The iron status of South African blood donors: balancing donor safety and blood demand.

BACKGROUND: Several studies in developed countries have demonstrated high levels of iron deficiency (ID) among blood donors. There is a paucity of data for developing countries where blood shortages remain a major concern. STUDY DESIGN AND METHODS: A total of 4412 donors were enrolled in the study. Specimens were collected for full blood count, iron, transferrin saturation, and ferritin assessment. Donor demographics were recorded. ID was indicated by a ferritin level of less than 20 ng/mL for men and less than 12 ng/mL for women. Anemia was defined as hemoglobin levels less than 12.5 g/dL. Regression models for predictors of ID were developed. RESULTS: A total of 17.5% of all donors had ID, with 16.3% prevalence in women and 18.6% in men. Low hemoglobin had the highest association with ID (adjusted odds ratio [AOR], 11.078; 95% confidence interval [CI], 7.915-15.505); male donors had twice the odds of ID compared to female donors (AOR, 2.501; 95% CI, 1.964-3.185), while increasing age was associated with lower odds (AOD, 0.965; 95% CI, 0.956-0.975). Among male donors, an interdonation interval of less than 3 months (AOR, 2.679; 95% CI, 1.929-3.720) was associated with ID. Compared to other females combined, colored female donors (AOR, 2.335; 95% CI, 1.310-4.160) had higher odds and black female donors (AOR, 0.559; 95% CI, 0.369-0.845) lower odds of ID. CONCLUSION: ID is common among South African donors; low hemoglobin, gender, ethnicity, and past donation history is independently associated with ID. Recommendations aimed at protecting donor health may increase blood shortages in South Africa.

The Hayflick Limit and Age-Related Adaptive Immune Deficiency.

The adaptive immune system (AIS) acquires significant deficiency during chronological ageing, making older individuals more susceptible to infections and less responsive to vaccines compared to younger individuals. At the cellular level, one of the most striking features of this ageing-related immune deficiency is the dramatic loss of T-cell diversity that occurs in elderly humans. After the age of 70 years, there is a sharp decline in the diversity of naïve T cells, including a >10-fold decrease in the CD4+ compartment and a >100-fold decrease in the CD8+ compartment. Such changes are detrimental because the AIS relies on a diverse naïve T-cell pool to respond to novel pathogens. Recent work suggests that this collapse of naïve T-cell diversity results from T cells reaching the Hayflick limit and being eliminated through both antigen-dependent and -independent pathways. The progressive attrition of telomeres is the molecular mechanism that underlies this Hayflick limit. Therefore, we propose that by measuring the telomere lengths of T cells with high resolution, it is possible to develop a unique biomarker of immune deficiency, potentially much better correlated with individual susceptibility to diseases compared to chronological age alone.

Reevaluating Cumulative HIV-1 Viral Load as a Prognostic Predictor: Predicting Opportunistic Infection Incidence and Mortality in a Ugandan Cohort.

Recent studies have evaluated cumulative human immunodeficiency virus type 1 (HIV-1) viral load (cVL) for predicting disease outcomes, with discrepant results. We reviewed the disparate methodological approaches taken and evaluated the prognostic utility of cVL in a resource-limited setting. Using data on the Infectious Diseases Institute (Makerere University, Kampala, Uganda) cohort, who initiated antiretroviral therapy in 2004-2005 and were followed up for 9 years, we calculated patients' time-updated cVL by summing the area under their viral load curves on either a linear scale (cVL1) or a logarithmic scale (cVL2). Using Cox proportional hazards models, we evaluated both metrics as predictors of incident opportunistic infections and mortality. Among 489 patients analyzed, neither cVL measure was a statistically significant predictor of opportunistic infection risk. In contrast, cVL2 (but not cVL1) was a statistically significant predictor of mortality, with each log10 increase corresponding to a 1.63-fold (95% confidence interval: 1.02, 2.60) elevation in mortality risk when cVL2 was accumulated from baseline. However, whether cVL is predictive or not hinges on difficult choices surrounding the cVL metric and statistical model employed. Previous studies may have suffered from confounding bias due to their focus on cVL1, which strongly correlates with other variables. Further methodological development is needed to illuminate whether the inconsistent predictive utility of cVL arises from causal relationships or from statistical artifacts.

