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Objectives: To investigate the beliefs of South African metropolitan adults regarding the importance of influencing cardiovascular health by eating certain food types, and to compare these beliefs between different race, living standards, age and gender groups.Design: Randomised cross-sectional study. Trained fieldworkers administered questionnaires by conducting face-to-face interviews with consumers.Subjects: Two thousand South Africans (16 years and older) were randomly selected from metropolitan areas in South Africa. The data were weighted to be representative of the total South African metropolitan population (N = 10695000) based on gender, age and race distribution.Results: The majority (94%) of the population indicated that it is important to influence cardiovascular risk-related health issues by eating certain food types, especially the higher LSM (Living Standard Measure) groups within the different race groups. Weight loss was considered the least important (61% indicated that it is important) compared with cholesterol lowering (80%), blood pressure (89%), diabetes (86%) and healthy blood vessels (89%). In the higher LSM groups (7-10) higher proportions of respondents agreed than in the lower LSM groups (2 and 3). No differences were seen in responses between different gender, race and age groups.Conclusions and Recommendations: This study shows that the metropolitan South African adult population considers the influence on cardiovascular health by eating certain food types to be important. However, modifying weight loss by eating certain food types was considered less important. [ABSTRACT FROM AUTHOR]

Populations at risk for tuberculosis (TB) may have a low n-3 polyunsaturated fatty acid (PUFA) status. Our research previously showed that post-infection supplementation of n-3 long-chain PUFA (LCPUFA) in TB without TB medication was beneficial in n-3 PUFA sufficient but not in low-status C3HeB/FeJ mice. In this study, we investigated the effect of n-3 LCPUFA adjunct to TB medication in TB mice with a low compared to a sufficient n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient (n-3FAD) or n-3 PUFA-sufficient (n-3FAS) diet for 6 weeks before TB infection. Post-infection at 2 weeks, both groups were switched to an n-3 LCPUFA [eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA)] supplemented diet and euthanized at 4- and 14- days post-treatment. Iron and anemia status, bacterial loads, lung pathology, lung cytokines/chemokines, and lung lipid mediators were measured. Following 14 days of treatment, hemoglobin (Hb) was higher in the n-3FAD than the untreated n-3FAS group ( p = 0.022), whereas the n-3FAS (drug) treated control and n-3FAS groups were not. Pro-inflammatory lung cytokines; interleukin-6 (IL-6) ( p = 0.011), IL-1α ( p = 0.039), MCP1 ( p = 0.003), MIP1- α ( p = 0.043), and RANTES ( p = 0.034); were lower, and the anti-inflammatory cytokine IL-4 ( p = 0.002) and growth factor GMCSF ( p = 0.007) were higher in the n-3FAD compared with the n-3FAS mice after 14 days. These results suggest that n-3 LCPUFA therapy in TB-infected mice, in combination with TB medication, may improve anemia of infection more in low n-3 fatty acid status than sufficient status mice. Furthermore, the low n-3 fatty acid status TB mice supplemented with n-3 LCPUFA showed comparatively lower cytokine-mediated inflammation despite presenting with lower pro-resolving lipid mediators., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hayford, Dolman, Ozturk, Nienaber, Ricci, Loots, Brombacher, Blaauw, Smuts, Parihar and Malan.)

