiple sclerosis is linked to MAPKERK overactivity in microglia.

Reassessment of published observations in patients with multiple sclerosis (MS) suggests a microglial malfunction due to inappropriate (over)activity of the mitogen-activated protein kinase pathway ERK (MAPKERK). These observations regard biochemistry as well as epigenetics, and all indicate involvement of this pathway. Recent preclinical research on neurodegeneration already pointed towards a role of MAPK pathways, in particular MAPKERK. This is important as microglia with overactive MAPK have been identified to disturb local oligodendrocytes which can lead to locoregional demyelination, hallmark of MS. This constitutes a new concept on pathophysiology of MS, besides the prevailing view, i.e., autoimmunity. Acknowledged risk factors for MS, such as EBV infection, hypovitaminosis D, and smoking, all downregulate MAPKERK negative feedback phosphatases that normally regulate MAPKERK activity. Consequently, these factors may contribute to inappropriate MAPKERK overactivity, and thereby to neurodegeneration. Also, MAPKERK overactivity in microglia, as a factor in the pathophysiology of MS, could explain ongoing neurodegeneration in MS patients despite optimized immunosuppressive or immunomodulatory treatment. Currently, for these patients with progressive disease, no effective treatment exists. In such refractory MS, targeting the cause of overactive MAPKERK in microglia merits further investigation as this phenomenon may imply a novel treatment approach.

The Novel Coronavirus and Inflammation.

The SARS-CoV-2 virus which causes COVID-19 disease was initially described in the Hubei Province of China and has since spread to more than 200 countries and territories of the world. Severe cases of the disease are characterised by release of high levels of pro-inflammatory cytokines and other inflammatory mediators in a process characterised as a cytokine storm. These inflammatory mediators are associated with pathological leukocyte activation states with tissue damage. Here, we review these effects with a focus on their potential use in diagnosis, patient stratification and prognosis, as well as new drug targets.

COVID-19 and Vulnerable Populations in Sub-Saharan Africa.

The novel corona virus 2019 (COVID-19) outbreak which started in Hubei province in China has now spread to every corner of the earth. While the pandemic started later in Africa, it is now found in all African countries to varying degrees. It is thought that the prevalence and severity of disease is influenced by a number of non-communicable diseases (NCDs) which are all becoming increasingly prevalent in sub-Saharan Africa (SSA). In addition, SSA bears the major burden of human immunodeficiency virus (HIV) and tuberculosis (TB) infections. While data from Europe and the United States show that children are spared severe disease, it is uncertain if the same holds true in SSA where children suffer from sickle cell disease and malnutrition in addition to other infectious diseases. There is limited data from Africa on the effects of these conditions on COVID-19. In this review, we discuss the epidemiology of some of these conditions in Africa and the possible pathogenesis for the interactions of these with COVID-19.

COVID-19-Related Laboratory Analyte Changes and the Relationship Between SARS-CoV-2 and HIV, TB, and HbA1c in South Africa.

We conducted a retrospective analysis on data of all adults tested for SARS-CoV-2 across our laboratory network in South Africa over a 4-month period. Out of 842,197 tests, 11.7% were positive and 88.3% negative. The prevalence of HIV was 6.25 and 6.31% in the SARS-CoV-2-positive and SARS-CoV-2-negative cohort, respectively (p = 0.444). However, the prevalence of HIV-positive individuals in the critical cohort (9.15%) was higher than in the noncritical group (6.24%) (p = 0.011). Active tuberculosis infection was approximately 50% less in SARS-CoV-2-positive than in SARS-CoV-2-negative individuals. The prevalence of uncontrolled diabetes was 3.4 times higher in SARS-CoV-2-positive cases but was not higher in the critical vs. noncritical cases (p = 0.612). The neutrophil-to-lymphocyte ratio, coagulation markers, urea, and cardiac- and liver-related analytes were significantly elevated in the critical compared to noncritical cases. Platelet count and creatinine concentration did not differ significantly between the two groups. These findings do not support increased prevalence of HIV or tuberculosis in individuals with SARS-CoV-2 infection but do suggest an association of increased disease severity with HIV-positive status. Uncontrolled diabetes was positively associated with a significantly higher prevalence of SARS-CoV-2, and our investigation into analyte changes associated with SARS-CoV-2 disease severity supported previous findings of raised inflammatory markers, coagulation markers, liver- and cardiac-related analytes, and urea but not for creatinine and platelet count.

