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Obesity-associated inflammatory mechanisms play a key role in the pathogenesis of metabolic-related diseases. Failure of anti-inflammatory control mechanisms within adipose tissue and peripheral blood mononuclear cells (PBMCs) have been implicated in disease progression. This study investigated the efficacy of allogeneic adipose tissue-derived mesenchymal stem cells conditioned media (ADSC-CM) to counteract persistent inflammation by inducing an anti-inflammatory phenotype and cytokine response within PBMCs derived from patients with and without metabolic syndrome. Forty-six (n = 46) mixed ancestry females (18–45 years) were subdivided into (a) healthy lean (HL) (n = 10) (BMI 2), (b) overweight/obese (OW/OB) (BMI ≥25 kg/m2, n = 22) and (c) metabolic syndrome (MetS) (visceral adiposity, ≥3 metabolic risk factors) (n = 14) groups. Body composition (DXA scan), metabolic (cholesterol, HDL, LDL, triglycerides, blood glucose) and inflammatory profiles (38-Plex cytokine panel) were determined. PBMCs were isolated from whole blood and treated ex vivo with either (i) autologous participant-derived serum, (ii) ADSCs-CM or (iii) a successive treatment regime. The activation status (CD11b+) and intracellular cytokine (IL6, IL10, TNFa) expression were determined in M1 (CD68+CD206−CD163−) and M2 (CD68+CD163+ CD206+) macrophage populations using flow cytometry. ADSC-CM treatment, promoted a M2 macrophage phenotype and induced IL10 expression, this was most pronounced in the OW/OB group. This response is likely mediated by multiple complementing factors within ADSC-CM, yet to be identified. This study is the first to demonstrate the therapeutic potential of ADSC-CM to restore the inflammatory balance in immune compromised obese individuals.

Introduction: Geriatric patients with a fragility fracture of the hip (FFH) are especially prone to sarcopenia with poor functional outcomes and quality of life. We assessed the prevalence of sarcopenia in older South African patients with FFH. Risk factors for sarcopenia were also investigated. Materials and Methods: From August 1 to November 30, 2018, all older patients with FFH were invited to participate. Sarcopenia was diagnosed based on the revised criteria of the European Working Group on Sarcopenia in Older People (EWGSOP2). Handgrip strength (HGS) and muscle strength were assessed. Muscle quantity was determined by dual-energy X-ray absorptiometry. Demographic information was collected, and 25-hydroxyvitamin D (25[OH]D) status was determined. Results: Of the 100 hip fracture cases, 65 were enrolled, and 52% (34/65) were sarcopenic (women: 62%; men: 38%). HGS accurately identified sarcopenia (sensitivity and specificity: 100%). Patients >80 years of age had a prevalence of sarcopenia twice (18/21 [83%]) that of younger patients (18/44 [36%]). Women with sarcopenia were smaller than those without (weight: p < 0.001; height: p < 0.001; body mass index: p = 0.018). Low 25(OH)D was almost universally present, with median 25(OH)D levels significantly lower in the patients with sarcopenia (27 nmol/L [interquartile range {IQR}: 20–39] vs. 40 nmol/L [IQR: 29–53]). Several risk factors, including advanced age; female sex; a smaller body size, especially among women; limited physical activity; and low 25(OH)D levels, were identified. Discussion: The accuracy of HGS testing in this cohort underscores EWGSOP2’s recommendation that muscle strength is key to sarcopenia. Further study and follow-up are required to determine the clinical relevance of sarcopenia among FFH patients. Conclusion: The prevalence of sarcopenia in our FFH population is high. Sarcopenia is associated with poor patient outcomes following surgical intervention. Orthopaedic surgeons should therefore be cognizant of the presentation and associated risk of sarcopenia as our patient populations age.

Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Conclusions: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

Limited data exist on the incidence of hip fractures in South Africa (SA). We report gender and ethnic specific incidence rates of hip fractures in SA.In a multicentre prospective study, conducted in geographically defined municipalities of three provinces in SA, a structured questionnaire was administered to all subjects aged 40 years and over, presenting with a new atraumatic hip fracture, from 1 April 2017 to 31 March 2018. Gender and ethnic specific incidence rates (IR) of hip fractures were calculated using population statistics from Statistics SA.Of the 2767 subjects enrolled, 1914 (69·2%) were women and 853 (30·8%) were men. The majority of subjects were from the White population (40·9%) followed by those from the African (26·4%), Coloured (18·7%) and Indian (13·9%) populations. Men with hip fractures were significantly younger than women in the total group (69 [IQR 59-79] versus 77 years [IQR 68-84], p 0·001) and in each ethnic group. White subjects were significantly older (p 0·0001) and Africans significantly younger (p 0·0001) than the other ethnic groups. In women, the highest IR was noted in the White population (176·0 per 100,000), followed by that in the Indian (147·7 per 100,000), Coloured (73·2 per 100,000) and African populations (43·6 per 100,000). A similar pattern was seen in men albeit at lower rates, with the highest rate in White men at 76·5 per 100,000. In the total study population and the African population, the IR was higher in men compared to women in subjects under 60 years. In the White population, the IR was higher in men compared to women in the 40-44 years age group. While in the Coloured and Indian populations the IR was higher in men compared to women in the 40-49 years and 45-54 years age groups, respectively. There was an increase in the relative risk ratios with age in the total study population, and in all ethnic groups in both women and men.Hip fractures occur in all ethnic groups in South Africa with higher IRs in the White and Indian populations compared to the Coloured and African populations. Consistent with the published literature, the overall hip fracture IR was higher in women than in men, except in the younger age groups, and increased with age.South African Medical Research Council and the University of KwaZulu-Natal Competitive Research Grant.

To evaluate point-of-care-testing (POCT) for the diagnosis of Type 2 diabetes mellitus 6-12 weeks post-partum in women with gestational diabetes (GDM).Post-partum glucose assessment (75-mg oral glucose tolerance test, OGTT) was performed prospectively in 122 women with GDM (1 November 2015 to 1 November 2017) at Tygerberg Hospital, Cape Town, South Africa. Individuals with known pre-existing diabetes were excluded. The accuracy and clinical utility of POCT (capillary finger-prick) were compared with laboratory plasma glucose (hexokinase and glucokinase methods). The OGTT consisted of two time points (fasting and 2 h) during which concurrent glucose samples (POCT and laboratory) were obtained. Bland-Altman plots and paired analysis were used to assess the analytical accuracy of POCT, whereas its diagnostic performance was determined using positive and negative predictive values to calculate specificity and sensitivity.Spearman's ranked correlation analysis indicated a strong association between POCT and laboratory glucose values at both OGTT time points (fasting, r = 0.95, P 0.0001; 2 h, r = 0.88, P 0.0001). Thirty-six women were diagnosed with Type 2 diabetes based on gold standard laboratory glucose levels (fasting 7 mmol/l; 2 h 11.1 mmol/l). POCT correctly identified Type 2 diabetes in 78% of women (28 of 36) with a positive predictive value of 89.3% and a negative predictive value of 96.7% at the fasting time point. The sensitivity and specificity of POCT to diagnose Type 2 diabetes were 89% (fasting), 85.7% (2 h) and 96.7% (fasting), 98.5% (2 h) respectively. POCT proved less sensitive to diagnose pre-diabetes (69%) but displayed satisfactory specificity (92%) at both time points assessed.POCT accurately identifies women with Type 2 diabetes 6-12 weeks after GDM.

It is known that advanced metabolic disorders such as type 2 diabetes compromise the functional and regenerative capacity of endogenous adipose-tissue resident stem cells (ADSCs). It is, however, still unclear at which stage of disease progression ADSCs become compromised and whether systemic factors contribute to their functional decline. It was therefore hypothesized that inflammatory changes in the systemic microenvironment during distinct stages of disease progression negatively affect the functional capacity of ADSCs. A total of forty-seven (n = 47) black African reproductive aged females (32 ± 8 years; mean ± SD) were included in this study and subdivided into: (a) healthy lean (C; body mass index, BMI ≤ 25 kg/m2), (b) healthy overweight/obese (OB; BMI ≥ 25 kg/m2), (c) obese metabolic syndrome (MetS; BMI ≥ 30 kg/m2), and (d) type 2 diabetes mellitus (T2DM; previously diagnosed and on treatment) groups. Participants underwent anthropometric assessments and a DXA scan to determine their body composition and adipose indices. Each persons' systemic metabolic- (cholesterol, HDL, LDL, triglycerides, and blood glucose) and inflammatory profiles (CRP, SDF1α, TNFα, IL6, IL8, IL10, and IFNy) were also evaluated. Participant-derived serum was then used to treat an ADSC cell line in vitro and its effect on viability (MTT-based assay), proliferation (BrdU), migration (wound healing assay), and osteogenic differentiation assessed. When exposed to serum derived from overweight/obese individuals (with or without metabolic syndrome), both the proliferative and migratory responses of ADSCs were less pronounced than when exposed to healthy control serum. Serum IL6 concentrations were identified as a factor influencing the proliferation of ADSCs, suggesting that long-term disruption to the systemic cytokine balance can potentially disrupt the proliferative responses of ADSCs. Obese participant-derived serum (with and without metabolic syndrome) furthermore resulted in lipid accumulation during osteogenic differentiation. This study, therefore demonstrated that systemic factors in obese individuals, regardless of the presence of metabolic syndrome, can be detrimental to the multifunctional properties of ADSCs.

