AI-assisted biparametric MRI surveillance of prostate cancer: feasibility study.

OBJECTIVES: To evaluate the feasibility of automatic longitudinal analysis of consecutive biparametric MRI (bpMRI) scans to detect clinically significant (cs) prostate cancer (PCa). METHODS: This retrospective study included a multi-center dataset of 1513 patients who underwent bpMRI (T2 + DWI) between 2014 and 2020, of whom 73 patients underwent at least two consecutive bpMRI scans and repeat biopsies. A deep learning PCa detection model was developed to produce a heatmap of all PIRADS ≥ 2 lesions across prior and current studies. The heatmaps for each patient's prior and current examination were used to extract differential volumetric and likelihood features reflecting explainable changes between examinations. A machine learning classifier was trained to predict from these features csPCa (ISUP > 1) at the current examination according to biopsy. A classifier trained on the current study only was developed for comparison. An extended classifier was developed to incorporate clinical parameters (PSA, PSA density, and age). The cross-validated diagnostic accuracies were compared using ROC analysis. The diagnostic performance of the best model was compared to the radiologist scores. RESULTS: The model including prior and current study (AUC 0.81, CI: 0.69, 0.91) resulted in a higher (p = 0.04) diagnostic accuracy than the current only model (AUC 0.73, CI: 0.61, 0.84). Adding clinical variables further improved diagnostic performance (AUC 0.86, CI: 0.77, 0.93). The diagnostic performance of the surveillance AI model was significantly better (p = 0.02) than of radiologists (AUC 0.69, CI: 0.54, 0.81). CONCLUSIONS: Our proposed AI-assisted surveillance of prostate MRI can pick up explainable, diagnostically relevant changes with promising diagnostic accuracy. KEY POINTS: • Sequential prostate MRI scans can be automatically evaluated using a hybrid deep learning and machine learning approach. • The diagnostic accuracy of our csPCa detection AI model improved by including clinical parameters.

Biological control of Meloidogyne spp. in glasshouse-grown chrysanthemum.

Root-knot nematodes (Meloidogyne spp.) are a major problem in soil-based glasshouse-grown chrysanthemums. To combat root-knot nematodes in the glasshouse, the soil is typically steamed every 5-6 production cycles. However, this method is expensive, environmentally unfriendly and reduces resistance and resilience of the soil against pathogens and pests. Here, we added biological pesticides/a basic substance and biostimulants both individually and in combination to determine individual or interactive effects against damage by root-knot nematodes in chrysanthemums. We found that the application of biological nematicides derived from garlic extract, the basic substance chitosan HCl and biostimulants comprised of sea minerals and plant oils correlated with reduced root-knot nematode damage. These effects may have been due to direct effects against the nematodes or through indirect effects such as increased resistance and resilience of the plants. Overall, the biostimulants increased the total number of free-living nematodes in the soil, which could lead to a beneficial increase in nutrient cycling in the soils. Our results demonstrate that biological reagents show promise in reducing root-knot nematode damage in glasshouse-grown chrysanthemum and may lead to more resistance and resilient soils.

Asymmetric dimethylarginine and symmetric dimethylarginine prospectively relates to carotid wall thickening in black men: the SABPA study.

The relationship of both asymmetric (ADMA) and symmetric (SDMA) dimethylarginine with carotid wall thickness is inconclusive especially among black populations. We aimed to compare carotid intima media thickness (cIMT) and dimethylarginine levels in 75 black and 91 white men at baseline and after a 3-year follow-up, and to investigate associations of percentage change in cIMT with percentage change in dimethylarginine levels (ADMA and SDMA). Plasma levels of ADMA and SDMA were determined with a liquid chromatography mass spectrometry method and B-mode ultrasonography was used to determine the cIMT at baseline and follow-up. In black men, mean cIMT (p = 0.79) and ADMA levels (p = 0.67) remained the same, but SDMA levels were lower (p < 0.001) when comparing baseline and follow-up. In white men, cIMT increased (p < 0.001), but both mean ADMA and SDMA levels decreased (p < 0.001) over time. In black men, percentage change in cIMT was positively associated with percentage change in ADMA (R 2 = 0.49; ß = 0.46; p < 0.001) and percentage change in SDMA (R 2 = 0.46; ß = 0.41; p < 0.001). These associations were absent in the white men. Despite lower mean SDMA and similar ADMA and cIMT in black men, percentage change in cIMT was independently associated with percentage change in ADMA and percentage change in SDMA. These results suggest an important role for ADMA and SDMA lowering strategies to delay carotid wall thickening, especially in black populations prone to the development of cardiovascular disease.