Age of the association between Helicobacter pylori and man.

When modern humans left Africa ca. 60,000 years ago (60 kya), they were already infected with Helicobacter pylori, and these bacteria have subsequently diversified in parallel with their human hosts. But how long were humans infected by H. pylori prior to the out-of-Africa event? Did this co-evolution predate the emergence of modern humans, spanning the species divide? To answer these questions, we investigated the diversity of H. pylori in Africa, where both humans and H. pylori originated. Three distinct H. pylori populations are native to Africa: hpNEAfrica in Afro-Asiatic and Nilo-Saharan speakers, hpAfrica1 in Niger-Congo speakers and hpAfrica2 in South Africa. Rather than representing a sustained co-evolution over millions of years, we find that the coalescent for all H. pylori plus its closest relative H. acinonychis dates to 88-116 kya. At that time the phylogeny split into two primary super-lineages, one of which is associated with the former hunter-gatherers in southern Africa known as the San. H. acinonychis, which infects large felines, resulted from a later host jump from the San, 43-56 kya. These dating estimates, together with striking phylogenetic and quantitative human-bacterial similarities show that H. pylori is approximately as old as are anatomically modern humans. They also suggest that H. pylori may have been acquired via a single host jump from an unknown, non-human host. We also find evidence for a second Out of Africa migration in the last 52,000 years, because hpEurope is a hybrid population between hpAsia2 and hpNEAfrica, the latter of which arose in northeast Africa 36-52 kya, after the Out of Africa migrations around 60 kya.

Activated intestinal macrophages in patients with cirrhosis release NO and IL-6 that may disrupt intestinal barrier function.

BACKGROUND & AIMS: Bacterial infections commonly occur in decompensated cirrhosis resulting from bacterial translocation from the intestine. We studied the role of intestinal macrophages and the epithelial barrier in cirrhosis. METHODS: Forty-four patients with NASH/ASH cirrhosis (decompensated n=29, compensated n=15) and nineteen controls undergoing endoscopy were recruited. Serum was obtained and LPS and LBP levels determined. Intestinal macrophages were characterized by flow cytometry, immunohistochemistry, and nitric oxide (NO) production measured in supernatant of cultured duodenal samples. Quantitative RT-PCR was performed on duodenal biopsies assessing 84 inflammatory genes. Protein levels of cytokines/chemokines were assessed in serum and supernatant. The duodenal wall was assessed by electron microscopy, tight junction protein expression determined by RT-PCR, immunohistochemistry, and Western blot and, functional analysis performed by transepithelial resistance measurement and permeability studies. RESULTS: Increased plasma LPS, LBP levels and higher numbers of duodenal CD33(+)/CD14(+)/Trem-1(+) macrophages, synthesizing iNOS and secreting NO were present in decompensated cirrhosis. Upregulation of IL-8, CCL2, CCL13 at the transcriptional level, and increased IL-8, and IL-6 were detected in supernatant and serum in cirrhosis. IL-6 and IL-8 co-localised with iNOS(+) and CD68(+), but not with CD11c(+) cells. Electron microscopy demonstrated an intact epithelial barrier. Increased Claudin-2 was detected by Western blot and immunohistochemistry, while decreased transepithelial resistance and increased duodenal permeability were detected in decompensated cirrhosis. CONCLUSIONS: Our study shows the presence of activated CD14(+)Trem-1(+)iNOS(+) intestinal macrophages, releasing IL-6, NO, and increased intestinal permeability in patients with cirrhosis, suggesting that these cells may produce factors capable of enhancing permeability to bacterial products.

A systematic review on prognostic indicators of acute on chronic liver failure and their predictive value for mortality.