Intakes of the omega-3 essential fatty acids (n-3 EFAs) are low in the general adult population, with high n-6/n-3 polyunsaturated fatty acid (PUFA) ratios and the accompanying suboptimal n-3 PUFA status. Eicosapentaenoic (EPA) and docosahexaenoic acid (DHA) have antibacterial and inflammation-resolving effects in tuberculosis (TB). However, whether switching to a diet with optimum n-3 EFA intake after the infection has comparable benefits has not been investigated. We aimed to compare the effects of a diet with sufficient n-3 EFA content in an acceptable n-6/n-3 PUFA ratio for rodents ((n-3)eFAS group) with those on the same diet supplemented with EPA and DHA (EPA/DHA group) in Mycobacterium tuberculosis (Mtb)-infected C3HeB/FeJ mice with a low n-3 PUFA status. Mice were conditioned on an n-3 PUFA-deficient diet with a high n-6/n-3 PUFA ratio for 6 weeks before Mtb infection and randomized to either (n-3)eFAS or EPA/DHA diets 1 week post-infection for 3 weeks. At endpoint, EPA and DHA compositions were higher and arachidonic acid, osbond acid, and total n-6 LCPUFAs lower in all lipid pools measured in the EPA/DHA group (all P < 0.001). Percentage body weight gain was higher (P = 0.017) and lung bacterial load lower (P < 0.001) in the EPA/DHA group. Additionally, the EPA/DHA group had a more pro-resolving lung lipid mediator profile and lower lung in IL-1α and IL-1β concentrations (P = 0.023, P = 0.049). Inverse correlations were found between the lung and peripheral blood mononuclear cell EPA and DHA and selected pro-inflammatory cytokines. These are the first findings that indicate that EPA/DHA supplementation provides benefits superior to a diet with sufficient n-3 EFAs concerning bacterial killing, weight gain and lung inflammation resolution in Mtb-infected mice with a low n-3 PUFA status. Therefore, EPA and DHA may be worth considering as adjunct TB treatment., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Severe acute malnutrition (SAM) is associated with a complex pattern of various clinical conditions. We investigated how risk factors cluster in children with SAM, the relationship between clusters of risk factors and mortality as well as length of stay in children with SAM. A prospective observational study design was used. Data were extracted from medical records of 601 infants and children aged 0-59 months admitted and treated for SAM in three Ghanaian referral hospital between June 2013 and June 2018. Among the 601 medical records extracted, ninety-nine died. Three clusters of medical features clearly emerged from data analyses. Firstly, an association was defined by eye signs, pallor, diarrhoea and vomiting with gastrointestinal infections and malaria. In this cluster, pallor and eye signs were related to 2- to 5-fold increased mortality risk. Secondly, HIV, oedema, fast pulse, respiratory infections and tuberculosis; among those features, HIV increased child mortality risk by 2-fold. Thirdly, shock, convulsions, dermatitis, cold hands and feet, weak pulse, urinary tract infections and irritability were clustered. Among those features, cold hands and feet, dermatitis, convulsions and shock increased child mortality risk in a range of 2- to 9-fold. Medical conditions and clinical signs in children diagnosed with SAM associate in patterns and are related to clinical outcomes.

Advancement in the understanding of inflammation regulation during tuberculosis (TB) treatment has led to novel therapeutic approaches being proposed. The use of immune mediators like anti-inflammatory and pro-resolving molecules for such, merits attention. Drug repurposing is a widely used strategy that seeks to identify new targets to treat or manage diseases. The widely explored nonsteroidal anti-inflammatory drug (NSAID) ibuprofen and a more recently explored pharmaconutrition therapy using omega-3 long-chain polyunsaturated fatty acids (n-3 LCPUFAs), have the potential to modulate the immune system and are thus considered potential repurposed drugs in this context. These approaches may be beneficial as supportive therapy to the already existing treatment regimen to improve clinical outcomes. Here, we applied adjunct ibuprofen and n-3 LCPUFA therapy, respectively, with standard anti-TB treatment, in a C3HeB/FeJ murine model of TB. Bacterial loads, lung pathology, lung cytokines/chemokines and lung lipid mediators were measured as outcomes. Lung bacterial load on day 14 post-treatment (PT) was lower in the n-3 LCPUFA, compared to the ibuprofen group ( p = 0.039), but was higher in the ibuprofen group than the treated control group ( p = 0.0315). Treated control and ibuprofen groups had more free alveolar space initially as compared to the n-3 LCPUFA group (4 days PT, p = 0.0114 and p = 0.002, respectively); however, significantly more alveolar space was present in the n-3 LCPUFA group as compared to the ibuprofen group by end of treatment (14 days PT, p = 0.035). Interleukin 6 (IL-6) was lower in the ibuprofen group as compared to the treated control, EPA/DHA and untreated control groups at 4 days PT ( p = 0.019, p = 0.019 and p = 0.002, respectively). Importantly, pro-resolving EPA derived 9-HEPE, 11-HEPE, 12-HEPE and 18-HEPE lipid mediators (LMs) were significantly higher in the EPA/DHA group as compared to the ibuprofen and treated control groups. This suggests that n-3 LCPUFAs do improve pro-resolving and anti-inflammatory properties in TB, and it may be safe and effective to co-administer as adjunct therapy with standard TB treatment, particularly longer-term. Also, our results show host benefits upon short-term co-administration of ibuprofen, but not throughout the entire TB treatment course., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hayford, Ozturk, Dolman, Blaauw, Nienaber, Loots, Brombacher, Smuts, Parihar and Malan.)