Leptin is positively associated with blood pressure in african men with a low body mass index: the SAfrEIC study.

Severe underweight may be a risk factor for hypertension in developing countries, although the manner whereby this occurs is unknown. Leptin is known to exert both beneficial and detrimental vascular effects, and is predictive of poor cardiovascular outcome at high levels, but also at low levels. We explored the relationship between blood pressure and leptin in black men from South Africa with a body mass index (BMI) in the underweight to normal range. We included 113 African men (BMI≤25 kg/m(2)) and took anthropometric, biochemical and cardiovascular measures. The blood pressure-leptin relationship was then investigated along quintiles of leptin and within BMI stratified median split (20 kg/m(2)) groups. Blood pressure increased across leptin quintiles 1-3 (p for trend≤0.040), whereas no relationship was observed along quintiles 3 to 5 (p for trend≥0.14) (adjusted for age and waist circumference). Blood pressure was similar in the two BMI median split groups (p≥0.083). In the low BMI group only, blood pressure associated positively with leptin following unadjusted, partial, and full adjustment (systolic blood pressure and diastolic blood pressure: R(2)=0.20-0.27, ß=0.32-0.34, p≤0.009). Decreasing leptin levels are not likely to contribute to hypertension prevalence in the underweight. Rather, in African men with a BMI≤20 kg/m(2), low leptin levels are positively and independently associated with elevated blood pressure, which is not seen at higher BMI (20-25 kg/m(2)). Our findings suggest a differential concentration dependent vascular effect of leptin in underweight and normal weight African men.

Evaluation of waist-to-height ratio to predict 5 year cardiometabolic risk in sub-Saharan African adults.

BACKGROUND AND AIMS: Simple, low-cost central obesity measures may help identify individuals with increased cardiometabolic disease risk, although it is unclear which measures perform best in African adults. We aimed to: 1) cross-sectionally compare the accuracy of existing waist-to-height ratio (WHtR) and waist circumference (WC) thresholds to identify individuals with hypertension, pre-diabetes, or dyslipidaemia; 2) identify optimal WC and WHtR thresholds to detect CVD risk in this African population; and 3) assess which measure best predicts 5-year CVD risk. METHODS AND RESULTS: Black South Africans (577 men, 942 women, aged >30years) were recruited by random household selection from four North West Province communities. Demographic and anthropometric measures were taken. Recommended diagnostic thresholds (WC > 80 cm for women, >94 cm for men; WHtR > 0.5) were evaluated to predict blood pressure, fasting blood glucose, lipids, and glycated haemoglobin measured at baseline and 5 year follow up. Women were significantly more overweight than men at baseline (mean body mass index (BMI) women 27.3 ± 7.4 kg/m(2), men 20.9 ± 4.3 kg/m(2)); median WC women 81.9 cm (interquartile range 61-103), men 74.7 cm (63-87 cm), all P < 0.001). In women, both WC and WHtR significantly predicted all cardiometabolic risk factors after 5 years. In men, even after adjusting WC threshold based on ROC analysis, WHtR better predicted overall 5-year risk. Neither measure predicted hypertension in men. CONCLUSIONS: The WHtR threshold of >0.5 appears to be more consistently supported and may provide a better predictor of future cardiometabolic risk in sub-Saharan Africa.

The link between vascular deterioration and branched chain amino acids in a population with high glycated haemoglobin: the SABPA study.

