Search

The association between hyperemesis gravidarum (HG) and abnormal thyroid function is well known. The prevalence, aetiology and course of thyrotoxicosis in women with hyperemesis gravidarum (HG) were studied. Women admitted for HG, who underwent thyroid function evaluation between 1 August 2016 and 30 April 2019, were studied. Laboratory data included baseline human chorionic gonadotropin (hCG) and baseline (t1), discharge (t2) and follow-up (t3) thyroid function tests (thyroid stimulating hormone [TSH] and free thyroxin [fT4]). Available TSH receptor antibody status was assessed. Eighty-two patients were included. The incidence of thyrotoxicosis was 49% based on local laboratory TSH range and 48% if trimester-specific ranges used. In the majority of normal pregnancies, thyrotoxicosis was hCG-mediated (72.5%), 15% were confirmed to have Graves' disease and 12% had a molar pregnancy. Very high fT4 levels (> 40 pmol/l) at baseline [t1] were documented in 24% of women with hCG-mediated thyrotoxicosis. Clinical features were absent in a third of women with Graves' disease and the diagnosis was reliant on positive antibody status. Free T4 values declined from (t1) to later in gestation (t3) (p < 0.001). The incidence of thyrotoxicosis in women with HG is high. Free-T4 values decrease with clinical stabilisation of HG, suggesting a contribution of dehydration to the large variation in baseline fT4 measurements. Testing for TSH-receptor antibodies should be considered in women with TSH < 0.01 pmol/l and persistent fT4 elevation on follow-up. Final review of thyroid function should be performed after 15 weeks' gestation. [ABSTRACT FROM AUTHOR]

The autoregressive–ARCH (AR–ARCH) and autoregressive–GARCH (AR–GARCH) models, which allow for conditional heteroskedasticity and autoregression, reduce to random walk or white noise for some values of the parameters. We consider generalized versions of the AR–ARCH(1) and AR–GARCH(1,1) models, and, under mild assumptions, calculate the asymptotic distributions of pseudo–likelihood ratio statistics for testing hypotheses that reflect these reductions. These hypotheses are of two kinds: the conditional volatility parameters may take their boundary values of zero, or the autoregressive component may take the form of a unit root process or not in fact be present. The limiting distributions of the resulting test statistics can be expressed in terms of functionals of Brownian motion related to the Dickey–Fuller statistic, together with independent chi–square components. The finite sample performances of the test statistics are assessed by simulations, and percentiles are tabulated. The results have applications in the analysis of financial time series and random coefficient models. [ABSTRACT FROM AUTHOR]