Progressive inflammation and anemia are common in tuberculosis (TB) and linked to poor clinical outcomes. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have inflammation-resolving properties, whereas iron supplementation in TB may have limited efficacy and enhance bacterial growth. We investigated effects of iron and EPA/DHA supplementation, alone and in combination, on inflammation, anemia, iron status markers and clinical outcomes in Mycobacterium tuberculosis -infected C3HeB/FeJ mice. One week post-infection, mice received the AIN-93 diet without (control) or with supplemental iron (Fe), EPA/DHA, or Fe+EPA/DHA for 3 weeks. Mice supplemented with Fe or EPA/DHA had lower soluble transferrin receptor, ferritin and hepcidin than controls, but these effects were attenuated in Fe+EPA/DHA mice. EPA/DHA increased inflammation-resolving lipid mediators and lowered lung IL-1α, IFN-γ, plasma IL-1β, and TNF-α. Fe lowered lung IL-1α, IL-1β, plasma IL-1β, TNF-α, and IL-6. However, the cytokine-lowering effects in the lungs were attenuated with Fe+EPA/DHA. Mice supplemented with EPA/DHA had lower lung bacterial loads than controls, but this effect was attenuated in Fe+EPA/DHA mice. Thus, individually, post-infection EPA/DHA and iron supplementation lowered systemic and lung inflammation and mitigated anemia of infection in TB, but not when combined. EPA/DHA also enhanced bactericidal effects and could support inflammation resolution and management of anemia.

Background: The potential role of adjunctive anti-inflammatory therapy to enhance tuberculosis (TB) treatment has recently received increasing interest. There is, therefore, a need to broadly examine current host-directed therapies (HDTs) that could accelerate treatment response and improve TB outcomes., Methods: This systematic review and meta-analysis included randomised controlled trials of vitamin D and other HDT agents in patients receiving antibiotic treatment for pulmonary TB. Sputum smear conversion rate at 4-8 weeks was the primary outcome. Secondary outcomes included blood indices associated with infectivity and inflammation, chest radiology and incidence of adverse events., Results: Fifty-five studies were screened for eligibility after the initial search, which yielded more than 1000 records. Of the 2540 participants in the 15 trials included in the meta-analysis, 1898 (74.7%) were male, and the age at entry ranged from 18 to 70 years. There was a 38% significantly (RR 1.38, 95% CI = 1.03-1.84) increased sputum smear negativity in patients administered with vitamin D in addition to standard TB treatment than those receiving only the TB treatment. Patients treated with other HDT anti-inflammatory agents in addition to TB treatment also had a 29% significantly increased sputum smear conversion rate (RR 1.29, 95% CI = 1.09-1.563). Lymphocyte to monocyte ratio was significantly higher in the vitamin D treatment groups compared to the controls (3.52 vs 2.70, 95% CI for difference 0.16-1.11, p = 0.009) and (adjusted mean difference 0.4, 95% CI 0.2 -- 0.6; p = 0.001); whilst tumour necrosis factor-alpha (TNF-α) showed a trend towards a reduction in prednisolone (p < 0.001) and pentoxifylline (p = 0.27) treatment groups. Vitamin D and N-acetylcysteine also accelerated radiographic resolution in treatment compared to placebo at 8 weeks. No differences were observed in the occurrence of adverse events among all HDT treatments., Conclusions: Vitamin D and other anti-inflammatory HDT medications used as adjunct TB treatment may be well tolerated and effective. They significantly improved sputum smear conversion rate and chest radiological appearance, and also exhibited an inflammation resolution effect.