Globally the prevalence of non-communicable diseases, such as hypertension and type 2 diabetes, are escalating. Metabolomic studies indicated that circulating branched chain amino acids (BCAAs) are associated with insulin resistance, coronary artery disease and increased risk for cardiovascular events. We aimed to extend the current understanding of the cardiovascular risk associated with BCAAs. We explored whether BCAAs are related to markers of cardiovascular disease in a bi-ethnic population and whether this relationship was influenced by chronic hyperglycaemia. We included 200 African and 209 Caucasian participants, and determined their ambulatory blood pressure and carotid intima-media thickness (cIMT). We analysed blood samples for glycated haemoglobin (HbA1c) and BCAAs. Participants were stratified into two groups according to their HbA1c value using the median cut-off value of 5.6%. Ambulatory BP, cIMT and BCAAs were significantly higher (all p < 0.001) in the high HbA1c group. Single regression analyses indicated significant positive associations of ambulatory blood pressure and cIMT with BCAAs (all p < 0.05) in both the groups. These associations between ambulatory systolic blood pressure (SBP) (r = 0.16, p = 0.035) and cIMT (r = 0.22, p = 0.004) with BCAAs remained in the high HbA1c group after adjusting for age, gender, ethnicity and body mass index (BMI) and were confirmed in multiple regression analyses (ambulatory SBP: R (2) = 0.17, ß = 0.21, p = 0.005 and cIMT: R (2) = 0.30, ß = 0.19, p = 0.003). Our results demonstrate that BCAAs are independently related to ambulatory BP and cIMT in individuals with high HbA1c levels and suggest that potential cardiovascular deterioration accompany the rise in BCAAs in conditions of hyperglycaemia.

Imaging vascular function for early stage clinical trials using dynamic contrast-enhanced magnetic resonance imaging.

Many therapeutic approaches to cancer affect the tumour vasculature, either indirectly or as a direct target. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) has become an important means of investigating this action, both pre-clinically and in early stage clinical trials. For such trials, it is essential that the measurement process (i.e. image acquisition and analysis) can be performed effectively and with consistency among contributing centres. As the technique continues to develop in order to provide potential improvements in sensitivity and physiological relevance, there is considerable scope for between-centre variation in techniques. A workshop was convened by the Imaging Committee of the Experimental Cancer Medicine Centres (ECMC) to review the current status of DCE-MRI and to provide recommendations on how the technique can best be used for early stage trials. This review and the consequent recommendations are summarised here. Key Points • Tumour vascular function is key to tumour development and treatment • Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascular function • Thus DCE-MRI with pharmacokinetic models can assess novel treatments • Many recent developments are advancing the accuracy of and information from DCE-MRI • Establishing common methodology across multiple centres is challenging and requires accepted guidelines.

Quantitative CT perfusion imaging in patients with pancreatic cancer: a systematic review.

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death with a 5-year survival rate of 10%. Quantitative CT perfusion (CTP) can provide additional diagnostic information compared to the limited accuracy of the current standard, contrast-enhanced CT (CECT). This systematic review evaluates CTP for diagnosis, grading, and treatment assessment of PDAC. The secondary goal is to provide an overview of scan protocols and perfusion models used for CTP in PDAC. The search strategy combined synonyms for 'CTP' and 'PDAC.' Pubmed, Embase, and Web of Science were systematically searched from January 2000 to December 2020 for studies using CTP to evaluate PDAC. The risk of bias was assessed using QUADAS-2. 607 abstracts were screened, of which 29 were selected for full-text eligibility. 21 studies were included in the final analysis with a total of 760 patients. All studies comparing PDAC with non-tumorous parenchyma found significant CTP-based differences in blood flow (BF) and blood volume (BV). Two studies found significant differences between pathological grades. Two other studies showed that BF could predict neoadjuvant treatment response. A wide variety in kinetic models and acquisition protocol was found among included studies. Quantitative CTP shows a potential benefit in PDAC diagnosis and can serve as a tool for pathological grading and treatment assessment; however, clinical evidence is still limited. To improve clinical use, standardized acquisition and reconstruction parameters are necessary for interchangeability of the perfusion parameters.

Effect of linagliptin monotherapy on glycaemic control and markers of ß-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial.