BACKGROUND: An early and proper diagnosis of acute on chronic liver failure (ACLF), together with the identification of indicators associated with disease severity is critical for outcome prediction and therapy. OBJECTIVE: To systematically identify and summarize prognostic indicators for patients with ACLF and to evaluate the predictive value of these indicators. METHODS: Embase and Ovid-Medline were searched for English-language articles. The search criteria focused on identifying clinical trials and observational studies reporting on indicators used for prediction of mortality in patients with ACLF. RESULTS: Of 2382 studies identified, 19 were included for detailed analysis. Thirteen different definitions of ACLF were found. The main differences were related to acute deterioration in liver function, coagulopathy and hyperbilirubinaemia/jaundice. Seventy three prognostic indicators and their association with mortality were extracted and categorized into seven categories: general markers (n = 13), viral markers (n = 6), bio-markers (n = 22), hemodynamics (n = 1), morphology/histology (n = 17), scoring systems (n = 10) and treatments (n = 4). CONCLUSIONS: The ambiguity and variability in the definition of ACLF and in its predictive indicators hampers comparability among studies. There is a need for a single uniform definition of ACLF. Also absence of a gold standard is an obstacle to render one indicator superior to another. The age, hepatic encephalopathy, model for end-stage liver disease score, total bilirubin and International normalized ratio (prothrombin time) appeared to be promising candidates for evaluation in future studies. The result of this review may be useful as a starting point in developing a standard list of indicators for clinical outcome that concur with the clinicians' subjective views on prognosis in ACLF.

Generative AI for brain image computing and brain network computing: a review.

Recent years have witnessed a significant advancement in brain imaging techniques that offer a non-invasive approach to mapping the structure and function of the brain. Concurrently, generative artificial intelligence (AI) has experienced substantial growth, involving using existing data to create new content with a similar underlying pattern to real-world data. The integration of these two domains, generative AI in neuroimaging, presents a promising avenue for exploring various fields of brain imaging and brain network computing, particularly in the areas of extracting spatiotemporal brain features and reconstructing the topological connectivity of brain networks. Therefore, this study reviewed the advanced models, tasks, challenges, and prospects of brain imaging and brain network computing techniques and intends to provide a comprehensive picture of current generative AI techniques in brain imaging. This review is focused on novel methodological approaches and applications of related new methods. It discussed fundamental theories and algorithms of four classic generative models and provided a systematic survey and categorization of tasks, including co-registration, super-resolution, enhancement, classification, segmentation, cross-modality, brain network analysis, and brain decoding. This paper also highlighted the challenges and future directions of the latest work with the expectation that future research can be beneficial.

A mechanistic model for long-term immunological outcomes in South African HIV-infected children and adults receiving ART.

Long-term effects of the growing population of HIV-treated people in Southern Africa on individuals and the public health sector at large are not yet understood. This study proposes a novel 'ratio' model that relates CD4+ T-cell counts of HIV-infected individuals to the CD4+ count reference values from healthy populations. We use mixed-effects regression to fit the model to data from 1616 children (median age 4.3 years at ART initiation) and 14,542 adults (median age 36 years at ART initiation). We found that the scaled carrying capacity, maximum CD4+ count relative to an HIV-negative individual of similar age, and baseline scaled CD4+ counts were closer to healthy values in children than in adults. Post-ART initiation, CD4+ growth rate was inversely correlated with baseline CD4+ T-cell counts, and consequently higher in adults than children. Our results highlight the impacts of age on dynamics of the immune system of healthy and HIV-infected individuals.