Introduction: in hospitals across Africa, the case fatality rates of severe acute malnutrition (SAM) have remained consistently high (over 20%), despite the existence of the WHO treatment guideline. This has been attributed to inconsistencies in the implementation of the WHO treatment guidelines in sub-Saharan African countries. In spite of this awareness, the SAM treatment guidelines adopted by various sub-Saharan African countries and hospitals are unknown. Knowledge of the exact treatment practices employed in the management of SAM in different hospitals in sub-Saharan Africa is not known. This study aims to investigate the admission criteria, in-patient treatment guidelines and practices and outcomes of complicated SAM in sub-Saharan African children aged 0-59 months., Methods: this is an observational study which involves the extraction of admission, treatment and discharge data from the medical records of infants and children aged 0-59 months diagnosed and treated for complicated SAM in sub-Saharan Africa. This information is being used to develop a comprehensive database on the treatment of complicated SAM across sub-Saharan Africa. Information on the national and hospital guidelines for the treatment of complicated SAM is also collected., Results: results of this study will serve as a useful resource on the true reflection of the treatment of complicated SAM across sub-Saharan Africa and will provide valuable information for optimising SAM treatment., Conclusion: in order to advocate best practice and reduce SAM-related mortality in sub-Saharan Africa, the identification of the different diagnostic and treatment methods and respective outcomes across different hospitals and countries is imperative., Competing Interests: The authors declare no competing interests., (Copyright: Janet Adede Carboo et al.)

This study aims to determine the prevalence of risk of malnutrition on admission and discharge in African hospitals, and to identify the association with selected indicators. In this multi-center prospective cohort study, adult patients from hospitals in South Africa, Kenya, and Ghana were screened on admission and discharge and contacted 3 months post-discharge. Relevant morbidity and mortality outcomes were assessed. At risk of malnutrition was indicated if NRS-2002 score ≥3. Adult patients ( n = 2126; 43.11 years, IQR: 31.95-55.60; 52.2% female) were screened on admission and 61% were identified as at risk of malnutrition. The proportion of at-risk patients for the three hospitals in Kenya and Ghana (66.2%) were significantly higher than that of the three South African hospitals (53.7%) (Chi 2 = 31.0; p < 0.001). Discharge risk of malnutrition was 71.2% ( n = 394). Mean length of stay (LOS) was 6.46 ± 5.63 days. During hospitalization, 20.6% lost ≥5% body weight, 18.8% were referred for nutrition support, and discharge BMI (23.87 ± 7.38 kg/m 2 ) was significantly lower than admission BMI (24.3 ± 7.3 kg/m 2 ) ( p < 0.001). Admission nutrition risk was associated with lower admission and discharge BMI ( p < 0.001), longer LOS ( p < 0.001), increased 3-month re-admission rates (Chi 2 = 1.35; p = 0.245) and increased mortality (Chi 2 = 21.68; p < 0.001). Nearly two-thirds of patients were at risk of malnutrition on admission. This was associated with longer LOS and greater hospital mortality. The nutritional status of patients deteriorated during hospitalization. Routine screening practices with appropriate nutrition support action should be implemented as a matter of urgency.

Objective: To determine undernutrition prevalence in 0-59-month-old children and its determinants during the period 2000-2015 in sub-Saharan Africa., Design: Ecological study of time series prevalence of undernutrition in sub-Saharan Africa assessed from 2000 to 2015., Setting: Underweight and stunting prevalence from the World Bank database (2000-2015) were analysed. Mixed models were used to estimate prevalence of underweight and stunting. Country-specific undernutrition prevalence variation was estimated and region comparisons were performed. A meta-regression model considering health and socio-economic characteristics at country level was used to explore and estimate the contribution of different undernutrition determinants., Participants: Countries of sub-Saharan Africa., Results: During 2000-2015, underweight prevalence in sub-Saharan Africa was heterogeneous, ranging between 7 and 40 %. On the other hand, stunting prevalence ranged between 20 and 60 %. In general, higher rates of underweight and stunting were estimated in Niger (40 %) and Burundi (58 %), respectively; while lowest rates of underweight and stunting were estimated in Swaziland (7 %) and Gabon (21 %). About 1 % undernutrition prevalence reduction per year was estimated across sub-Saharan Africa, which was not statistically significant for all countries. Health and socio-economic determinants were identified as main determinants of underweight and stunting prevalence variability in sub-Saharan Africa., Conclusions: Undernutrition represents a major public health threat in sub-Saharan Africa and its prevalence reduction during the period 2000-2015 was inconsistent. Improving water accessibility and number of medical doctors along with reducing HIV prevalence and poverty could significantly reduce undernutrition prevalence in sub-Saharan Africa.