Skeletal stem cells (SSCs) reside in various niche locations within long bones to maintain bone homeostasis and facilitate fracture repair. Bone fragility, associated with ageing, increases the susceptibility of the femoral head to fractures due to an increase in bone adipocytes and concomitant loss of structural integrity. However, the specific contribution of epiphyseal SSCs to fragility is unknown. To explore this, a comparative analysis was performed on the transcriptional profiles and lineage commitment of Wistar rat femoral SSCs derived from the bone marrow (BM-), diaphyseal cortical bone (CB-) and proximal epiphyseal trabecular bone (PF-SSCs) isolated from the same long bones. SSCs were characterized based on morphology, immunophenotype (CD90/CD45), growth rate (population doubling time), gene expression profiles and differentiation capacity (Oil Red O, Alizarin Red S). qRT-PCR micro-arrays were performed on SSCs to evaluate the expression of stemness, SSC and lineage-specific markers in both undifferentiated and differentiated states. Our findings support the hypothesis that SSCs from different bone regions exhibit distinct transcriptional profiles, reflecting their specific niche environments. CB-SSCs displayed superior osteogenic potential as evidenced by the expression of key osteogenic genes and higher levels of mineralization. In contrast, PF-SSCs had a reduced osteogenic capacity with a higher adipogenic potential. Overall, the study revealed the importance of niche-specific stem cell properties for use in regenerative medicine applications and provides insight into the potential role of PF-SSCs in bone fragility and fracture risk., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Chronic wounds are a severe complication of diabetes. Dysregulated inflammatory signalling is thought to underly the poor healing outcomes. Yet, there is little information available on the acute response following injury and its impact on healing., Methods: Using a murine full thickness excisional wound model, the current study therefore assessed the expression of pro-inflammatory and pro-resolving lipid mediators during the early stages post injury in acute and diabetic wounds and compared the timeframe for transitioning through the phases of healing. Tissue eicosanoid (LTB4, PGE2, TxA2, MaR1, RvE1, RvD1, PD) and MMP-9 levels were assessed at 6 h post wounding using ELISAs. Wound closure, healing dynamics (histology), cellular infiltration and MPO, TNF-α expression (IHC) were assessed at 6 h, day2, day7 post wounding., Results: Eicosanoid expression did not differ between groups (LTB4 24-125 pg/mL, PGE2 63-177 pg/mL, TxA2 529-1184 pg/mL, MaR1 365-2052 pg/mL, RvE1 43-1157 pg/mL, RvD1 1.5-69 pg/mL, PD1 11.5-4.9 ng/mL). An inverse relationship (p < 0.05) between MMP-9 and eicosanoids were however only evident in acute and not in diabetic wounds. Diminished cellular infiltration (x5 fold) (p < 0.05) in diabetic wounds coincided with a significant delay in the expression of TNF-α (pro-inflammatory cytokine) and MPO (neutrophil marker). A significant difference in the expression of TNF-α (C 1.8 ± 0.6; DM 0.7 ± 0.1 MFI) and MPO (C 4.9 ± 1.9; DM 0.9 ± 0.4 MFI) (p < 0.05) was observed as early as 6 h post wounding, with histology parameters supporting the notion that the onset of the acute inflammatory response is delayed in diabetic wounds., Conclusion: These observations imply that the immune cells are unresponsive to the initial eicosanoid expression in the diabetic wound tissue., (© 2025 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Adipose tissue stromal cells (ADSCs) are prone to functional decline and senescence during metabolic disturbances. In diabetes mellitus (DM), the pathogenic microenvironment induces oxidative stress causing ADSCs to senesce. The senescence associated secretory phenotype (SASP) in turn drives disease progression. The pathogenesis of DM is thus both a cause and consequence of senescence. Therapeutically preventing the onset of senescence in ADSCs may play a significant role in preventing disease progression and directly impact the onset of comorbidities. The purpose of this study was to establish an in vitro model that mimic the DM micro-environment to use as a screening tool to assess the therapeutic efficacy of preventative and restorative agents. Exposing ADSCs (cip1 , p16 INK4A ), apoptosis (p53), inflammation (TNFα, IL6, PTX3, IL10) and adipogenesis (PPARγ, UCP3) was assessed, with AAP pretreatment significantly reducing PTX3 expression. Although this study only investigated the early stages following senescence induction (3 days), subsequent studies could employ this model for longer duration and gain insight into premature senescence and the functional decline of ADSCs within the diabetic context, whilst limiting the use of animals., Competing Interests: Declaration of competing interest No conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Diabetic ketoacidosis (DKA) during pregnancy poses significant risks to both the mother and fetus, with an increased risk of fetal demise. Although more prevalent in women with Type I diabetes (T1D); those with Type 2 diabetes (T2D) and gestational diabetes mellitus (GDM) can also develop DKA. A lack of information about DKA during pregnancy exists worldwide, including in South Africa., Objective: This study examined the characteristics and outcomes associated with DKA during pregnancy., Methods: The study took place between 1 April 2020 and 1 October 2022. Pregnant women with DKA, admitted to Tygerberg Hospital's Obstetric Critical Care Unit (OCCU) were included. Maternal characteristics, precipitants of DKA, adverse events during treatment, and maternal-fetal outcomes were examined., Results: There were 54 episodes of DKA among 47 women. Most DKA's were mild and occurred in the third trimester. Pregestational diabetes dominated (31/47; 60%), with 47% having T1D and 94% requiring insulin. Seven women (7/47, 15%; T2D:6, T1D:1) had two episodes of DKA during the same pregnancy. Most women (32/47; 68%) were either overweight or obese. Yet, despite the T2D phenotype, biomarkers indicated that auto-immune diabetes was prevalent among women without any prior history of T1D (6/21; 29%). Twelve women (26%) developed gestational hypertension during pregnancy, and 17 (36%) pre-eclampsia. Precipitating causes of DKA included infection (14/54; 26%), insulin disruption (14/54; 26%) and betamethasone administration (10/54; 19%). More than half of the episodes of DKA involved hypokalemia (35/54, 65%) that was associated with fetal death (P=0.042) and hypoglycemia (28/54, 52%). Preterm birth (<37 weeks' gestation) occurred in 85% of women. No maternal deaths were recorded. A high fetal mortality rate (13/47; 28%) that included 11 spontaneous intrauterine deaths and two medical terminations, was observed., Conclusion: Women with DKA have a high risk of fetal mortality as well as undiagnosed auto-immune diabetes. There is a strong link between maternal hypokalemia and fetal loss, suggesting an opportunity to address management gaps in pregnant women with DKA., 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 © 2023 Coetzee, Hall, Langenegger, van de Vyver and Conradie.)