Breast cancer, as the most common malignancy in women, remains a major public health issue despite countless advances across decades. Endocrine therapy is the cornerstone of treatment of the hormone-sensitive subtype of breast cancer. The use of aromatase inhibitors (AIs) in the postmenopausal women has extended the survival beyond that of Tamoxifen, but harbors a subset of side effects, most notably accelerated bone loss. This, however, does not occur in all women undergoing treatment. It is vital to identify susceptible patients early, to limit such events, employ early treatment thereof, or alter drug therapy. International trials on AIs, predominantly performed in North American and European females, provide little information on what to expect in women in developing countries. Here, surgeons often prescribe and manage endocrine therapy. The prescribing surgeon should be aware of the adverse effect of the endocrine therapy and be able to attend to side effects. This review highlights clinical and biochemical factors associated with decrease in bone mineral density in an, as yet, unidentified subgroup of postmenopausal women. In the era of personalized medical care, appropriate management of bone health by surgeons based on these factors becomes increasingly important.

Background. Non-thyroidal illness syndrome (NTIS) can be defined as the presence of abnormal thyroid function in the absence of primary thyroid dysfunction and is associated with acute illness. Thyroid function testing is generally not advised in the critically ill patient. Thyroidstimulating hormone (TSH) measurement is the preferred screening test for thyroid disease, but results may be misleading and variable in the setting of critical illness. Objective . To describe the pattern of requests for TSH testing in patients admitted to the emergency department and intensive care units at Tygerberg Hospital, Cape Town, South Africa. Methods. A retrospective, descriptive (observational) study was conducted over a 6-month period to determine the number of requests for TSH testing received for patients admitted to the emergency department and intensive care units. Results. A total of 1 139 requests for TSH testing were received from the emergency department and intensive care units, of which 166 were excluded. Of the 973 requests evaluated, 14% yielded abnormal results. The majority (79.4%) of the abnormal TSH results were most likely attributed to NTIS. Follow-up TSH results after 6 - 8 weeks were available in only 18% of cases with abnormal TSH levels at initial presentation. Conclusion. We found that TSH testing was often requested in critically ill patients, but that most results were either normal or indicative of NTIS. Follow-up testing of abnormal TSH results was rarely performed. We recommend continued education of junior clinicians regarding thyroid function testing in critically ill patients.

The data presented in this paper are related to the research article entitled “Synthesis, characterisation and electrochemistry of eight Fe coordination compounds containing substituted 2-(1-(4-R-phenyl-1H-1,2,3-triazol-4-yl)pyridine ligands, R=CH3, OCH3, COOH, F, Cl, CN, H and CF3.” (Conradie et al., 2019) [1]. This paper presents electrochemical and density functional theory data of 4-phenyl-substituted dichloro(bis{2-[1-(4-R-phenyl)-1H-1,2,3-triazol-4-yl-κN3]pyridine-κN})iron(II) compounds, containing differently substituted 2-(1-(4-R-phenyl)-1H-1,2,3-triazol-1-yl)pyridine ligands (L2 – L9) (Tawfiq et al., 2014) [2]. Density functional theory calculated data of five different structural isomers for each compound, consistently show that the title compounds are octahedral and that the isomer with the chloride atoms, the pyridine nitrogens and the triazol nitrogens trans to each other, has the lowest energy. Natural bonding orbital (NBO) data and quantum theory of atoms in molecules (QTAIM) data of dichloro(bis{2-[1-(phenyl)-1H-1,2,3-triazol-4-yl-κN3]pyridine-κN})iron(II) show origin for the preference of the trans isomer.