The promotion and support of human milk banks (HMBs) can enhance exclusive breastfeeding rates. The success and sustainability of HMBs depend on the support from relevant healthcare workers and related communities. This study aimed to determine attitudes of key stakeholders, including mothers, healthcare workers and grandmothers, regarding the donation and receipt of human breastmilk. This study was conducted at a public hospital and clinics in the North West Province, South Africa. Eight focus group discussions explored the attitudes regarding donating and receiving human breastmilk: three groups with mothers of infants (n = 13), three with grandmothers (>60 years old) (n = 17) and two with healthcare professionals working with infants (n = 11). Four main themes emerged: perception regarding breast and formula feeding; exposure to the concept of "wet nursing"; breastmilk donation; and utilization and opinions of community members and traditional healers. Specific barriers identified included the processes for donating and receiving milk, safety, human immuno-deficiency virus (HIV) screening and cultural beliefs. Mothers' fears included having insufficient milk for their own infants, changes in the quality of donated milk during pasteurization and transportation and HIV transmission. Despite barriers towards donations to and the use of HMBs, sufficient information could enhance donations by mothers and breastmilk utilization., Competing Interests: The authors declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Hyperglycaemia remains a challenge in type 1 diabetes since current regimes used to determine meal insulin requirements prove to be ineffective. This is particularly problematic for meals containing high amounts of protein and fat. We aimed to determine the post-prandial glycaemic response and total insulin need for mixed meals, using sensor-augmented insulin pumps in children with type 1 diabetes., Methods: Twenty-two children with type 1 diabetes, aged 4-17 years on insulin pump therapy completed this home-based, cross-over, randomised controlled trial. Two meals with identical carbohydrate content - one with low fat and protein (LFLP) and one with high fat and protein (HFHP) contents - were consumed using normal insulin boluses. Blood glucose monitoring was done for 10 h post-meal, with correction bolus insulin given two-hourly if required., Results: The HFHP meal required significantly more total insulin (3.48 vs. 2.7 units) as a result of increased post-meal correction insulin requirement (1.2 vs. 0.15 units) spread over a longer duration (6 vs. 3 h). The HFHP meals significantly increased the time spent above target glucose level. Duration of diabetes and total daily insulin use significantly influenced the post-prandial blood glucose response to the two meals., Conclusion: When consuming carbohydrate-based mixed meals, children with type 1 diabetes on insulin pump therapy, required significantly more insulin over a longer period of time than the insulin requirement calculated using current regimes. This additional amount required is influenced by the duration of diabetes and total daily insulin use.

Background: Not only is glutamine deficiency an independent predictor of mortality in intensive care unit (ICU) patients, but glutamine supplementation is also recommended for its proven outcome benefits. However, recent data suggest that early glutamine supplementation in certain patient groups increase mortality. The aim of this study was to investigate plasma glutamine levels of adult ICU patients in the South African setting and to determine relationships between glutamine levels, gender, diagnostic categories and selected inflammatory markers. The data from this study will be used as baseline measurement to support a large scale study that will be undertaken in the South African ICU population., Methods: This cross-sectional, analytical study included 60 mixed adult ICU patients within 24 h post ICU admission. Plasma glutamine levels were determined on admission. The relationship between glutamine levels, Interleukin-6 (IL-6) and C-reactive protein (CRP); as well as gender- and diagnosis-related differences in glutamine levels were also investigated. A non-parametric ROC curve was computed to determine the CRP concentration cut-off point above which glutamine becomes deficient., Results: The median plasma glutamine level (497 μmol/L) was in the normal range; however, 38.3 % (n = 23) of patients had deficient (<420 μmol/L) and 6.7 % (n = 4) had supra-normal glutamine levels (>930 μmol/L). No significant difference could be detected between glutamine levels and gender or diagnosis categories as a group. When only the medical and surgical categories were compared, the median plasma glutamine level of the medical patients were significantly lower than that of the surgical patients (p = 0.042). Glutamine showed inverse associations with CRP levels (r = -0.44, p < 0.05) and IL-6 concentrations (r = -0.23, p = 0.08). A CRP cut-off value of 95.5 mg/L was determined above which glutamine levels became deficient., Conclusions: About a third of patients (38 %) were glutamine deficient on admission to ICU, whereas some presented with supra-normal levels. While glutamine levels correlated inversely with inflammatory markers, and a CRP value of above 95.5 mg/L indicated potential glutamine deficiency, the clinical application of this finding needs further investigation.