AIM: To assess the safety and efficacy of the potent and selective dipeptidyl peptidase-4 inhibitor linagliptin 5 mg when given for 24 weeks to patients with type 2 diabetes who were either treatment-naive or who had received one oral antidiabetes drug (OAD). METHODS: This multicentre, randomized, parallel group, phase III study compared linagliptin treatment (5 mg once daily, n = 336) with placebo (n = 167) for 24 weeks in type 2 diabetes patients. Before randomization, patients pretreated with one OAD underwent a washout period of 6 weeks, which included a placebo run-in period during the last 2 weeks. Patients previously untreated with an OAD underwent a 2-week placebo run-in period. The primary endpoint was the change in HbA1c from baseline after 24 weeks of treatment. RESULTS: Linagliptin treatment resulted in a placebo-corrected change in HbA1c from baseline of -0.69% (p < 0.0001) at 24 weeks. In patients with baseline HbA1c ≥ 9.0%, the adjusted reduction in HbA1c was 1.01% (p < 0.0001). Patients treated with linagliptin were more likely to achieve a reduction in HbA1c of ≥0.5% at 24 weeks than those in the placebo arm (47.1 and 19.0%, respectively; odds ratio, OR = 4.2, p < 0.0001). Fasting plasma glucose improved by -1.3 mmol/l (p < 0.0001) with linagliptin vs. placebo, and linagliptin produced an adjusted mean reduction from baseline after 24 weeks in 2-h postprandial glucose of -3.2 mmol/l (p < 0.0001). Statistically significant and relevant treatment differences were observed for proinsulin/insulin ratio (p = 0.025), Homeostasis Model Assessment-%B (p = 0.049) and disposition index (p = 0.0005). There was no excess of hypoglycaemic episodes with linagliptin vs. placebo and no patient required third-party intervention. Mild or moderate renal impairment did not influence the trough plasma levels of linagliptin. CONCLUSIONS: Monotherapy with linagliptin produced a significant, clinically meaningful and sustained improvement in glycaemic control, accompanied by enhanced parameters of ß-cell function. The safety profile of linagliptin was comparable with that of placebo.

Automated 3-dimensional segmentation of pelvic lymph nodes in magnetic resonance images.

PURPOSE: Computer aided diagnosis (CAD) of lymph node metastases may help reduce reading time and improve interpretation of the large amount of image data in a 3-D pelvic MRI exam. The purpose of this study was to develop an algorithm for automated segmentation of pelvic lymph nodes from a single seed point, as part of a CAD system for the classification of normal vs metastatic lymph nodes, and to evaluate its performance compared to other algorithms. METHODS: The authors' database consisted of pelvic MR images of 146 consecutive patients, acquired between January 2008 and April 2010. Each dataset included four different MR sequences, acquired after infusion of a lymph node specific contrast medium based on ultrasmall superparamagnetic particles of iron oxide. All data sets were analyzed by two expert readers who, reading in consensus, annotated and manually segmented the lymph nodes. The authors compared four segmentation algorithms: confidence connected region growing (CCRG), extended CCRG (ECC), graph cut segmentation (GCS), and a segmentation method based on a parametric shape and appearance model (PSAM). The methods were ranked based on spatial overlap with the manual segmentations, and based on diagnostic accuracy in a CAD system, with the experts' annotations as reference standard. RESULTS: A total of 2347 manually annotated lymph nodes were included in the analysis, of which 566 contained a metastasis. The mean spatial overlap (Dice similarity coefficient) was: 0.35 (CCRG), 0.57 (ECC), 0.44 (GCS), and 0.46 (PSAM). When combined with the classification system, the area under the ROC curve was: 0.805 (CCRG), 0.890 (ECC), 0.807 (GCS), 0.891 (PSAM), and 0.935 (manual segmentation). CONCLUSIONS: We identified two segmentation methods, ECC and PSAM, that achieve a high diagnostic accuracy when used in conjunction with a CAD system for classification of normal vs metastatic lymph nodes. The manual segmentations still achieve the highest diagnostic accuracy.

A randomized targeted amino acid therapy with behaviourally at-risk adopted children.

BACKGROUND: Increasing numbers of children are at-risk for behavioural and emotional disorders, a phenomenon contributing to increased use of pharmacological interventions for paediatric clients. Adverse side effects and other risks associated with pharmacological approaches have helped fuel interest in nutritional interventions for behaviourally at-risk children. METHODS: The current randomized clinical trial evaluates the efficacy of a neurochemical intervention involving the glutamine and glutamate analogue L-theanine and 5-hydroxytryptophan, the precursor for serotonin, with children adopted from traumatic backgrounds. RESULTS: Results include significant increases in urinary levels of the biomarkers for serotonin and gamma-aminobutyric acid, coupled with significant decreases in parent reports of the children's behaviour problems. CONCLUSIONS: While further research is needed, these initial findings are encouraging and are consistent with a growing number of studies indicating the efficacy of nutritional approaches to help behaviourally at-risk children.

Interactive 3D U-net for the segmentation of the pancreas in computed tomography scans.