The human immunodeficiency virus (HIV) remains an ongoing global pandemic. There is currently no cure for HIV, but antiretroviral therapies can keep the virus in check and allow individuals with HIV to live longer, healthier lives. These drugs work in two ways. They block the ability of the virus to multiply and they allow numbers of an important type of infection-fighting cell called CD4+ T cells to rebound. As more patients with HIV survive and transition from one life stage to the next, it is critical to understand how long-term antiretroviral therapies will affect normal age-related changes in their immune systems. The health of an immune system can be evaluated by looking at the number of CD4+ T cells an individual has, though this will vary by age and location. Clinicians use the same metrics to assess the immune health of individuals with HIV, however, as they age, it becomes a challenge to identify if a patient's immune system recovers normally or insufficiently. Thus, learning more about age-related differences in CD4+ T cells in people living with HIV may help improve their care. Using data from 1,616 children and 14,542 adults from South Africa, Ujeneza et al. created a simple mathematical model that can compare the immune system of person with HIV with the immune system of a similarly aged healthy individual. The model shows that among individuals with HIV receiving antiretroviral therapies, children have CD4+ T-cell numbers that are closest to the numbers seen in healthy individuals of the same age. This suggests that children may be more able to recover immune system function than adults after beginning treatment. Children also start antiretroviral therapies before their immune system has been severely damaged, while adults tend to start treatment much later when they have fewer CD4+ T cells left. Ujeneza et al. show that the fewer CD4+ T cells a person has when they start treatment, the faster the number of these cells grows after starting treatment. This suggests that the more damaged the immune system is, the harder it works to recover. This reinforces the need to identify people infected with HIV as soon as possible through testing and to begin treatment promptly. The new model may help clinicians and policy makers develop screening and treatment protocols tailored to the specific needs of children and adults living with HIV.

Correction: Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models.

[This corrects the article DOI: 10.1371/journal.pone.0224723.].

Comparison of Lymphocyte Subset Populations in Children From South Africa, US and Europe.

Background: Typically, African healthcare providers use immunological reference intervals adopted from Europe and the United States (US). This may be inappropriate in a setting with many differences including exposure to different environmental stimuli and pathogens. We compared immunological reference intervals for children from Europe and the US with South African children to explore whether healthy children living in settings with high rates of infectious diseases have different baseline immunological parameters. Methodology: Blood was taken from 381 HIV-uninfected children aged between 2 weeks and 13 years of age from a Child Wellness Clinic in an informal settlement in Cape Town to establish local hematological and lymphocyte reference intervals for South African children. Flow-cytometry quantified percentage and absolute counts of the B-cells, NK-cells, and T-cells including activated, naïve, and memory subsets. These parameters were compared to three separate studies of healthy children in Europe and the US. Results: Increased activated T-cells, and natural killer cells were seen in the younger age-groups. The main finding across all age-groups was that the ratio of naïve/memory CD4 and CD8 T-cells reached a 1:1 ratio around the first decade of life in healthy South African children, far earlier than in resource-rich countries, where it occurs around the fourth decade of life. Conclusions: This is the largest data set to date describing healthy children from an African environment. These data have been used to create local reference intervals for South African children. The dramatic decline in the naïve/memory ratio of both CD4 and CD8 T-cells alongside increased activation markers may indicate that South African children are exposed to a wider range of environmental pathogens in early life than in resource-rich countries. These marked differences illustrate that reference intervals should be relevant to the population they serve. The implications for the developing pediatric immune system requires further investigation.

Imaging glucose metabolism in perfluorocarbon-perfused hepatocyte bioreactors using positron emission tomography.

In vitro hepatocyte bioreactor functionality depends particularly on maintaining appropriate oxygen levels and exposure to nonparenchymal cells. An attractive solution without immunological consequences to the patient is incorporating a perfluorocarbon oxygen carrier in the circulating medium and co-culturing hepatocytes with stellate cells. Since bioreactors are normally sealed sterile units, demonstrating metabolic functionality is hindered by limited access to the cells after their aggregation in the matrix. A novel possibility is to use positron emission tomography (PET) to image cellular radioactive glucose uptake under O(2)-limited conditions. In this study, primary cell isolation procedures were carried out on eight pigs. Pairs of cell-seeded and cell-free (control) bioreactors with and without perfluorocarbon were cultured under identical conditions and were oxygenated using hypoxic (5% O(2)) and ambient (20% O(2)) gas mixes. Sixteen PET scans were conducted 24 h after cell isolation, the same timescale as that involved in treating a liver failure patient with a primary-cell bioreactor. In all cases, cell-seeded bioreactors without perfluorocarbon were more radioactive, i.e., were more glycolytic, than those with perfluorocarbon. This difference was significant in the hypoxic pair of bioreactors but not in the ambient pair of bioreactors. Additionally, in the same hypoxic bioreactors, circulating extracellular steady-state glucose levels were significantly lower and lactate levels were higher than those in the ambient bioreactors. Similar findings have been made in other in vitro hepatocyte studies investigating the effects of perfluorocarbons. PET is attractive for studying in situ O(2)-dependent bioreactor metabolism because of its visual and numerically quantifiable outputs. Longer-term metabolic studies (e.g., 5-10 days) investigating the effect of perfluorocarbon on bioreactor longevity will complement these findings in the future.

