Investigating the role of a FAM111B mutation in hereditary fibrosing poikiloderma (POIKTMP) using induced pluripotent stem cell (iPSC) model

Hereditary fibrosing poikiloderma is an autosomal dominant disorder that is characterised by mottled pigmentation and telangiectasia, accompanied by tendon contractures, myopathy and pulmonary fibrosis (POIKTMP). Mutations in POIKTMP cases have been shown to harbour the Family with sequence similarity 111B (FAM111B) gene. However, its function is unknown. The aim of this study was to investigate the causative role of the FAM111B mutation (c.1861T>G) in the multi-systemic fibrosis affecting the South African kindred with POIKTMP. Dermal fibroblasts from two affected siblings and a familial control were reprogrammed into induced pluripotent stem cells (iPSCs) via the Sendai virus vector (SeVdp) packaged with pluripotency transgenes (OCT4; SOX2; KLF4; C-MYC). The derived iPSCs successfully showed a) endogenous expression of pluripotency markers (OCT4; NANOG; TRA-1-60), b) in vitro differentiation into the three germ layers (endoderm; mesoderm; ectoderm) and c) normal karyotyping. Next, the iPSCs from two patients, a Familial control and a Non-familial control were differentiated into mesenchymal stem/stromal cells (iPSC-MSCs) as a cell model in this study. Characterisation of derived iPSC-MSCs indicated positive expression of MSC markers (CD73; CD90; α-SMA). Differentiation of iPSC-MSCs demonstrated adequate osteogenicity but limited adipogenicity. Patient-derived iPSC-MSCs were thereafter analysed by qPCR and collagen staining to determine whether the FAM111B mutation alters endogenous expression of pro-fibrotic markers as well as collagen synthesis in patient cells compared to controls. Messenger RNA expression of pro-fibrotic markers (COL1A1; COL3A1; α-SMA) was similar between patient and control iPSC-MSCs. Collagen staining and quantification also showed no statistical differences between patient and control cells. These results suggest that FAM111B does not directly alter the expression of these profibrotic genes in this in vitro model system. Growth curves were then carried out to investigate if the FAM111B mutation modulates cell proliferation and it was found that patient cells proliferated at a higher rate compared to controls. To explore the mechanisms underlying the rate change, analyses of FAM111B expression during cell cycle progressions were conducted. Extensive optimization experiments using the double thymidine block approach were necessary to establish the appropriate synchronization protocol, keeping in mind the extended doubling time of iPSCMSCs. The results revealed that FAM111B mRNA expression was temporally regulated, with a peak at the S-phase and low at the G2/M phase. While there were no pattern differences between patient and control cells, FAM111B mRNA expression was significantly higher in the patient cells compared to controls at the G1- and S-phase. These results suggest that the mutation in FAM111B might affect the stability or perdurance of the mRNA. Unfortunately, analysis of the FAM111B protein data was inconclusive. Problems related to synchronization of the cells and the specificity of the antibody would have to be rectified in order to follow this further. The overall findings in this in vitro study reveal that the FAM111B mutation does not alter expression of pro-fibrotic markers but does affect the cell proliferation rate of patient cells compared to controls. Future work will focus on further optimisation of iPSC-MSCs synchronisation to determine correlation of FAM111B mRNA and protein expression during cell cycle progression in the patient cells. Furthermore, 3D in vitro cellular models that recapitulate some parts of the POIKTMP phenotype will need to be created. Future work will also explore the gain-of-function hypothesis to further understand the role of FAM111B in fibrosis and cancer phenotype in POIKTMP

Towards a developmental state? Provincial economic policy in South Africa

This paper explores the meaning of the developmental state for spatial economic policy in South Africa. Two main questions are addressed: do provincial governments have a role to play in promoting economic prosperity, and to what extent do current provincial policies possess the attributes of a developmental state? These attributes are defined as the ability to plan longer term, to focus key partners on a common agenda, and to mobilise state resources to build productive capabilities. The paper argues that the developmental state must harness the power of government at every level to ensure that each part of the country develops to its potential. However, current provincial capacity is uneven, and weakest where support is needed most. Many provinces seem to have partial strategies and lack the wherewithal for sustained implementation. Coordination across government appears to be poor. The paper concludes by suggesting ways provincial policies could be strengthened