The increasing incidence of pancreatic cancer will make it the second deadliest cancer in 2030. Imaging based early diagnosis and image guided treatment are emerging potential solutions. Artificial intelligence (AI) can help provide and improve widespread diagnostic expertise and accurate interventional image interpretation. Accurate segmentation of the pancreas is essential to create annotated data sets to train AI, and for computer assisted interventional guidance. Automated deep learning segmentation performance in pancreas computed tomography (CT) imaging is low due to poor grey value contrast and complex anatomy. A good solution seemed a recent interactive deep learning segmentation framework for brain CT that helped strongly improve initial automated segmentation with minimal user input. This method yielded no satisfactory results for pancreas CT, possibly due to a sub-optimal neural network architecture. We hypothesize that a state-of-the-art U-net neural network architecture is better because it can produce a better initial segmentation and is likely to be extended to work in a similar interactive approach. We implemented the existing interactive method, iFCN, and developed an interactive version of U-net method we call iUnet. The iUnet is fully trained to produce the best possible initial segmentation. In interactive mode it is additionally trained on a partial set of layers on user generated scribbles. We compare initial segmentation performance of iFCN and iUnet on a 100CT dataset using dice similarity coefficient analysis. Secondly, we assessed the performance gain in interactive use with three observers on segmentation quality and time. Average automated baseline performance was 78% (iUnet) versus 72% (FCN). Manual and semi-automatic segmentation performance was: 87% in 15 min. for manual, and 86% in 8 min. for iUNet. We conclude that iUnet provides a better baseline than iFCN and can reach expert manual performance significantly faster than manual segmentation in case of pancreas CT. Our novel iUnet architecture is modality and organ agnostic and can be a potential novel solution for semi-automatic medical imaging segmentation in general.

Localization of cell surface glycoproteins in membrane domains associated with the underlying filament network.

To visualize the localization of cell surface constituents in relation to the plasma membrane-associated filament network, we developed a method based on a combination of immunogold labeling and dry-cleaving. For labeling we used trinitrophenyl-derivatized ligand, anti-TNP antibodies, and protein A-coated colloidal gold. Dry-cleaving (Mesland, D. A. M., H. Spiele, and E. Roos, 1981, Exp. Cell Res., 132: 169-184) involves cleavage of lightly fixed critical point-dried cells by means of adhesive tape. Since cells cleave close to the cell surface, the remaining layer is thin enough to be examined in transmission electron microscopy. Using this method, we studied concanavalin A-binding constituents on the medium-facing surface of H35 hepatoma cells. The distribution of the gold particles, which was partly dispersed and partly patchy, coincided strikingly with membrane-associated filaments, and label was virtually absent from areas overlying openings in the filament network. In stereo pairs we observed the label to be localized to areas of somewhat enhanced electron density at the plane of the membrane. These areas were interconnected in a pattern congruent with the filament network. Preliminary observations on wheat germ agglutinin receptors on the hepatoma cells as well as concanavalin A receptors on isolated hepatocytes yielded comparable results. It thus appears that surface glycoproteins, although seemingly randomly distributed as observed in thin sections, may actually be localized to particular membrane domains associated with underlying filaments.

Relation of phenotype evolution of HIV-1 to envelope V2 configuration.

Biological variability of human immunodeficiency virus type-1 (HIV-1) is involved in the pathogenesis of acquired immunodeficiency syndrome (AIDS). Syncytium-inducing (SI) HIV-1 variants emerge in 50 percent of infected individuals during infection, preceding accelerated CD4+ T cell loss and rapid progression to AIDS. The V1 to V2 and V3 region of the viral envelope glycoprotein gp120 contained the major determinants of SI capacity. The configuration of a hypervariable locus in the V2 domain appeared to be predictive for non-SI to SI phenotype conversion. Early prediction of HIV-1 phenotype evolution may be useful for clinical monitoring and treatment of asymptomatic infection.

Classifying Africans with the metabolic syndrome.