Non-toxicity of IV injected perfluorocarbon oxygen carrier in an animal model of liver regeneration following surgical injury.

Lethal dose experiments in animals have demonstrated that second-generation perfluorocarbon oxygen carriers are remarkably non-toxic. However, this non-toxicity has not previously been demonstrated in a liver failure scenario. A surgical liver damage and regeneration model in rats was selected using a well-controlled cross tabulated study design. A large number of physiological, biochemical, and hematological parameters were measured. No indications were found that intravenously injected perfluorooctyl bromide emulsion was toxic at the concentrations employed, in either healthy or severe liver injury scenarios. Neither was there any significant impact on the rate of liver regeneration following the injuries. Bearing in mind prior human clinical studies, it is therefore safe to assume that perfluorocarbon emulsions are also non-toxic in bioartificial liver treatments.

Cumulative viral load as a predictor of CD4+ T-cell response to antiretroviral therapy using Bayesian statistical models.

INTRODUCTION: There are Challenges in statistically modelling immune responses to longitudinal HIV viral load exposure as a function of covariates. We define Bayesian Markov Chain Monte Carlo mixed effects models to incorporate priors and examine the effect of different distributional assumptions. We prospectively fit these models to an as-yet-unpublished data from the Tshwane District Hospital HIV treatment clinic in South Africa, to determine if cumulative log viral load, an indicator of long-term viral exposure, is a valid predictor of immune response. METHODS: Models are defined, to express 'slope', i.e. mean annual increase in CD4 counts, and 'asymptote', i.e. the odds of having a CD4 count ≥500 cells/µL during antiretroviral treatment, as a function of covariates and random-effects. We compare the effect of using informative versus non-informative prior distributions on model parameters. Models with cubic splines or Skew-normal distributions are also compared using the conditional Deviance Information Criterion. RESULTS: The data of 750 patients are analyzed. Overall, models adjusting for cumulative log viral load provide a significantly better fit than those that do not. An increase in cumulative log viral load is associated with a decrease in CD4 count slope (19.6 cells/µL (95% credible interval: 28.26, 10.93)) and a reduction in the odds of achieving a CD4 counts ≥500 cells/µL (0.42 (95% CI: 0.236, 0.730)) during 5 years of therapy. Using informative priors improves the cumulative log viral load estimate, and a skew-normal distribution for the random-intercept and measurement error results is a better fit compared to using classical Gaussian distributions. DISCUSSION: We demonstrate in an unpublished South African cohort that cumulative log viral load is a strong and significant predictor of both CD4 count slope and asymptote. We argue that Bayesian methods should be used more frequently for such data, given their flexibility to incorporate prior information and non-Gaussian distributions.

Computer simulation and physical phantom models for estimating the dielectric properties of rhinoceros tissue.