The role of serological testing in the SARS-CoV-2 outbreak.

Antibody tests for the novel coronavirus, SARS-CoV2, have been developed both as rapid diagnostic assays and for high-throughput formal serology platforms. Although these tests may be a useful adjunct to a diagnostic strategy, they have a number of limitations. Because of the antibody and viral dynamics of the coronavirus, their sensitivity can be variable, especially at early time points after symptom onset. Additional data are required on the performance of the tests in the South African population, especially with regard to development and persistence of antibody responses and whether antibodies are protective against reinfection. These tests may, however, be useful in guiding the public health response, providing data for research (including seroprevalence surveys and vaccine initiatives) and development of therapeutic strategies.

Increased prevalence of Barrett's esophagus in patients with MUTYH-associated polyposis (MAP).

Barrett's oesophagus (BE) has been associated with an increased risk of both colorectal adenomas and colorectal cancer. A recent investigation reported a high frequency of BE in patients with adenomatous polyposis coli (APC)-associated polyposis (FAP). The aim of the present study is to evaluate the prevalence of BE in a large cohort of patients with MUTYH-associated polyposis (MAP) and APC-associated adenomatous polyposis. Patients with a genetically confirmed diagnosis of familial adenomatous polyposis (FAP) or MAP were selected and upper gastrointestinal (GI) endoscopy reports, pathology reports of upper GI biopsies were reviewed to determine the prevalence of BE in these patients. Histologically confirmed BE was found in 7 (9.7%) of 72 patients with MAP. The mean age of diagnosis was 60.2 years (range 54.1-72.4 years). Two patients initially diagnosed with low grade dysplasia showed fast progression into high grade dysplasia and esophageal cancer, respectively. Only 4 (1.4%) of 365 patients with FAP were found to have pathologically confirmed BE. The prevalence of BE in patients with MAP is much higher than reported in the general population. We recommend that upper GI surveillance of patients with MAP should not only focus on the detection of gastric and duodenal adenomas but also on the presence of BE.

Prostate cancer age-standardised incidence increase between 2006 and 2016 in Gauteng Province, South Africa: A laboratory data-based analysis.

BACKGROUND: Prostate cancer (PCa) is the leading male neoplasm in South Africa (SA) and is the second most frequently diagnosed cancer among men globally. Age-specific incidence rates (ASIRs) vary by up to 189-fold globally, with an ASIR of 68.0 per 100 000 in 2018 in SA. OBJECTIVES: To describe PCa among men undergoing prostate biopsy in Gauteng Province, SA. METHODS: We undertook a retrospective descriptive study using prostate biopsy data collected from the National Health Laboratory Service (NHLS) database between 2006 and 2016. We extracted the Systematized Nomenclature of Medicine (SNOMED) clinical terms morphology and topography codes to assign histological findings using the International Classification of Diseases for Oncology. PCa was defined as adenocarcinoma with a reported Gleason Score (GS). The new grade group (GG) based on the GS is defined as follows; (i) GG1 for a GS ≤6; (ii) GG2 for a GS of 3 + 4 = 7 ; (iii) GG3 for a GS of 4 + 3 = 7; (iv) GG4 for a GS of 8; and (v) GG5 for a GS ≥9. Higher-grade disease was defined as GG4 and GG5 (GS ≥8), in line with local guidelines. We reported associations of PCa with a GS ≥7 with age and race and used provincial and world standard population data to determine annual ASIRs. RESULTS: We identified 22 937 biopsies referred to the NHLS between 2006 and 2016. Of the 6 448 biopsies (39%) with a PCa finding for black Africans, 46% were diagnosed with high-risk PCa compared with 36 - 40% for other race groups (p<0.0001). Black Africans were more likely than whites to have GG4 or GG5 PCa (odds ratio 1.45; 95% confidence interval 1.27 - 1.67). The ASIR increased from 44.9 per 100 000 in 2006 to 57.3 per 100 000 in 2016. CONCLUSIONS: Black African men were significantly more likely to present with PCa with a GS ≥8 (GG4 and GG5) compared with the other racial groups in Gauteng. The ASIR increased dramatically during the study period, perhaps as a result of increased screening and awareness. There is a need for additional research to better understand why black African men present with higher-grade disease.