Revival of the magnetar PSR J1622-4950: observations with MeerKAT, Parkes, XMM-Newton, Swift, Chandra, and NuSTAR

New radio (MeerKAT and Parkes) and X-ray (XMM-Newton, Swift, Chandra, and NuSTAR) observations of PSR J1622-4950 indicate that the magnetar, in a quiescent state since at least early 2015, reactivated between 2017 March 19 and April 5. The radio flux density, while variable, is approximately 100x larger than during its dormant state. The X-ray flux one month after reactivation was at least 800x larger than during quiescence, and has been decaying exponentially on a 111+/-19 day timescale. This high-flux state, together with a radio-derived rotational ephemeris, enabled for the first time the detection of X-ray pulsations for this magnetar. At 5%, the 0.3-6 keV pulsed fraction is comparable to the smallest observed for magnetars. The overall pulsar geometry inferred from polarized radio emission appears to be broadly consistent with that determined 6-8 years earlier. However, rotating vector model fits suggest that we are now seeing radio emission from a different location in the magnetosphere than previously. This indicates a novel way in which radio emission from magnetars can differ from that of ordinary pulsars. The torque on the neutron star is varying rapidly and unsteadily, as is common for magnetars following outburst, having changed by a factor of 7 within six months of reactivation.Comment: Published in ApJ (2018 April 5); 13 pages, 4 figure

Governance, Restructuring and the New Public Management Reform: South African Perspectives

In the last two decades an array of management techniques and practices have been adopted and implemented by most governments to ameliorate public administration. This was principally because most governments got ensnared in huge debts, operational inefficiency, and ineffectiveness in service delivery including lack of accountability from political elites and public servants. These problems emanated from the quaint methods of fiscal management that were implemented and practiced resulting in rampant corruption and feeble public services. This led to widespread disgruntlement and demand for good governance hence the rise of the New Public Management (NPM). Theories like public choice theory and principal–agent theory propelled the rise of the New Public Management (NPM) with its consonant reforms and practices of restructuring. The colonial–independence-globalization theory also gave impetus to the emergence of the NPM theory for most former colonies like South Africa which had colonialism of a special type. Most African countries including South Africa have socio-political and economic conditions different from their Western counterparts because of decades of colonialism and apartheid and therefore experienced NPM uniquely. This paper explores the concepts of governance, restructuring and the NPM in the context of South Africa. DOI: 10.5901/jesr.2014.v4n6p4

A Double-Edged Sword? Reflections on the Development of the San Community of Botswana

A large part of the discourse of development envisages a symbiotic relationship between development and democracy, with some theorists and practitioners arguing that there is a strong positive relationship between development and democracy. In particular, it is presumed that both development and democracy inform and blend into one another. Essentially, democracy is believed to be a basic requirement for development as well as an indicator of it. Significantly, the very idea that democracy is a prerequisite or a basic pre-condition of development is symbolically important and suggests that development is fundamentally founded on a healthy democratic tradition. In similar manner, high levels of development are presumed to give impetus to democratic impulses. It is thus widely presumed that economic development provides impetus to the transformation of political systems and the full enjoyment of human rights. Perhaps this position is a result of the growing realization that problems of economic performance and governance are interconnected, such that solution to one of the problems may often be found in the solution to the other. This paper seeks to present a cautionary perspective on this widely accepted position by arguing that while the two inform and blend into one another, the outcome may not always be desirable or beneficial. Using the right based approach to development as the conceptual framework the paper presents a critical assessment of this relationship, noting that in some instances, development interventions have had negative effects on basic civil and political freedoms of the San people of Botswana. DOI: 10.5901/mjss.2014.v5n20p292

Allopathic medicine practitioners’ experiences with non-disclosure of traditional medicine use