Inflammation, as indicated by C-reactive protein concentrations (CRP), is a risk factor for chronic diseases. Both genetic and environmental factors affect susceptibility to inflammation. As dietary interventions can influence inflammatory status, we hypothesized that dietary effects could be influenced by interactions with single nucleotide polymorphisms (SNPs) in the CRP gene. We determined 12 CRP SNPs, as well as various nutrition status markers in 2010 black South Africans and analyzed their effect on CRP. Interactions were observed for several genotypes with obesity in determining CRP. Lipid intake modulated the pro-inflammatory effects of some SNPs, i.e., an increase in both saturated fatty acid and monounsaturated fatty acid intake in those homozygous for the polymorphic allele at rs2808630 was associated with a larger increase in CRP. Those harboring the minor alleles at rs3093058 and rs3093062 presented with significantly higher CRP in the presence of increased triglyceride or cholesterol intake. When harboring the minor allele of these SNPs, a high omega-6 to -3 ratio was, however, found to be anti-inflammatory. Carbohydrate intake also modulated CRP SNPs, as HbA1C and fasting glucose levels interacted with some SNPs to influence the CRP. This investigation highlights the impact that nutritional status can have on reducing the inherent genetic susceptibility to a heightened systemic inflammatory state.

Objective: Urbanization is generally associated with increased CVD risk and accompanying dietary changes. Little is known regarding the association between increased CVD risk and dietary changes using approaches such as diet quality. The relevance of predefined diet quality scores (DQS) in non-Western developing countries has not yet been established., Design: The association between dietary intakes and CVD risk factors was investigated using two DQS, adapted to the black South African diet. Dietary intake data were collected using a quantitative FFQ. CVD risk was determined by analysing known CVD risk factors., Setting: Urban and rural areas in North West Province, South Africa., Subjects: Apparently healthy volunteers from the South African Prospective Urban and Rural Epidemiological (PURE) study population (n 1710)., Results: CVD risk factors were significantly increased in the urban participants, especially women. Urban men and women had significantly higher intakes of both macro- and micronutrients with macronutrient intakes well within the recommended CVD guidelines. While micronutrient intakes were generally higher in the urban groups than in the rural groups, intakes of selected micronutrients were low in both groups. Both DQS indicated improved diet quality in the urban groups and good agreement was shown between the scores, although they seemed to measure different aspects of diet quality., Conclusions: The apparent paradox between improved diet quality and increased CVD risk in the urban groups can be explained when interpreting the cut-offs used in the scores against the absolute intakes of individual nutrients. Predefined DQS as well as current guidelines for CVD prevention should be interpreted with caution in non-Western developing countries.

The platinum(IV) complexes: [PtCl(4)(en)], cis,trans-[PtCl(2)(OAc)(2)(en)], cis,trans-[PtCl(2)(OH)(2)(en)] and trans-[Pt(OH)(2)(ethmal)(en)], encompassing a range of reduction potentials and their platinum(II) analogue [PtCl(2)(en)], have been assayed for their protein binding ability in the presence of albumin, albumin and L-cysteine and RPMI 1640 tissue culture medium supplemented with foetal calf serum (RPMI/FCS). cis,trans-[PtCl(4)(en)] exhibited significant protein binding in all three experiments, in a similar fashion to the platinum(II) complex, presumably as a consequence of its rapid reduction. The remaining three platinum(IV) complexes displayed little if any protein binding, with the greatest amount of binding observed in the RPMI/FCS experiment. The extent of binding in the RPMI/FCS correlated with the reduction potentials of the complexes, with the most readily reduced species binding to the greatest extent.