Using Big Data Techniques to Improve Prostate Cancer Reporting in the Gauteng Province, South Africa.

Prostate cancer (PCa) data is of public health importance in South Africa. Biopsy data is recorded as semi-structured narrative text that is not easily analysed. Our study reports a pilot study that applied predictive analytics and text mining techniques to extract prognostic information that guides patient management. In particular, the Gleason score (GS) reported in a number of formats were extracted successfully. Our study reports that predominantly older men were diagnosed with PCa reporting a high-risk GS (8-10). Where cell differentiation was reported, 64% of biopsies reported poor differentiation. The approaches demonstrated in our study should be extended to a larger dataset to assess whether it has the potential to scale up to the national level.

Biomimetic sensory feedback through peripheral nerve stimulation improves dexterous use of a bionic hand.

We describe use of a bidirectional neuromyoelectric prosthetic hand that conveys biomimetic sensory feedback. Electromyographic recordings from residual arm muscles were decoded to provide independent and proportional control of a six-DOF prosthetic hand and wrist-the DEKA LUKE arm. Activation of contact sensors on the prosthesis resulted in intraneural microstimulation of residual sensory nerve fibers through chronically implanted Utah Slanted Electrode Arrays, thereby evoking tactile percepts on the phantom hand. With sensory feedback enabled, the participant exhibited greater precision in grip force and was better able to handle fragile objects. With active exploration, the participant was also able to distinguish between small and large objects and between soft and hard ones. When the sensory feedback was biomimetic-designed to mimic natural sensory signals-the participant was able to identify the objects significantly faster than with the use of traditional encoding algorithms that depended on only the present stimulus intensity. Thus, artificial touch can be sculpted by patterning the sensory feedback, and biologically inspired patterns elicit more interpretable and useful percepts.

Haemoglobin A1c or Glycated Albumin for Diagnosis and Monitoring Diabetes: An African Perspective.

Diabetes mellitus (DM) has reached epidemic proportions across the globe with the largest increases seen in sub-Saharan Africa. Those that are diagnosed are largely poorly controlled. This review summarizes the limitations of the use of glycated haemoglobin (HBA1c) in Africa and current knowledge on the utility of glycated albumin and fructosamine in African patients. The diagnosis and monitoring of DM in African patients may be compromised by associated conditions like sickle cell anaemia, chronic kidney disease and HIV infection. Glycated albumin reflects short term glycaemia and is not affected by many conditions that alter HbA1c. It can be measured enzymatically, and this review discusses methods for analysis, and discusses the advantages and limitations in specific situations with an emphasis on conditions that also affect HbA1c.

Diabetes and abnormal glucose tolerance in subjects with tuberculosis in a South African urban center.

SETTING: Primary health care clinics. OBJECTIVES: To determine the prevalence of diabetes mellitus (DM) in tuberculosis (TB) patients using glycated haemoglobin (HbA1c), and to compare the performance of laboratory and point-of-care (POC) HbA1c measurement. METHODS: This was a cross-sectional study of 325 patients. Screening was at POC using laboratory HbA1c methods; DM was confirmed by the oral glucose tolerance test (OGTT). Multivariate regression analysis was performed to determine predictors of HbA1c. RESULTS: Mean laboratory-derived HbA1c was significantly higher than mean POC HbA1c (P = 0.007). Of 83 subjects who underwent OGTT, 2 (2.4%) were diagnosed with DM, 3 (3.60%) with impaired fasting glucose and 15 (18.1%) with impaired glucose tolerance. Twelve (14.5%) had an HbA1c of 6.50% using POC HbA1c and 21 (25.3%) using laboratory HbA1c. In multivariate regression analysis, age and weight were positively associated with both laboratory and POC HBA1c, while duration of anti-tuberculosis treatment was negatively associated with both. CONCLUSION: Glucose and HbA1c levels fell with increased duration of anti-tuberculosis treatment, suggesting that the optimal time for DM screening in this population was at least 5 months after TB was first diagnosed. Our data suggest that the use of HbA1c is inappropriate for testing glycaemia in patients with TB.

Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry.