Glucocorticoid-induced osteoporosis (GCOP) is predominantly caused by inhibition of bone formation, resulting from a decrease in osteoblast numbers. Employing mouse (MBA-15.4) and human (MG-63) osteoblast cell lines, we previously found that the glucocorticoid (GC) dexamethasone (Dex) inhibits cellular proliferation as well as activation of the MAPK/ERK signaling pathway, essential for mitogenesis in these cells, and that both these effects could be reversed by the protein tyrosine phosphatase (PTP) inhibitor vanadate. In a rat model of GCOP, the GC-induced changes in bone formation, mass, and strength could be prevented by vanadate cotreatment, suggesting that the GC effects on bone were mediated by one or more PTPs. Employing phosphatase inhibitors, qRT-PCR, Western blotting, and overexpression/knockdown experiments, we concluded that MKP-1 was upregulated by Dex, that this correlated with the dephosphorylation of ERK, and that it largely mediated the in vitro effects of GCs on bone. To confirm the pivotal role of MKP-1 in vivo, we investigated the effects of the GC methylprednisolone on the quantitative bone histology of wild-type (WT) and MKP-1 homozygous knockout (MKP-1(-/-)) mice. In WT mice, static bone histology revealed that GC administration for 28 days decreased osteoid surfaces, volumes, and osteoblast numbers. Dynamic histology, following time-spaced tetracycline labeling, confirmed a significant GC-induced reduction in osteoblast appositional rate and bone formation rate. However, identical results were obtained in MKP-1 knockout mice, suggesting that in these animals upregulation of MKP-1 by GCs cannot be regarded as the sole mediator of the GC effects on bone.

Skeletal mass is maintained by a balance between formation and resorption, cell proliferation and apoptosis. In vitro, glucocorticoids (GCs) decrease extracellular signal-regulated kinases (ERK) activation by mitogens, thus inhibiting osteoblast proliferation. Both ERK activity and proliferation are restored by co-treatment with the protein tyrosine phosphatase inhibitor, vanadate. Since ERK signalling may also be anti-apoptotic, we explored the effects of vanadate on GC-induced apoptosis in vitro and in vivo. Apoptosis in MBA-15.4 pre-osteoblasts increased from 6 h and remained up to eightfold higher through 6 days of 10− 6 M dexamethasone (Dex) treatment. Co-incubation with 10− 7 M vanadate markedly reduced apoptosis at all time points. Vanadate also prevented GC-induced poly-ADP-ribose polymerase cleavage. We assessed the transcriptional profiles of seven anti-apoptotic proteins (Bcl-2, Bcl-XL, inhibitors of apoptosis protein-1 (IAP-1), IAP-2, X-linked IAP (XIAP), Fas-associated death-domain-like IL-1β-converting enzyme-inhibitory protein (FLIPLong) and FLIPShort) in osteoblasts subjected to various stimuli using real-time quantitative PCR. Although these anti-apoptotic genes responded to different mitogenic conditions, Dex failed to repress their expression, and in fact significantly up-regulated Bcl-XL, IAP-2 and XIAP. Dex may therefore induce apoptosis by up-regulating pro-apoptotic gene expression. We have previously demonstrated that rats treated with GC develop low formation osteoporosis (bone histomorphometry and DEXA) and skeletal fragility (breaking strength) that were largely prevented by co-treatment with vanadate. We report here that vertebrae from rats treated with 3.5 mg/kg per day methylprednisolone for 9 weeks showed increased incidence of terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick end-labelling-positive apoptotic osteocytes, which was reduced by vanadate co-treatment. We conclude that vanadate prevents GC-induced apoptosis of pre-osteoblasts in vitro and osteocytes in vivo, and this may contribute to its bone-sparing effects in vivo.