Background: South African women of childbearing age are disproportionally affected by obesity and at significant risk of Type 2 Diabetes Mellitus (T2DM). Unless pregnant, they do not readily undergo screening for T2DM. With a local focus on improved antenatal care, hyperglycemia is often first detected in pregnancy (HFDP). This may erroneously be attributed to Gestational Diabetes Mellitus (GDM) in all without considering T2DM. Glucose evaluation following pregnancy is essential for early detection and management of women with T2DM in whom persistent hyperglycemia is to be expected. Conventional testing with an oral glucose tolerance test (OGTT) is cumbersome, prompting investigation for alternate solutions., Aim: To compare the diagnostic performance of HbA1c to the current gold standard OGTT in women with HFDP 4-12 weeks post-delivery., Methods: Glucose homeostasis was assessed with OGTT and HbA1c in 167 women with HFDP, 4-12 weeks after delivery. Glucose status was based on American Diabetes Association criteria., Results: Glucose homeostasis was assessed at 10 weeks (IQR 7-12) after delivery. Of the 167 participants, 52 (31%) had hyperglycemia, which was comprised of 34 (20%) prediabetes and 18 (11%) T2DM. Twelve women in the prediabetes subgroup had diagnostic fasting plasma glucose (FPG) and 2-hour plasma glucose (2hPG), but in two-thirds of the patients (22/34) only one time point proved diagnostic. The FPGs and the 2hPGs of six women with HbA1c-based T2DM were both within the prediabetes diagnostic range. According to the HbA1c measurements, 85% of 52 participants with gold standard OGTT defined hyperglycemia (prediabetes and T2DM) as well as 15 of 18 women with postpartum persistent T2DM were correctly classified. According to FPG, 15 women with persistent hyperglycemia would have been missed (11 with prediabetes and four with T2DM; 29%). When compared to an OGTT, a single HbA1c of 6.5% (48mmol/mol) postpartum demonstrated a sensitivity of 83% and specificity of 97% for the identification of T2DM., Conclusion: HbA1c may improve access to postpartum testing in overburdened clinical settings where the required standards of OGTT cannot be guaranteed. HbA1c is a valuable test to detect women who will benefit most from early intervention but cannot unequivocally replace OGTT., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Coetzee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Globally, there is a rising trend in obesity, known to increase morbidity and mortality. Metabolic surgery and adequate weight loss decrease mortality but may worsen pre-existing nutrient deficiencies. Most data on pre-existing nutritional deficiencies in the population undergoing metabolic surgery is from the developed world, where an extensive micronutrient assessment is achievable. In resource-constrained environments, the cost of a comprehensive micronutrient assessment must be weighed against the prevalence of nutritional deficiencies and the potential harm if one or more nutritional deficiencies are missed., Methods: This cross-sectional study investigated the prevalence of micronutrient and vitamin deficiencies in participants scheduled to undergo metabolic surgery in Cape Town, South Africa, a low-middle income country. 157 participants were selected and 154 reported on; who underwent a baseline evaluation from 12 July 2017 to 19 July 2020. Laboratory measurements were conducted, including vitamin B12 (Vit B12), 25-hydroxy vitamin D (25(OH)D), folate, parathyroid hormone (PTH), thyroid-stimulating hormone (TSH), thyroxine (T4), ferritin, glycated haemoglobin (HbA1c), magnesium, phosphate, albumin, iron, and calcium., Results: Participants were predominantly female, aged 45 years (37-51), with a preoperative BMI of 50.4 kg/m 2 (44.6-56.5). A total of 64 individuals had Type 2 diabetes mellitus (T2D), with 28 undiagnosed cases at study entry (18% of study population). 25(OH)D deficiency was most prevalent (57%), followed by iron deficiency (44%), and folate deficiency (18%). Other deficiencies (vitamin B12, calcium, magnesium, phosphate) were rarely encountered and affected ≤1% of participants. Folate and 25(OH)D deficiency were related to obesity classification, with a higher prevalence in participants with a BMI ≥40 kg/m 2 (p <0.01)., Conclusion: A higher prevalence of some micronutrient deficiencies was noted compared with data from similar populations in the developed world. The minimum baseline/preoperative nutrient evaluation in such populations should include 25(OH)D, iron studies, and folate. Additionally, screening for T2D is recommended. Future efforts should seek to collate broader patient data on a national scale and include longitudinal surveillance after surgery. This may provide a more holistic picture of the relationship between obesity, metabolic surgery and micronutrient status inform more appropriate evidence-based care., 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 © 2023 Sadhai, Coetzee, Conradie-Smit, Greyling, van Gruting, du Toit, Lubbe, van de Vyver and Conradie.)