PURPOSE: Recent transcriptomic analyses have identified four distinct molecular subtypes of colorectal cancer with evident clinical relevance. However, the requirement for sufficient quantities of bulk tumor and difficulties in obtaining high-quality genome-wide transcriptome data from formalin-fixed paraffin-embedded tissue are obstacles toward widespread adoption of this taxonomy. Here, we develop an immunohistochemistry-based classifier to validate the prognostic and predictive value of molecular colorectal cancer subtyping in a multicenter study. EXPERIMENTAL DESIGN: Tissue microarrays from 1,076 patients with colorectal cancer from four different cohorts were stained for five markers (CDX2, FRMD6, HTR2B, ZEB1, and KER) by immunohistochemistry and assessed for microsatellite instability. An automated classification system was trained on one cohort using quantitative image analysis or semiquantitative pathologist scoring of the cores as input and applied to three independent clinical cohorts. RESULTS: This classifier demonstrated 87% concordance with the gold-standard transcriptome-based classification. Application to three validation datasets confirmed the poor prognosis of the mesenchymal-like molecular colorectal cancer subtype. In addition, retrospective analysis demonstrated the benefit of adding cetuximab to bevacizumab and chemotherapy in patients with RAS wild-type metastatic cancers of the canonical epithelial-like subtypes. CONCLUSIONS: This study shows that a practical and robust immunohistochemical assay can be employed to identify molecular colorectal cancer subtypes and uncover subtype-specific therapeutic benefit. Finally, the described tool is available online for rapid classification of colorectal cancer samples, both in the format of an automated image analysis pipeline to score tumor core staining, and as a classifier based on semiquantitative pathology scoring. Clin Cancer Res; 23(2); 387-98. ©2016 AACR.

Visceral adiposity is a predictor of parathyroid hormone levels in healthy adults.

PURPOSE: Parathyroid hormone (PTH) has been shown to correlate positively with fat mass, however there are no studies that have investigated whether this association is a result of, or is modified by, body fat distribution. The aim of this study was to investigate the association of PTH with several body composition indices, namely visceral (VAT) and subcutaneous adiposity (SCAT) as well as with lean mass and with serum leptin, which has been reported to increase PTH. METHODS: This was a cross-sectional study in which PTH was measured by chemiluminescent assay; body fat and lean mass by dual-energy X-ray absorptiometry (DXA) and abdominal fat by ultrasonography in 714 healthy adults aged 18-65 years. Serum leptin was measured by ELISA. RESULTS: In a multivariate linear regression model that included height, age, gender, ethnicity, serum 25 hydroxyvitamin D, leptin levels, calcium, magnesium and phosphate concentrations, glomerular filtration rate, smoking status, and calcium and vitamin D supplementation as independent variables and PTH as the dependent variable, VAT (ß = 0.094, p = 0.035) correlated significantly with PTH levels but SCAT (ß = -0.045, p = 0.386) and body fat mass (ß = 0.098, p = 0.126) did not. Leptin did not correlate with PTH (ß = 0.013, p = 0.832) in this regression model. CONCLUSIONS: Plasma PTH is significantly associated with VAT in healthy adults. In view of the association of PTH with increased cardiovascular mortality, it is important to investigate this association further.

Complexity of Multi-Channel Electroencephalogram Signal Analysis in Childhood Absence Epilepsy.

Absence epilepsy is an important epileptic syndrome in children. Multiscale entropy (MSE), an entropy-based method to measure dynamic complexity at multiple temporal scales, is helpful to disclose the information of brain connectivity. This study investigated the complexity of electroencephalogram (EEG) signals using MSE in children with absence epilepsy. In this research, EEG signals from 19 channels of the entire brain in 21 children aged 5-12 years with absence epilepsy were analyzed. The EEG signals of pre-ictal (before seizure) and ictal states (during seizure) were analyzed by sample entropy (SamEn) and MSE methods. Variations of complexity index (CI), which was calculated from MSE, from the pre-ictal to the ictal states were also analyzed. The entropy values in the pre-ictal state were significantly higher than those in the ictal state. The MSE revealed more differences in analysis compared to the SamEn. The occurrence of absence seizures decreased the CI in all channels. Changes in CI were also significantly greater in the frontal and central parts of the brain, indicating fronto-central cortical involvement of "cortico-thalamo-cortical network" in the occurrence of generalized spike and wave discharges during absence seizures. Moreover, higher sampling frequency was more sensitive in detecting functional changes in the ictal state. There was significantly higher correlation in ictal states in the same patient in different seizures but there were great differences in CI among different patients, indicating that CI changes were consistent in different absence seizures in the same patient but not from patient to patient. This implies that the brain stays in a homogeneous activation state during the absence seizures. In conclusion, MSE analysis is better than SamEn analysis to analyze complexity of EEG, and CI can be used to investigate the functional brain changes during absence seizures.