In vivo and ex vivo sensors have the potential to aid tracking and anti-poaching endeavours and provide new insights into rhinoceros physiology and environment. However, the propagation of electromagnetic signals in rhinoceros tissue is currently not known. We present simulation and agar models of the rhinoceros that allow the investigation of electromagnetic propagation by in vivo and ex vivo devices without the need for surgery. Since the dielectric properties of rhinoceros tissue have not been documented, the conductivity and permittivity of the skin, fat, muscle, blood and other organs are first approximated by means of a meta-analysis that includes animals with similar physical properties. Subsequently, we develop anatomical models that include dermal layers, internal organs and a skeleton. We also develop a flank model that serves as an approximation of the anatomical model in certain situations. These models are used to determine the viability of communication between an in vivo device and an ex vivo device attached to the hind leg of the animal. Two types of antenna (microstrip-fed planar elliptical monopole antenna and printed inverted-F antenna) and three feasible implant locations (back, neck and chest) are considered. In addition to the computer models, phantom recipes using salt, sugar and agar are developed to match the dielectric properties of each tissue type at the industrial, scientific and medical (ISM) frequencies of 403MHz, 910MHz and 2.4GHz. The average error between the measured and theoretically predicted dielectric values was 6.22% over all recipes and 4.49% for the 2.4 GHz recipe specifically. When considering the predicted efficiency of the transmitting and receiving antennas, an agreement of 67.38% was demonstrated between the computer simulations and laboratory measurements using the agar rhinoceros flank models. Computer simulations using the anatomical model of the rhinoceros indicate that the chest is the optimal implant location and that best signal propagation is achieved using the planar inverted-F antenna (PIFA). Using this configuration, the simulations indicate that communication between the implant and an ex vivo device attached to the hind leg is challenging but possible. Furthermore, we find that the inclusion of factors such as the density and temperature of the phantom materials were found to be critical to the achievement of good agreement between practice and simulation.

Systematic review of statistically-derived models of immunological response in HIV-infected adults on antiretroviral therapy in Sub-Saharan Africa.

INTRODUCTION: In Sub-Saharan African (SSA) resource limited settings, Cluster of Differentiation 4 (CD4) counts continue to be used for clinical decision making in antiretroviral therapy (ART). Here, HIV-infected people often remain with CD4 counts <350 cells/µL even after 5 years of viral load suppression. Ongoing immunological monitoring is necessary. Due to varying statistical modeling methods comparing immune response to ART across different cohorts is difficult. We systematically review such models and detail the similarities, differences and problems. METHODS: 'Preferred Reporting Items for Systematic Review and Meta-Analyses' guidelines were used. Only studies of immune-response after ART initiation from SSA in adults were included. Data was extracted from each study and tabulated. Outcomes were categorized into 3 groups: 'slope', 'survival', and 'asymptote' models. Wordclouds were drawn wherein the frequency of variables occurring in the reviewed models is indicated by their size and color. RESULTS: 69 covariates were identified in the final models of 35 studies. Effect sizes of covariates were not directly quantitatively comparable in view of the combination of differing variables and scale transformation methods across models. Wordclouds enabled the identification of qualitative and semi-quantitative covariate sets for each outcome category. Comparison across categories identified sex, baseline age, baseline log viral load, baseline CD4, ART initiation regimen and ART duration as a minimal consensus set. CONCLUSION: Most models were different with respect to covariates included, variable transformations and scales, model assumptions, modelling strategies and reporting methods, even for the same outcomes. To enable comparison across cohorts, statistical models would benefit from the application of more uniform modelling techniques. Historic efforts have produced results that are anecdotal to individual cohorts only. This study was able to define 'prior' knowledge in the Bayesian sense. Such information has value for prospective modelling efforts.

Standardization criteria for an ischemic surgical model of acute hepatic failure in pigs.