Objective: To describe the pregnancy outcomes and complications observed in a series of cases of transabdominal cerclage (TAC), which is reserved for highly selected women with recurrent mid-trimester pregnancy loss, due to cervical insufficiency., Methods: A retrospective audit covering 25 years (January 1, 1997 to December 31, 2021) was performed at the Obstetric Special Care division, Tygerberg Academic Hospital in Cape Town, South Africa. All 118 pregnancies from 94 procedures, operated and managed by the principal author were included for descriptive analysis., Results: Eighty-four (91.3%) of the 92 first pregnancies after first insertion had successful outcomes. All second and third pregnancies (24/24; 100%) were successful. Eight pregnancies did not achieve viability, two women (2/8) did however achieve a successful pregnancy after a subsequent repeat TAC procedure. For the viable pregnancies (110/118), the median gestational age at delivery was 37 weeks (range 28-39 weeks). The median intraoperative blood loss during cerclage insertion was 100 ml (range 25-750 ml)., Conclusion: In experienced hands, TAC during pregnancy is a safe and effective operation, when other less invasive procedures have failed., (© 2022 The Authors. International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Inflammation is part of the body's innate immune response and is an essential process that not only defends against harmful bacteria and pathogens but also plays a key role in the maintenance and repair of tissues. Under pathological conditions, there is bilateral crosstalk between immune regulation and aberrant metabolism resulting in persistent inflammation in the absence of infection. This phenomenon is referred to as sterile metabolic inflammation (metainflammation) and occurs if the initiating stimulus is not removed or if the resolution process is disrupted. Disruption of this tightly regulated immune response and its failure to resolve as is evident in metabolic disorders is not only associated with disease progression but also leads to immune senescence and should not be neglected in the clinical management of patients. This review gives an overview of the mechanisms underlying chronic metabolic inflammation, the aberrant metabolic activation of innate immune cells (neutrophils, macrophages, mast cells, dendritic cells), and its role in disease progression using obesity-diabetes as a prime example. Addressing the underlying subclinical metabolic inflammation in addition to achieving glucose control may contribute significantly towards therapeutic interventions aimed at preventing the onset of co-morbidities in diabetic patients.

Purpose: To investigate factors affecting the co-creation and implementation of care pathways for patients treated with oral anticancer drugs., Methods: An explorative qualitative process evaluation was performed at four Belgian hospitals, co-creating and implementing a care pathway for patients on oral anticancer drugs. Semistructured interviews and focus groups were performed by a) local coordinators leading an interprofessional project team during the co-creation and implementation stage, b) external implementation coaches, and c) teams of healthcare professionals with a role in the care pathway. In total, 47 stakeholders were interviewed. Interviews were audio-taped, transcribed verbatim, and analyzed thematically., Results: We found four factors affecting co-creation and implementation of care pathways for patients on oral anticancer drugs. Developing an adequate supporting context using motivated interprofessional project teams of clinical and management staff led by competent coordinators is one important facilitator. Leadership of local coordinators and oncologists is crucial for progressing the co-creation. Other factors included the complexity of the oral anticancer drug intervention, the interprofessional character of the care pathway, and involving primary care. External coaching during co-creation proved an important facilitator., Conclusions: Prior investigation of willingness and motivation to change in clinical and management staff, competent coordinators, and leadership of oncologists are needed. In addition, external support determines the success of co-creating and implementing care pathways for patients on oral anticancer drugs., Competing Interests: Declaration of competing interest During this research project and during the preparation of this manuscript, there was no conflict of interest to declare for none of the authors., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Monitoring wound progression over time is a critical aspect for studies focused on in-depth molecular analysis or on evaluating the efficacy of potential novel therapies. Histopathological analysis of wound biopsies can provide significant insight into healing dynamics, yet there is no standardized and reproducible scoring system currently available. The purpose of this study was to develop and statistically validate a scoring system based on parameters in each phase of healing that can be easily and accurately assessed using either Hematoxylin & Eosin (H&E) or Masson's Trichrome (MT) staining. These parameters included re-epithelization, epithelial thickness index, keratinization, granulation tissue thickness, remodeling, and the scar elevation index. The initial phase of the study was to (1) optimize and clarify healing parameters to limit investigator bias and variability; (2) compare the consistency of parameters assessed using H&E versus MT staining. During the validation phase of this study, the accuracy and reproducibility of this scoring system was independently iterated upon and validated in four different types of murine skin wound models (Excisional; punch biopsy; pressure ulcers; burn wounds). A total of n  = 54 histology sections were randomized, blinded, and assigned to two groups of independent investigators ( n  = 5 per group) for analysis. The sensitivity of each parameter (ranging between 80% and 95%) is reported with illustrations on the appropriate assessment method using ImageJ software. In the validated scoring system, the lowest score (score:0) is associated with an open/unhealed wound as is evident immediately and within the first day postinjury, whereas the highest score (score:12) is associated with a completely closed and healed wound without excessive scarring. This study defines and describes the minimum recommended criteria for assessing wound healing dynamics using the SPOT skin wound score. The acronym SPOT refers to the academic and scientific institutions that were involved in the development of the scoring system, namely, Stellenbosch University, Polish Academy of Sciences, Obatala Sciences, and the University of Texas Southwestern.