Sample entropy analysis of EEG signals via artificial neural networks to model patients' consciousness level based on anesthesiologists experience.

Electroencephalogram (EEG) signals, as it can express the human brain's activities and reflect awareness, have been widely used in many research and medical equipment to build a noninvasive monitoring index to the depth of anesthesia (DOA). Bispectral (BIS) index monitor is one of the famous and important indicators for anesthesiologists primarily using EEG signals when assessing the DOA. In this study, an attempt is made to build a new indicator using EEG signals to provide a more valuable reference to the DOA for clinical researchers. The EEG signals are collected from patients under anesthetic surgery which are filtered using multivariate empirical mode decomposition (MEMD) method and analyzed using sample entropy (SampEn) analysis. The calculated signals from SampEn are utilized to train an artificial neural network (ANN) model through using expert assessment of consciousness level (EACL) which is assessed by experienced anesthesiologists as the target to train, validate, and test the ANN. The results that are achieved using the proposed system are compared to BIS index. The proposed system results show that it is not only having similar characteristic to BIS index but also more close to experienced anesthesiologists which illustrates the consciousness level and reflects the DOA successfully.

Early life exposure to allergen and ozone results in altered development in adolescent rhesus macaque lungs.

In rhesus macaques, previous studies have shown that episodic exposure to allergen alone or combined with ozone inhalation during the first 6 months of life results in a condition with many of the hallmarks of asthma. This exposure regimen results in altered development of the distal airways and parenchyma (Avdalovic et al., 2012). We hypothesized that the observed alterations in the lung parenchyma would be permanent following a long-term recovery in filtered air (FA) housing. Forty-eight infant rhesus macaques (30 days old) sensitized to house dust mite (HDM) were treated with two week cycles of FA, house dust mite allergen (HDMA), ozone (O3) or HDMA/ozone (HDMA+O3) for five months. At the end of the five months, six animals from each group were necropsied. The other six animals in each group were allowed to recover in FA for 30 more months at which time they were necropsied. Design-based stereology was used to estimate volumes of lung components, number of alveoli, size of alveoli, distribution of alveolar volumes, interalveolar capillary density. After 30 months of recovery, monkeys exposed to HDMA, in either group, had significantly more alveoli than filtered air. These alveoli also had higher capillary densities as compared with FA controls. These results indicate that early life exposure to HDMA alone or HDMA+O3 alters the development process in the lung alveoli.

L-DOPA-induced dysregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson's disease.

Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine (L-DOPA) as a treatment for Parkinson's disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-hydroxydopamine (6-OHDA) infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA's effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24h after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD.

The European Medicines Agency review of pazopanib for the treatment of advanced renal cell carcinoma: summary of the scientific assessment of the Committee for Medicinal Products for Human Use.

On June 14, 2010, the European Commission issued a conditional marketing authorization valid throughout the European Union for pazopanib for the treatment of advanced renal cell carcinoma. Pazopanib is an antineoplastic agent that inhibits multiple receptor tyrosine kinases. The recommended oral dose is 800 mg once daily. The benefit of pazopanib is an increased progression-free survival. In the pivotal trial VEG105192, the median progression-free survival was 9.2 months (95% confidence interval, 7.4-12.9) in the pazopanib arm compared with 4.2 months (95% confidence interval, 2.8-4.2) in the placebo arm. The most common side effects include diarrhea, hair color change, hypertension, nausea, fatigue, anorexia, vomiting, dysgeusia, elevated alanine aminotransferase, elevated aspartate aminotransferase, and abdominal pain. The objective of this article is to summarize the scientific review of the application that led to approval in the European Union.