Glucocorticoid-induced osteoporosis is characterized by decreased osteoblast numbers and a marked impairment of new bone formation. We found that, in vitro, dexamethasone inhibits both preosteoblast proliferation and mitogenic kinase activity in response to mitogens, and that inhibition of protein tyrosine phosphatases (PTPs) using sodium orthovanadate prevents this. Therefore, dexamethasone may act by either upregulating antiproliferative PTPs or downregulating promitogenic tyrosine-phosphorylated substrates. In this study, osteoporosis was induced in 3.5-month-old rats by subcutaneous injection with methylprednisolone 3.5 mg/kg per day for 9 weeks. Rats were treated with steroid alone or in combination with 0.5 mg/mL sodium orthovanadate, administered continuously in drinking water. Steroid-treated bones were significantly (p < 0.005) osteopenic (according to dual-energy X-ray absorptiometry) and physically weaker (p < 0.05) than controls. Quantitative bone histology confirmed a significant decrease in osteoid surfaces (p < 0.001), osteoblast numbers (p < 0.05), and rate of bone formation (p < 0.001). Concomitant treatment with vanadate largely prevented the densitometric, histologic, and physical abnormalities induced by prednisolone. This study supports our finding that PTPs are central to the negative regulation of osteoblast proliferation by glucocorticoids and, furthermore, suggests that PTP inhibitors such as sodium orthovanadate should be considered as novel anabolic agents for the treatment of steroid-induced osteoporosis.

Black women are generally regarded as being less prone to the development of osteoporosis. This study reports a similar prevalence of morphometric vertebral fractures in black (9.1 %) and white (5.0 %) South African women. Clinical risk factors and bone strength parameters contributed differently to fracture risk in the two ethnic cohorts. Vertebral fracture represents one of the most common osteoporotic fractures and is a significant cause of morbidity and mortality. Little is known regarding the prevalence of vertebral fractures on the African continent. We therefore prospectively examined the prevalence of vertebral fracture on radiographs of the thoraco-lumbar spine in otherwise healthy community-dwelling older black and white South African women. Radiographs of the spine (T4–L5) were obtained randomly in 189 women (47 % black), aged 40 years or older, for the analysis of vertebral fracture. Radiographs were evaluated by a single radiologist, blinded to clinical data, using Genant’s semi-quantitative method. Clinical risk factors for osteoporosis, risk factors for falls (fall history, quadriceps strength, lateral sway and reaction time), areal and volumetric bone mineral density of the spine and hip, calcaneal ultrasonography (QUS) and vertebral macro-geometry were assessed in the two ethnic groups and the association with prevalent vertebral fractures examined. Vertebral fracture prevalence in older South African black and white women was similar (9.1 % in black and 5.0 % in white women). In black women, lower body weight and lower areal and volumetric bone mineral density (BMD) at all sites could serve as markers of increased fracture risk. Older age, physical inactivity, lower muscle strength and lower femoral BMD were associated with vertebral fracture risk in whites. Our findings are noteworthy and the first attempt to compare vertebral fracture risk in women of different ethnicities on the African continent. A similar vertebral fracture risk between black and white women in South Africa must be considered at present to ensure appropriate evaluation in all subjects who present with clinical risk factors for osteoporosis, regardless of ethnicity.

Ethnic differences in bone mineral density (BMD) between healthy adult black and white South African women were studied. Higher BMD was only noted at the femoral sites in black women. Body weight significantly impacted these findings. A lower fracture risk at all skeletal sites cannot be assumed in black South African (SA) women.Bone mineral density (BMD) varies amongst women of different ethnicities. African-Americans have higher BMD at all skeletal sites compared with whites. On the African continent, bone density studies suggest site-specific ethnic differences in BMD. To examine the contribution of body weight and lifestyle characteristics to ethnic differences in BMD between adult black and white South African women, we assessed lumbar spine (SBMD), femoral neck (FNBMD) and total femoral BMD (FTBMD) by dual-energy X-ray absorptiometry (DXA) in 184 black and 143 white women aged between 23 and 82 years.BMDs were compared amongst pre- and postmenopausal blacks and whites before and after adjustment for covariates with significant univariate association with BMD. Volumetric bone mineral apparent density (BMAD) of the spine and femoral neck was also calculated to account for ethnic differences in bone size.Before adjustment, SBMD was lower (p 0.05), FTBMD similar and FNBMD (p 0.01) higher in premenopausal black women. Similar SBMD, but significantly higher BMD at the femoral sites (p 0.01), was noted in postmenopausal blacks compared with whites. Amongst anthropometric measures and lifestyle factors, only adjustment for weight significantly altered these observed ethnic differences in bone density. After adjustment for weight, SBMD remained lower in premenopausal blacks and became lower in young postmenopausal blacks. Weight adjustment eliminated all ethnic differences in proximal femoral BMD measurements, with the exception of FNBMD that remained higher in younger postmenopausal blacks. Before adjustment, calculated SBMAD was similar and FNBMAD consistently higher in blacks in all the menstrual groups. Adjustment for weight did not alter these findings.Most of the observed ethnic difference in BMD was explained by differences in body weight between black and white SA women. The higher femoral BMD in older blacks may explain, the lower hip fracture prevalence in black South African women. The lower SBMD in pre- and postmenopausal black women in this study suggests that factors other than BMD should be considered to explain a lower vertebral fracture prevalence in blacks, if a lower fracture prevalence does indeed exist.