Adipocytes in the breast tumour microenvironment promotes acquired treatment resistance. We used an in vitro adipocyte-conditioned media approach to investigate the direct paracrine effects of adipocyte secretory factors on MDA-MB-231 breast cancer cells treated with doxorubicin to clarify the underlying treatment resistance mechanisms. Cell-viability assays, and Western blots were performed to determine alterations in apoptotic, proliferation and lipid metabolism protein markers. Free fatty acids (FFA) and inflammatory markers in the collected treatment-conditioned media were also quantified. Adipocyte secretory factors increased the cell-viability of doxorubicin-treated cells (p < 0.0001), which did not correspond to apoptosis or proliferation pathways. Adipocyte secretory factors increased the protein expression of hormone-sensitive lipase (p < 0.05) in doxorubicin-treated cells. Adipocyte secretory factors increased the utilization of leptin (p < 0.05) and MCP-1 (p < 0.01) proteins and possibly inhibited release of linoleic acid by doxorubicin-treated cells (treatment-conditioned media FFA profiles). Adipocyte secretory factors induced doxorubicin treatment resistance, by increasing the utilization of inflammatory mediators and inhibiting the release of FFA by doxorubicin-treated cells. This further promotes inflammation and lipid metabolic reprogramming (lipid storage) in the tumour microenvironment, which breast cancer cells use to evade the toxic effects induced by doxorubicin and confers to acquired treatment resistance.

Diabetes is a complex multifactorial disorder associated with hyperglycemia, oxidative stress, and inflammation. The pathological microenvironment impairs mesenchymal stem cell (MSC) viability and dysregulates their proregenerative and immune-modulatory function causing maladaptive tissue damage. Targeting stem cells to protect them against impairment could thus delay the onset of complications and enhance the quality of life in diabetes mellitus patients. The aim of this study was to investigate the efficacy of N-acetylcysteine (NAC) and ascorbic-acid-2-phosphate (AAP) oral supplementation as preventative measure against MSC impairment. Healthy wild-type control (C57BL/6J) (male, n  = 24) and obese diabetic (B6.C-Lep ob /J) (ob/ob) (male, n  = 24) mice received either placebo or antioxidant (NAC/AAP) supplementation for a period of 6 weeks. Metabolic parameters (weight and blood glucose) and the oxidative status (serum total serum antioxidant capacity, malondialdehyde) of animals were assessed. At the end of the 6-week supplementation period, bone marrow MSCs were isolated and their functionality (growth rate, viability, adipogenesis, and osteogenesis) assessed ex vivo. Real time quantitative polymerase chain reaction microarray analysis was also performed to assess the expression of 84 genes related to oxidative stress in MSCs. Despite no change in the metabolic profile, NAC/AAP supplementation improved the antioxidant status of diabetic animals and reduced lipid peroxidation, which is indicative of cellular damage. NAC/AAP also improved the population doubling time of MSCs (first 6-days postisolation) and significantly downregulated the expression of two genes ( Nox1 and Rag2 ) associated with oxidative stress compared to placebo treatment. Taken together, this study has shown reduced oxidative stress and improvements in MSC function following in vivo antioxidant supplementation in healthy control and type 2 diabetic mice.

