Medicine and the Law: Partial relief from the regulatory vacuum involving human tissues through enactment of chapter 8 of the National Health Act and regulations thereto

Human tissue legislation is complex. An exhaustive understanding of the law, thorough understanding of human tissue biology and pathophysiology and an appreciation of the diversity of the areas covered in this field, is critical. The importance of interdisciplinary co-operation in the drafting, interpretation and implementation of legislation in this area cannot be overemphasised. Severalfactors underscore this, including the complexity and volume of the information involved, rapid advances in science, reciprocal dependence of the law and science on one another for relevance and accuracy, and above all the need to ensure that the patient’s well-being and safety are not compromised. The development of technology also must be encouraged in a non-obstructive legislative setting

Is South Africa on the verge of a medical malpractice litigation storm?

South Africa is witnessing a sharp increase in medical malpractice litigation as patients increasingly become aware of their rights in a setting of an overburdened health system with limited resources. Legitimate claims need to be compensated. However, the consequences of increased litigation are: (i) a further reduction in the state’s ability to finance health care as a result of large payouts; and (ii) a continuing increase in malpractice premiums in the private sector. A healthy tension between the medical and legal professions should lead to an overall improvement in quality of health care, but consideration will need to be given to issues such as specialist courts, alternative means of resolution, claim quantum determination and capping. Although these issues will technically not minimise the risk of negligence, they may assist in tempering the increasing litigation spiral. Adequate allocation of funding by the state will reduce the risk of claims against the state that result from inadequate human and other resources; this is an important political/policy debate that speaks indirectly to the litigation issue. The recent implementation of the Consumer Protection Act will increasingly place additional and direct responsibility on health professionals for claims made by patients for which they may be directly or indirectly held responsible

A global comparative overview of the legal regulation of stem cell research and therapy: Lessons for South Africa

Stem cell research and its potential translation to regenerative medicine, tissue engineering and cell and gene therapy, have led to controversy and debates similar to the calls nearly 25 years ago for a ban involving recombinant DNA. Global legislative efforts in this field have been characterised by many legal, ethical and practical challenges, stemming from conflicting views regarding human embryonic research and cloning. National policy and regulatory developments have primarily been shaped by different understandings of relevant scientific objectives, as well as those relating to the moral and legal status of the human embryo, which have been used to justify or limit a range of permissible activities. Legal obscurity in this field, a consequence of inconsistent or vague legislative responses at a national and international level, leads to negative results, which include, among others, ethical violations; lack of collaboration and co-operation among researchers across national borders; stunted scientific progress; lack of public trust in stem cell research; proliferation of untested ‘stem cell therapies’; and safety issues. The purpose of this article is to explore the legal regulation of stem cell research and therapy globally, by comparing the permissibility of specific stem cell research activities in 35 selected jurisdictions, followed by a comparison of the regulatory approaches with regard to stem cell-based products in the European Union and the USA. A clearer understanding of the global regulatory framework will assist in formulating more effective legal responses at a national level and in navigating the uncertainties and risks associated with this complex and evolving scientific field

HLA typing: Conventional techniques v. next-generation sequencing

Background. The large number of population-specific polymorphisms present in the HLA complex in the South African (SA) population reduces the probability of finding an adequate HLA-matched donor for individuals in need of an unrelated haematopoietic stem cell transplantation (HSCT). Next-generation sequencing (NGS) has numerous advantages compared with conventional typing techniques.Objective. To evaluate whether NGS can provide any additional value over conventional techniques in the SA context for the purpose of HSCT and cord blood banking.Methods. HLA genotyping was performed using NGS on 20 samples that had previously been HLA typed by conventional methods to evaluate whether NGS might provide any additional value over conventional HLA determination techniques.Results. NGS of routinely sequenced loci and exons yielded accurate genotypes for 98.5% of the five loci of interest, compared with 98% when additional exons were included.Conclusion. The study shows that the additional value of NGS over conventional techniques is limited, and unless done on a large scale to reduce cost may not be appropriate in SA at this stage in the context of HSCT and cord blood banking

The legal position on the classification of human tissue in South Africa: Can tissues be owned?

The ownership of tissue samples donated for medical research is an ongoing subject of dispute. Some advocates assert that patients have ongoing ownership rights in their tissues, including an unfettered right to determine what happens to their tissue sample. Researchers argue that giving patients property rights in their samples will turn the human body and body parts into a commodity and bring research to a halt. The question of the human body as property involves complex and philosophical dimensions. The law displays an uneasiness in making sense of the human body in the context of ownership and property, as the notion of owning oneself (and one’s tissues) implies that persons are able to objectify their selves, and in the process become susceptible to objectification by others. The creation of commercial products from human tissue has generated very difficult legal and ethical questions that have no clear, universally accepted answers

BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors

B-cell acute lymphoblastic leukemia (B-ALL) is an aggressive hematological disease that kills ~50% of adult patients. With the exception of some BCR-ABL1(+) patients who benefit from tyrosine kinase inhibitors, there are no effective targeted therapies for adult B-ALL patients and chemotherapy remains first-line therapy despite adverse side effects and poor efficacy. We show that, although the MEK/ERK pathway is activated in B-ALL cells driven by different oncogenes, MEK inhibition does not suppress B-ALL cell growth. However, MEK inhibition synergized with BCL-2/BCL-XL family inhibitors to suppress proliferation and induce apoptosis in B-ALL cells. We show that this synergism is mediated by the pro-apoptotic factor BIM, which is dephosphorylated as a result of MEK inhibition, allowing it to bind to and neutralize MCL-1, thereby enhancing BCL-2/BCL-XL inhibitor-induced cell death. This cooperative effect is observed in B-ALL cells driven by a range of genetic abnormalities and therefore has significant therapeutic potential