This study was aimed to compare prevalences of the metabolic syndrome in Africans using five definitions as proposed by the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults [Adult Treatment Panel (ATPIII)], the American College of Endocrinology (ACE), and the International Diabetes Federation (IDF). A further objective was to identify difficulties in classifying Africans with the metabolic syndrome and to suggest specific areas where criteria adjustments for identifying Africans should be made. A case-case-control cross-sectional study involved 102 urban African women. Except for microalbumin data, all data necessary for classification of the metabolic syndrome were collected, including fasting and 2-h glucose and insulin, anthropometric measurements, blood pressure, and lipids. The metabolic syndrome prevalences ranged from 5.4% (EGIR), 15.7% (ATPIII), >or=19.4% (WHO), 24.8% (IDF) to 25.5% (ACE). Only 2.9% (n=3) had a triglyceride level >or=1.69 mmol/l, but 58.8% (n=60) had a HDL-level <1.29 mmol/l, whereas 27% (n=26) were insulin resistant, 22.3% (n=21), had a blood pressure >or=140/90 or used hypertension medication. It seems as if the classification of hypertension, insulin resistance and hyperglycemia might have been adequate, but body composition and dyslipidemia criteria need adjustment for Africans. Since neither definition seems completely suitable for Africans it is suggested that clinical emphasis should rather be on treating any specific cardiovascular disease risk factor that is present, than on diagnosing a patient with the metabolic syndrome.

In vivo validation of cardiac output assessment in non-standard 3D echocardiographic images.

Automatic segmentation of the endocardial surface in three-dimensional (3D) echocardiographic images is an important tool to assess left ventricular (LV) geometry and cardiac output (CO). The presence of speckle noise as well as the nonisotropic characteristics of the myocardium impose strong demands on the segmentation algorithm. In the analysis of normal heart geometries of standardized (apical) views, it is advantageous to incorporate a priori knowledge about the shape and appearance of the heart. In contrast, when analyzing abnormal heart geometries, for example in children with congenital malformations, this a priori knowledge about the shape and anatomy of the LV might induce erroneous segmentation results. This study describes a fully automated segmentation method for the analysis of non-standard echocardiographic images, without making strong assumptions on the shape and appearance of the heart. The method was validated in vivo in a piglet model. Real-time 3D echocardiographic image sequences of five piglets were acquired in radiofrequency (rf) format. These ECG-gated full volume images were acquired intra-operatively in a non-standard view. Cardiac blood flow was measured simultaneously by an ultrasound transit time flow probe positioned around the common pulmonary artery. Three-dimensional adaptive filtering using the characteristics of speckle was performed on the demodulated rf data to reduce the influence of speckle noise and to optimize the distinction between blood and myocardium. A gradient-based 3D deformable simplex mesh was then used to segment the endocardial surface. A gradient and a speed force were included as external forces of the model. To balance data fitting and mesh regularity, one fixed set of weighting parameters of internal, gradient and speed forces was used for all data sets. End-diastolic and end-systolic volumes were computed from the segmented endocardial surface. The cardiac output derived from this automatic segmentation was validated quantitatively by comparing it with the CO values measured from the volume flow in the pulmonary artery. Relative bias varied between 0 and -17%, where the nominal accuracy of the flow meter is in the order of 10%. Assuming the CO measurements from the flow probe as a gold standard, excellent correlation (r = 0.99) was observed with the CO estimates obtained from image segmentation.

Should obesity be blamed for the high prevalence rates of hypertension in black South African women?

Hypertension is highly prevalent in South Africa, resulting in high stroke mortality rates. Since obesity is very common among South African women, it is likely that obesity contributes to the hypertension prevalence. The aims were to determine whether black African women have higher blood pressures (BPs) than Caucasian women, and whether obesity is related to their cardiovascular risk. African (N=102) and Caucasian (N=115) women, matched for age and body mass index, were included. Correlations between obesity (total body fat, abdominal obesity and peripheral fat) and cardiovascular risk markers (haemodynamic parameters, lipids, inflammatory markers, prothrombotic factors, adipokines, HOMA-IR (homoeostasis model assessment insulin resistance)) were compared between the ethnic groups (adjusted for age, smoking, alcohol and physical activity). Comparisons between low- and high-BP groups were also made for each ethnic group. Results showed that African women had higher BP (P<0.01) with increased peripheral vascular resistance. Surprisingly, African women showed significantly weaker correlations between obesity measures and cardiovascular risk markers when compared to Caucasian women (specifically systolic BP, arterial resistance, cardiac output, fibrinogen, plasminogen activator inhibitor-1, leptin and resistin). Interestingly, the latter risk markers were also not significantly different between low- and high-BP African groups. African women, however, presented significant correlations of obesity with triglycerides, C-reactive protein and HOMA that were comparable to the Caucasian women. Although urban African women have higher BP than Caucasians, their obesity levels are weakly related to traditional cardiovascular risk factors compared to Caucasian women. The results, however, suggest a link with the development of insulin resistance.