Background Despite changes in WHO guidelines, stavudine is still used extensively for treatment of pediatric HIV in the developing world. Lipoatrophy in sub-Saharan African children can be stigmatizing and have far-reaching consequences. The severity and extent of lipoatrophy in pre-pubertal children living in sub-Saharan Africa is unknown. Methods In this cross-sectional study, children who were 3-12 years old, on antiretroviral therapy and pre-pubertal were recruited from a Family HIV Clinic in South Africa. Lipoatrophy was identified and graded by consensus between two HIV pediatricians using a standardized grading scale. A professional dietician performed formal dietary assessment and anthropometric measurements of trunk and limb fat. Previous antiretroviral exposures were recorded. In a Dual-Energy X-ray Absorbtiometry (DXA) substudy body composition was determined in 42 participants. Results Among 100 recruits, the prevalence of visually obvious lipoatrophy was 36% (95% CI: 27%–45%). Anthropometry and DXA measurements corroborated the clinical diagnosis of lipoatrophy: Both confirmed significant, substantial extremity fat loss in children with visually obvious lipoatrophy, when adjusted for age and sex. Adjusted odds ratio for developing lipoatrophy was 1.9 (95% CI: 1.3 - 2.9) for each additional year of accumulated exposure to standard dose stavudine. Cumulative time on standard dose stavudine was significantly associated with reductions in biceps and triceps skin-fold thickness (p=0.008). Conclusions The prevalence of visually obvious lipoatrophy in pre-pubertal South African children on antiretroviral therapy is high. The amount of stavudine that children are exposed to needs review. Resources are needed to enable low-and-middle-income countries to provide suitable pediatric-formulated alternatives to stavudine-based pediatric regimens. The standard stavudine dose for children may need to be reduced. Diagnosis of lipoatrophy at an early stage is important to allow timeous antiretroviral switching to arrest progression and avoid stigmatization. Diagnosis using visual grading requires training and experience, and DXA and comprehensive anthropometry are not commonly available. A simple objective screening tool is needed to identify early lipoatrophy in resource-limited settings where specialized skills and equipment are not available.

Statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1, 5, 10, and 20 mg · kg −1 · d −1 ), atorvastatin (2.5 mg · kg −1 · d −1 ), and pravastatin (10 mg · kg −1 · d −1 ) administered orally for 12 weeks to intact female Sprague-Dawley rats and the effect of 20 mg · kg −1 · d −1 simvastatin in sham-operated and ovariectomized rats on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH) and compared them with controls. BMD was decreased by 1 mg · kg −1 · d −1 simvastatin ( P =0.042), atorvastatin ( P =0.0002), and pravastatin ( P =0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA, P =0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by 20 mg · kg −1 · d −1 simvastatin in 2 separate groups of intact rats and were reflected by a relatively unchanged BMD. At lower doses, 1 mg · kg −1 · d −1 simvastatin decreased bone formation while increasing bone resorption, as reflected by a marked decrease in BMD. Ovariectomized animals receiving 20 mg · kg −1 · d −1 simvastatin showed no change in BMD relative to the untreated, ovariectomized controls; their increase in bone formation was smaller than in sham-operated rats receiving simvastatin, and there was no change in bone resorption. Dose-response curves of simvastatin for bone formation and resorption differed. These studies indicate that (1) statins decrease BMD in rodents, (2) high-dose simvastatin increases bone formation and resorption, (3) low-dose simvastatin decreases bone formation and increases bone resorption, (4) the effects of simvastatin on QBH differ at different dosages, (5) the effects of simvastatin seen in intact rats are not observed in ovariectomized rats, and (6) simvastatin is unable to prevent bone loss caused by ovariectomy.

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. 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. 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. Osteoporosis caused by portasystemic shunting may be partially ameliorated by rapamycin in the rat model of hepatic osteodystrophy