Electronic cigarette use was not associated with quitting of conventional cigarettes in youth smokers

postprin

Occurrence and Treatment of Bone Atrophic Non-Unions Investigated by an Integrative Approach

Recently developed atrophic non-union models are a good representation of the clinical situation in which many nonunions develop. Based on previous experimental studies with these atrophic non-union models, it was hypothesized that in order to obtain successful fracture healing, blood vessels, growth factors, and (proliferative) precursor cells all need to be present in the callus at the same time. This study uses a combined in vivo-in silico approach to investigate these different aspects (vasculature, growth factors, cell proliferation). The mathematical model, initially developed for the study of normal fracture healing, is able to capture essential aspects of the in vivo atrophic non-union model despite a number of deviations that are mainly due to simplifications in the in silico model. The mathematical model is subsequently used to test possible treatment strategies for atrophic non-unions (i.e. cell transplant at post-osteotomy, week 3). Preliminary in vivo experiments corroborate the numerical predictions. Finally, the mathematical model is applied to explain experimental observations and identify potentially crucial steps in the treatments and can thereby be used to optimize experimental and clinical studies in this area. This study demonstrates the potential of the combined in silico-in vivo approach and its clinical implications for the early treatment of patients with problematic fractures

Parasite fate and involvement of infected cells in the induction of CD4+ and CD8+ T cell responses to Toxoplasma gondii

During infection with the intracellular parasite Toxoplasma gondii, the presentation of parasite-derived antigens to CD4+ and CD8+ T cells is essential for long-term resistance to this pathogen. Fundamental questions remain regarding the roles of phagocytosis and active invasion in the events that lead to the processing and presentation of parasite antigens. To understand the most proximal events in this process, an attenuated non-replicating strain of T. gondii (the cpsII strain) was combined with a cytometry-based approach to distinguish active invasion from phagocytic uptake. In vivo studies revealed that T. gondii disproportionately infected dendritic cells and macrophages, and that infected dendritic cells and macrophages displayed an activated phenotype characterized by enhanced levels of CD86 compared to cells that had phagocytosed the parasite, thus suggesting a role for these cells in priming naïve T cells. Indeed, dendritic cells were required for optimal CD4+ and CD8+ T cell responses, and the phagocytosis of heat-killed or invasion-blocked parasites was not sufficient to induce T cell responses. Rather, the selective transfer of cpsII-infected dendritic cells or macrophages (but not those that had phagocytosed the parasite) to naïve mice potently induced CD4+ and CD8+ T cell responses, and conferred protection against challenge with virulent T. gondii. Collectively, these results point toward a critical role for actively infected host cells in initiating T. gondii-specific CD4+ and CD8+ T cell responses

Reprogramming energy metabolism and inducing angiogenesis : co-expression of monocarboxylate transporters with VEGF family members in cervical adenocarcinomas

Background: Deregulation of cellular energetic metabolism was recently pointed out as a hallmark of cancer cells. This deregulation involves a metabolic reprogramming that leads to a high production of lactate. Lactate efflux, besides contributing for the glycolytic flux, also acts in the extracellular matrix, contributing for cancer malignancy, by, among other effects, induction of angiogenesis. However, studies on the interplay between cancer metabolism and angiogenesis are scarce. Therefore, the aim of the present study was to evaluate the metabolic and vascular molecular profiles of cervical adenocarcinomas, their co-expression, and their relation to the clinical and pathological behavior. Methods: The immunohistochemical expression of metabolism-related proteins (MCT1, MCT4, CD147, GLUT1 and CAIX) as well as VEGF family members (VEGF-A, VEGF-C, VEGF-D, VEGFR-1, VEGFR-2 and VEGFR-3) was assessed in a series of 232 cervical adenocarcinomas. The co-expression among proteins was assessed and the expression profiles were associated with patients’ clinicopathological parameters. Results: Among the metabolism-related proteins, MCT4 and CAIX were the most frequently expressed in cervical adenocarcinomas while CD147 was the less frequently expressed protein. Overall, VEGF family members showed a strong and extended expression with VEGF-C and VEGFR-2 as the most frequently expressed and VEGFR-1 as the less expressed member. Co-expression of MCT isoforms with VEGF family members was demonstrated. Finally, MCT4 was associated with parametrial invasion and HPV18 infection, CD147 and GLUT1 with distant metastasis, CAIX with tumor size and HPV18 infection, and VEGFR-1 with local and lymphnode metastasis. Conclusions: The results herein presented provide additional evidence for a crosstalk between deregulating cellular energetics and inducing angiogenesis. Also, the metabolic remodeling and angiogenic switch are relevant to cancer progression and aggressiveness in adenocarcinomas.CP received a post-doctoral fellowship (SFRH/BPD/69479/2010) and FM-S received a doctoral fellowship (SFRH/BD/87139/2012) from FCT (Portuguese Foundation for Science and Technology). This work was supported by the FCT grant ref. PTDC/SAU-FCF/104347/2008, under the scope of "Programa Operacional Tematico Factores de Competitividade" (COMPETE) of "Quadro Comunitario de Apoio III" and co-financed by Fundo Comunitario Europeu FEDER, and also by FAPESP 2008/03232-1