Chronic wounds are a serious and debilitating complication of diabetes. A better understanding of the dysregulated healing responses following injury will provide insight into the optimal time frame for therapeutic intervention. In this study, a direct comparison was done between the healing dynamics and the proteome of acute and obese diabetic wounds on days 2 and 7 following injury. Full thickness excisional wounds were induced on obese diabetic (B6.Cg-lepob/J, ob/ob, n = 14) (blood glucose 423.25 ± 127.92 mg/dL) and WT control (C57BL/6J, n = 14) (blood glucose 186.67 ± 24.5 mg/dL) mice. Histological analysis showed no signs of healing in obese DM wounds whereas complete wound closure/re-epithelisation, the formation of granulation tissue and signs of re-vascularisation, was evident in acute wounds on day 7. In obese DM wounds, substance P deficiency and increased MMP-9 activity on day 2 coincided with increased cytokine/chemokine levels within wound fluid. LC-MS/MS identified 906 proteins, of which 23 (Actn3, Itga6, Epb41, Sncg, Nefm, Rsp18, Rsp19, Rpl22, Macroh2a1, Rpn1, Ppib, Snrnp70, Ddx5, Eif3g, Tpt1, FABP5, Cavin1, Stfa1, Stfa3, Cycs, Tkt, Mb, Chmp2a) were differentially expressed in wounded tissue on day 2 (P < 0.05; more than two-fold) and 6 (Cfd, Ptms, Hp, Hmga1, Cbx3, Syap1) (P < 0.05; more than two-fold) on day 7. A large number of dysregulated proteins on day 2 was associated with an inability to progress into the proliferative stage of healing and suggest that early intervention might be pivotal for effective healing outcomes. The proteomic approach highlighted the complexity of obese DM wounds in which the dysregulation involves multiple regulatory pathways and biological processes.

Aims: Pregnant women with diabetes often require preterm delivery. Antenatal betamethasone reduces perinatal morbidity and mortality, but induces hyperglycemia. The primary objective was to observe glucose excursions and determine the preliminary safety of a protocol for subcutaneous insulin following betamethasone administration in an antenatal ward., Material and Methods: This retrospective study included all women with diabetes who received betamethasone due to anticipated preterm delivery. Glucose excursions were evaluated in the fasting state and 2-h postprandial. Blood glucose values ≥14mmol/L or ≤3.5mmol/L were regarded as unacceptable hyper- and hypoglycemia respectively. Events over the first 96 h were documented., Results: This study spanned 52 months and included fifty-nine women. Eleven episodes of defined hypoglycemia occurred in six women, all receiving insulin therapy, but none after a corrective dose of insulin. No serious hypoglycemic incident was reported. Seventeen women experienced hyperglycemic incidents almost entirely (47/56) within 48 h of betamethasone administration, most often postprandially (34/56) and in 85% of episodes, preceded by pre-prandial values >9 mmol/L (29/34). 14 (82.4%) of these women were receiving background insulin therapy. No case with gestational diabetes encountered defined hyperglycemia., Conclusions: This small study demonstrated preliminary safety of the protocol. Enhanced surveillance is necessary for 72 h after initiation of betamethasone., 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 Paulsen, Hall, Mason, van de Vyver, Coetzee and Conradie.)

Mesenchymal stem cell (MSC) dysfunction is a serious complication in ageing and age-related inflammatory diseases such as type 2 diabetes mellitus. Inflammation and oxidative stress-induced cellular senescence alter the immunomodulatory ability of MSCs and hamper their pro-regenerative function, which in turn leads to an increase in disease severity, maladaptive tissue damage and the development of comorbidities. Targeting stem/progenitor cells to restore their function and/or protect them against impairment could thus improve healing outcomes and significantly enhance the quality of life for diabetic patients. This review discusses the dysregulation of MSCs' immunomodulatory capacity in the context of diabetes mellitus and focuses on intervention strategies aimed at MSC rejuvenation. Research pertaining to the potential therapeutic use of either pharmacological agents (NFкB antagonists), natural products (phytomedicine) or biological agents (exosomes, probiotics) to improve MSC function is discussed and an overview of the most pertinent methodological considerations given. Based on in vitro studies, numerous anti-inflammatory agents, antioxidants and biological agents show tremendous potential to revitalise MSCs. An integrated systems approach and a thorough understanding of complete disease pathology are however required to identify feasible candidates for in vivo targeting of MSCs.