The establishment of a reliable large animal model of acute hepatic failure (AHF) is critical for the evaluation of supportive therapies such as bioartificial liver support systems (BALSS). Large animal surgical models bear some resemblance to the clinical syndrome of AHF in humans. However, these are inherently complex and are predisposed to inter-individual variation. The development of considerable skill is required and no precise standardization criteria for such models have been defined as yet. This study investigates a surgically induced ischemic model of AHF in 15 female Landrace pigs. A large set of systemic and biochemical variables were measured. The absolute values of systemic variables during the surgery and the rates of change of the biochemical variables following the surgery were correlated with the duration of survival of each animal. A multivariate prognosis was revealed, with several variables simultaneously determining survival. Those of importance in the surgical period included the duration of portal occlusion, the pulse rate during this time, the total blood lost, the mean arterial pressure and the body temperature after the procedure. In the post-surgical period the rates of change of blood ammonia, branch chain amino acids, haemoglobin, hematocrit, body temperature, total urinary excretion and mean blood pH all demonstrated some importance to survival. Based on the above and clinical experience, standardization criteria specific for this model were defined. Additional variables that posses value in AHF but demonstrate lower correlations with survival were also included, e.g. the prothrombin time, clotting factors, liver enzymes, potassium, bilirubin, creatinine and lactate. Valuable procedural information was generated, which stabilized the model, limited unnecessary blood sampling and cut laboratory costs. The criteria allow the early exclusion of compromized animals and the identification of those demonstrating characteristics predictive of longer survival prior to BALSS connection. This is likely to allow more accurate comparisons between small treatment and control groups. In effect, the above are the converse of the King's college criteria (for humans) as they are designed to exclude animals with prognoses that are insufficiently bleak or due to factors other than AHF. The statistical analysis employed also identified the variables that in future may allow the evaluation of prognosis in real-time.

Effect of rapamycin on hepatic osteodystrophy in rats with portasystemic shunting.

AIM: To study if T-cell activation related to portasystemic shunting causes osteoclast-mediated bone loss through RANKL-dependent pathways. We also investigated if T-cell inhibition using rapamycin would protect against bone loss in rats. METHODS: Portasystemic shunting was performed in male Sprague-Dawley rats and rapamycin 0.1 mg/kg was administered for 15 wk by gavage. Rats received powderized chow and supplemental feeds to prevent the effects of malnutrition on bone composition. Weight gain and growth was restored after surgery in shunted animals. At termination, biochemical parameters of bone turnover and quantitative bone histology were assessed. Markers of T-cell activation, inflammatory cytokine production, and RANKL-dependent pathways were measured. In addition, the roles of IGF-1 and hypogonadism were investigated. RESULTS: Portasystemic shunting caused low turnover osteoporosis that was RANKL independent. Bone resorbing cytokine levels, including IL-1, IL-6 and TNFalpha, were not increased in serum and TNFalpha and RANKL expression were not upregulated in PBMC. Portasystemic shunting increased the circulating CD8+ T-cell population. Rapamycin decreased the circulating CD8+ T-cell population, increased CD8+ CD25+ T-regulatory cell population and improved all parameters of bone turnover. CONCLUSION: Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy.

Observed full blood count and lymphocyte subset values in a cohort of clinically healthy South African children from a semi-informal settlement in Cape Town.

BACKGROUND: The paediatric full blood count and lymphocyte subset reference intervals used by the National Health Laboratory Service (NHLS), South Africa (SA), are taken from two international reference interval publications. Differences in reference intervals suggest that international data sets may not be appropriate for use in SA. OBJECTIVE: To study immunohaematological values of a group of clinically healthy children from an informal settlement in Cape Town, SA, to assess whether international paediatric reference intervals used by the NHLS are appropriate. METHODS: A cross-sectional study of 207 female and 174 male HIV-uninfected children living in an informal settlement in Cape Town was performed. Full blood counts, automated differential counts and lymphocyte subset analysis were done using internationally accepted technologies. Data were categorised by age and reference intervals compiled using medians and 95% confidence intervals (CIs). Gender comparisons were calculated by non-parametric tests. RESULTS: Although median and 95% CI values differed slightly, physiological trends for red cell, platelet, white blood cell differential and lymphocyte subsets were similar to international reference intervals currently in use at the NHLS. Benign ethnic neutropenia was not a significant finding, and gender-specific intervals were not necessary until 12 years of age. Lower overall median values for haemoglobin and haematocrit, and higher median values for mean cell volume and red cell distribution width, were noted. Assessment of haemoglobin, red cell distribution width and calculated Mentzer ratios suggested underlying iron deficiency in 14.2% of participants. CONCLUSION: Paediatric immunohaematological reference intervals observed in this study are similar to, and support continued use of, international paediatric reference intervals. Underlying iron and related nutritional deficiencies may be contributing to lower haemoglobin levels noted in local children. A larger nationwide study, including all ethnic groups, is recommended.