Background: A pertinent issue impacting patient treatment outcomes is the nondisclosure of traditional medicine (TM) use to Allopathic medicine practitioners (AMPs). For years, TM has been a controversial practice, with patients often using it alongside allopathic medicine without disclosing their use. It is imperitive to learn and understand the experiences of AMPs regarding the disclosure of TM use in Gauteng province to enable them to provide the best possible treatment outcomes for patients who use TM. Aim: This study aimed to explore the experiences of AMPs regarding non-disclosure of TM use in Gauteng province. Setting: This study was conducted in four district hospitals where outpatient care and services are rendered in Gauteng Province. Methods: An interpretive phenomenological analysis (IPA) design was followed. Fourteen purposefully sampled AMPs participated in face-to-face, one-on-one, and semi-structured interviews. Interpretive phenomenological analysis in Atlas.ti was conducted. Results: Three themes emerged: bedside manner of AMPs; stigmatising TM use; and individual belief systems. The belief of patients’ disclosure hesitancy because of fear of judgment by the AMPs underpinned these themes. Conclusion: Allopathic medicine practitioners are aware that patients who use TM could feel guilty and stigmatised. They acknowledged that patients use TM because of cultural and ethnic reasons, which should not be disregarded. Contribution: The study highlighted that patients do not disclose their TM use because of AMPs’ attitudes, stigmatising TM use, and their prejudices against the cultural beliefs of patients. Allopathic medicine practitioners should establish good communication with patients by providing patient-centred communication to facilitate disclosure of TM use

Malaria control – two years' use of insecticide treated bednets compared with insecticide house spraying in Kwazulu-Natal

Objectives_ The objective of this study was to produce data indicating whether insecticide-treated bednets should replac insecticide house spraying as a malaria control method in South Africa_ We report 2 years of preliminary data on malaria incidence comparing areas receiving insecticidetreated bednets and those subjected to house spraying in northern KwaZulu-Natal.Design, setting and subjects. In order to measure significant reductions in malaria incidence between the two interventions, a geographical information system (GIS) was used to identify and create seven pairs of geographical blood ; (areas) in the malaria high-risk areas of Ndumu and Makani in Ingwavuma magisterial district, KwaZulu-Natal, Individual blocks were then randomly allocated to either insecticide-treated bednets or house spraying with deltamethrin. Malaria cases were either routinely recorded by surveillance agents at home or were reported to the nearest health facility_Results and conclusions. The results show that 2 years' use of insecticide-treated bednets by communities in Ndumu and Makanis, KwaZulu-Natal, significantly reduced the malaria incidence both in 1997 (rate ratio (RR) =0_879, 95% confidence interval (Cn 0.80 - 0.95, P =0.04) and in 1998 (RR = 0.667, Cl 0_61 - 0.72, P = 0.0001). Using a t-test, these significant reductions were further confirmed by an assessment of the rate of change between 1996 and 1998, showing a 16% reduction in malaria incidence in blocks using bednets and an increase of 45% in sprayed areas (t = 2.534, P = 0.026 (12 df». In order to decide whether bednets : should replace house spraying in South Africa, we need more : data on the efficacy of treated bednets, their long-term acceptability and the cost of the two interventions

A reflection on ethical and methodological challenges of using separate interviews with adolescent-older carer dyads in rural South Africa.

BACKGROUND: This article discusses our reflections on ethical and methodological challenges when conducting separate interviews with individuals in dyads in the uMkhanyakude district, South Africa. Our work is embedded in an ethnographic study exploring care relationships between adolescents and their older carers in the context of a large-donor funded HIV programme. We use these reflections to discuss some of the challenges and present possible management strategies that may be adopted in conducting dyadic health research in resource-poor settings. METHODS: Drawing from the relational agency, three rounds of separate interviews and participant observation were undertaken with dyads of adolescents aged between 13 and 19 and their older carers aged 50+ from October 2017 to September 2018. A reflexive journal was kept to record the interviewer's experiences of the whole research process. We identified methodological and ethical challenges from these data during the thematic analysis. RESULTS: A total of 36 separate interviews were conducted with six pairs of adolescent-older carer dyads (n = 12 participants). Five themes emerged: recruitment of dyads, consenting dyads, confidentiality, conducting separate interviews with adolescents and older carers, and interviewer-dyad interaction. We also illustrated how we dealt with these challenges. CONCLUSIONS: Results from this study can guide the recruitment, consenting and collecting data for health studies that employ a similar form of enquiry in LMICs. However, ethical and methodological challenges should be recognised as features of the relationships between cross-generation dyads rather than weaknesses of the method