Background: Women with hyperglycaemia first detected in pregnancy (HFDP), including those with gestational diabetes mellitus (GDM), should undergo a glucose evaluation 4-12 weeks after delivery. Globally, suboptimal postpartum return rates limit the opportunity to intervene in women with sustained hyperglycaemia and pragmatic solutions should be sought to bridge this gap., Objective: To assess the utility of postpartum in-hospital glucose evaluation to predict the outcome of the oral glucose tolerance test (OGTT) performed 4-12 weeks after delivery., Methods: The study was performed prospectively at Tygerberg Hospital, Cape Town, South Africa. Women with HFDP, classified as GDM based on the modified National Institute for Health and Care Excellence criteria, who delivered between November 2018 and June 2019 were included in the study. Fasting plasma glucose (FPG) was performed 24-72 hours after delivery (t1) in the postnatal ward, provided glucose lowering medication was discontinued at delivery. An OGTT 4-12 weeks postpartum (t2) was scheduled for the total cohort. We compared glucose values and glucose categories at t1 and t2 and evaluated antenatal characteristics of women who returned, compared to the group that was lost to follow-up., Results: In-hospital post-delivery glucose assessment (t1) was performed in 115 women. Glucose levels were significantly lower at t1 compared to antenatal diagnostic values (t0) and assessment at t2. Of the fourteen women with hyperglycaemia at t2, none had abnormal fasting glucose concentrations at t1. Women with HFDP who fulfilled criteria for overt diabetes at t0, all (24/115) had normal fasting glucose levels at t1 except for IFG in one (1/24). The antenatal characteristics of women with HFDP who returned at t2, were similar to the women who did not return., Conclusion: Based on this study, in-hospital fasting glucose 24-72 hours postpartum cannot replace the OGTT 4-12 weeks postpartum. Pragmatic solutions for low postpartum return rates in women with HFDP should be pursued., Competing Interests: The authors have declared that no competing interests exist.

The advancement of autologous mesenchymal stem cell (MSC) therapy for the treatment of non-healing diabetic wounds is hampered by endogenous MSC dysfunction and limited viability of cells post-transplantation into the pathological wound environment. The development of effective strategies to restore the functional capabilities of these impaired MSCs prior to transplantation may be a key to their ultimate success as wound repair mediators. The current study therefore investigated whether antioxidant preconditioning [7.5 mM N-acetylcysteine (NAC) + 0.6 mM ascorbic 2-phosphate (AAP)] could restore the growth rate, migration ability and viability of impaired MSCs and whether this restored state is maintained in the presence of diabetic wound fluid (DWF). Healthy control (source: wild type, C57BL/6J mice) (n = 12) and impaired/diabetic MSCs (source: obese prediabetic, B6.Cg-Lepob/J mice) (n = 12) were isolated from the bone marrow of mice. Treatment groups post-isolation were as follow: (a) No treatment (baseline phenotype): MSCs expanded in standard growth media (SGM) (±8 days) and only exposed to growth media. (b) DWF (baseline response): MSCs expanded in SGM (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). (c) Antioxidant preconditioning (preconditioned phenotype): MSCs expanded in the presence of NAC/AAP (±8 days). (d) Antioxidant preconditioning + DWF (preconditioned response): MSCs expanded in the presence of NAC/AAP (±8 days) followed by exposure to DWF (24 hours, 48 hours, 96 hours). The results demonstrated that expansion of MSCs (both healthy control and impaired diabetic) in the presence of combined NAC/AAP treatment improved ex vivo MSC viability and protected MSCs in the presence of DWF. Despite improved viability, AAP/NAC could however not rescue the reduced proliferation and migration capacity of impaired diabetic MSCs. The protective effect of NAC/AAP preconditioning against the toxicity of DWF could however be a potential strategy to improve cell number post-transplantation., (© 2020 by the Wound Healing Society.)

Disease-associated impairment/dysfunction of stem cell populations is prominent in chronic metabolic and inflammatory diseases, such as type 2 diabetes mellitus (DM) where the multifunctional properties (viability, proliferation, paracrine secretion, multilineage differentiation) of bone marrow resident mesenchymal stem cells (MSCs) can be affected. The growth and viability impairments make it difficult to study the underlying molecular mechanisms related to the dysfunction of these cells in vitro. We have consequently optimized the isolation and culture conditions for impaired/dysfunctional bone marrow MSCs from B6.Cg-Lep ob /J obese prediabetic mice. The method described here permits ex vivo investigations into disease-associated functional impairments and the dysregulated molecular mechanisms in these primary MSCs through direct comparisons with their healthy wild-type C57BL6/J control mouse counterparts.

Aim: 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)., Methods: 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., Results: 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., Conclusion: POCT accurately identifies women with Type 2 diabetes 6-12 weeks after GDM., (© 2019 Diabetes UK.)