Genetic polymorphisms of beta2- and beta3-adrenergic receptor genes associated with characteristics of the metabolic syndrome in black South African women.

BACKGROUND: Genetic variation in the beta2 (ADRB2) and beta3 (ADRB3) adrenergic receptor genes are associated with obesity and insulin resistance. To further elucidate the role of these genes in the pathophysiology of obesity the present study investigated associations between certain polymorphisms in ADRB2 and ADRB3 and parameters of carbohydrate and lipid metabolism in a population of African origin. MATERIAL AND METHODS: Data of 102 black South African women obtained in the POWIRS (Profile of Obese Women with the Insulin Resistance Syndrome) study were used. Endpoint measurements included several anthropometric variables, resting blood pressure, plasma glucose, insulin, free fatty acids (FFA), ghrelin, leptin and lipids, and insulin resistance as estimated by the homeostasis model assessment (HOMA-IR) index. Polymorphisms were analyzed via PCR based methods. RESULTS: The percentage body fat was significantly lower (p< or =0.05) and the FFA significantly higher (p< or =0.05) in lean subjects (BMI< or =25 kg/m2) with the Glu27 variant allele compared to subjects with the Gln27 wildtype allele of the ADRB2 gene. In contrast, the variant allele of the ADRB2 gene was significantly positive associated (p< or =0.05) with the HOMA-IR-index in overweight black African women (BMI>25 kg/m2). No significant differences in parameters of the metabolic syndrome were apparent between subjects with the wildtype and variant alleles in the ADRB3 gene. CONCLUSION: The presence of the Glu27 and Arg64 polymorphisms of the ADRB2 and ADRB3 genes are not directly related to indices of the metabolic syndrome.

HIV-1 macrophage tropism is determined at multiple levels of the viral replication cycle.

The ability of HIV-1 to infect macrophages is thought to be essential in AIDS pathogenesis. We tested the ability of 19 primary virus isolates to infect monocyte-derived macrophages (MDM) from different donors. Two HIV-1 isolates were able to establish a productive infection in MDM from all donors tested, whereas eight completely lacked this capacity. Next to these isolates with extreme phenotypes, 50% of the primary isolates under study displayed an intermediate phenotype. These intermediate macrophage-tropic isolates established a productive infection in MDM from some but not all donors tested. PCR analysis demonstrated that the capacity to replicate in MDM could be determined at the previously described level of virus entry. However, for intermediate macrophage-tropic isolates replication was abrogated at the level of reverse transcription. Entry of highly macrophage-tropic isolates resulted in efficient completion of the reverse transcription process, whereas entry of intermediate macrophage-tropic isolates did not. Our experiments indicate that primary HIV-1 isolates may differ in their dependency on cellular factors required for reverse transcription in MDM. Differences in susceptibility of MDM for in vitro HIV-1 infection suggest variation in the availability of these cellular factors between MDM from different individuals.

Proliferation-dependent HIV-1 infection of monocytes occurs during differentiation into macrophages.

Requirements for the establishment of productive infection with the human immunodeficiency virus type 1 (HIV-1) in primary monocytes were investigated. In vitro, monocytes rendered susceptible for infection after at least a 2-d culture, but when cultured in the presence of differentiation-inducing agent IL-4, accelerated susceptibility was seen. Complete resistance to HIV-1 infection was observed in monocytes that had been treated for 5 d with rIL-4, and comparable results were obtained with other differentiation inducers such as dexamethasone or 1,25(OH)2 vitamin D3 (1,25(OH)2vitD3). The inhibition of productive infection was not caused by downregulation of CD4 expression or HIV-1 transcription, nor by intracellular accumulation of virions. Since treatment with rIL-4, dexamethasone, or 1,25(OH)2vitD3 also resulted in complete inhibition of monocyte proliferation, we studied whether establishment of productive infection in monocytes is proliferation dependent. Irradiation or mitomycin-C treatment within 24 h after inoculation prevented productive HIV-1 infection of monocytes, suggesting a proliferation-dependent step early in the virus replication cycle. Polymerase chain reaction (PCR) analysis revealed the presence of only incomplete proviral DNA species in non-proliferating monocytes, indicating restriction of viral replication at the level of reverse transcription. Thus, in analogy with HIV-1 infection of CD4+ T cells, proliferation of monocytes during differentiation into macrophages is a prerequisite for productive infection with HIV.