Purified mesenchymal stem cells (MSCs) may be used for a multitude of applications, from the study of biological processes such as cell division and coordinated gene expression to tissue engineering and regenerative medicine. However, although highly similar, MSCs isolated and purified from different tissues may be biologically different in the ability of the cells to respond to environmental cues that instigate and propagate changes in cell fate such as differentiation, proliferation, apoptosis, and senescence. Selecting which MSC subtype to study may therefore profoundly influence the outcome of the investigation. Here we outline the isolation, purification, and differentiation of three different MSC subtypes derived from various depots within rat bone. These include MSCs from bone marrow, compact bone, and the proximal femur. Osteoblastic and adipogenic differentiation exemplify differences between these cells.

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/m 2 ), (b) healthy overweight/obese (OB; BMI ≥ 25 kg/m 2 ), (c) obese metabolic syndrome (MetS; BMI ≥ 30 kg/m 2 ), 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.

Mesenchymal stem cells (MSCs) are a promising therapeutic tool for the treatment of nonhealing diabetic wounds. The pathological nature of the niche microenvironment limits the use of autologous cell therapy in diabetic patients. Prolonged exposure of endogenous MSCs to a pathological microenvironment in vivo reduces their ability to respond to environmental cues. This study investigated the effectiveness of ex vivo antioxidant treatment [ N -acetylcysteine (7.5 mM NAC) and Ascorbic acid 2-phosphate (0.6 mM AAP)] to restore the paracrine function of diabetic MSCs. Healthy control [bone marrow stem cells derived from wild-type mice (SC WT )] (source: wild-type C57BL/6J mice) ( n  = 12) and impaired/dysfunctional [bone marrow stem cells derived from ob/ob mice (SC ob )] (source: obese diabetic, B6.Cg-Lep ob /J mice) ( n  = 12) MSCs were isolated. Ex vivo treatment groups (SC WT vs. SC ob ) were as follows: (1) no treatment (baseline phenotype), (2) stimulated with diabetic wound fluid (DWF) (baseline response), (3) antioxidant preconditioning (preconditioned phenotype), and (4) antioxidant preconditioned with subsequent stimulation with DWF (preconditioned response). The paracrine responsiveness on both the molecular (mRNA expression of 80 cytokines and receptors, quantitative polymerase chain reaction microarray) and protein (23-plex bead-array Luminex assay) level was assessed. At baseline, 31 genes were overexpressed (> × 2-fold) and 39 genes were underexpressed (> × 2-fold) in SC ob versus SC WT . In conditioned media, significant differences ( P  < 0.05) were detected at baseline for two proinflammatory cytokines [tumor necrosis factor alpha (TNFα) and interferon gamma (IFNγ)], four chemokines [keratinocyte chemoattractant (KC), granulocyte colony-stimulating factor (GCSF), Eotaxin, and macrophage chemoattractant protein (MCP1)], and one anti-inflammatory cytokine [interleukin 10 (IL10)]. Following stimulation with DWF, significant differences ( P  < 0.05) were detected in the secretion of two chemokines [granulocyte macrophage colony-stimulating factor (GMCSF) and Eotaxin], three proinflammatory cytokines (TNFα, IFNγ, and IL9), and four anti-inflammatory cytokines (IL10, IL4, IL13, and IL3). Antioxidant preconditioning significantly dampened the excessive TNFα response observed in SC ob and improved the secretion of IL10. Taken together these data suggest that the combined ex vivo treatment of autologous stem cells with NAC and AAP could potentially be an effective strategy to restore the paracrine function of impaired diabetic MSCs before transplantation.

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 < 25 kg/m2), b) overweight/obese (OW/OB) (BMI ≥ 25 kg/m2, < 3 metabolic risk factors) (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.

Mesenchymal stem cells derived from bone marrow (BM-MSCs) have multifunctional properties that have made them a promising therapeutic agent for many regenerative, anti-inflammatory, and autoimmune applications. Under chronic pathological conditions, however, BM-MSCs can become functionally compromised due to long-term exposure to changes in the systemic and localized stem cell niche microenvironments. In addition to the fact that functionally compromised BM-MSCs may be therapeutically ineffective, impairment of BM-MSCs is potentially a contributing factor to disease progression and development of comorbidities. For the purpose of this review, MSC-based therapies for treatment of nonhealing wounds in diabetic patients will be used as an example to demonstrate the effect that the diabetic host environment has on the regenerative capacity of endogenous BM-MSCs. This review will also discuss the mechanism by which the pathogenesis of diabetes mellitus leads to intrinsic dysfunction of the bone marrow stem cell niche that ultimately results in MSC failure and will highlight potential strategies for counteracting the functional decline of BM-MSCs.