Tiazofurin: biological effects and clinical uses

Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and therefore, a sensitive target of chemotherapy. Tiazofurin selectively blocks IMPDH activity. Tiazofurin was found to have an antiproliferative effect on tumor cells in vitro and in the murine system. Based on these findings, Phase I trials were started elsewhere in patients with solid tumors, but were discontinued because of toxicity. In leukemic patients, we were able to demonstrate a good correlation between biochemical parameters (i.e., decline in IMPDH activity and GTP concentrations in blast cells) and clinical response. The most consistent responses to therapy were seen in patients with myeloid blast crisis of chronic myeloid leukemia. Severe toxicity was seen in the earlier patients in the study. However, better patient selection, limitation of treatment duration and earlier recognition and treatment of complications have now made it possible to administer tiazofurin without undue toxicity.     

Issues for cross-cultural psychiatric research in South Africa

South Africa's heterogenous society offers many opportunities for cross-cultural psychiatric research, but researchers in the country are subject to a number of restraints. Apart from legally enforced segregation, there are strict censorship laws and restricted access to certain types of information. The issues surrounding categorization of cultures and factors affecting publishing research from South Africa have important implications for the type of work that is done. It is a central argument of this article that the issues affecting research in South Africa are relevant to other countries as well, and parallels between the local and international context are drawn. The South African experience suggests that analysis of the research enterprise itself is a useful part of the business of cross-cultural psychiatric research.I am grateful to Beverley Jo Dickman, Terry Dowdall, Ronith Elk, Alan Flisher, Don Foster, Jane Steere and Sally Swartz for their comments on this article. Emile Boonzaaier provided a useful critique on an earlier draft. The arguments presented in this article are, however, my responsibility alone.     

Proteomics in clinical trials and practice: present uses and future promise

The study of clinical proteomics is a promising new field that has the potential to have many applications, including the identification of biomarkers and monitoring of disease, especially in the field of oncology. Expression proteomics evaluates the cellular production of proteins encoded by a particular gene and exploits the differential expression and post-translational modifications of proteins between healthy and diseased states. These biomarkers may be applied towards early diagnosis, prognosis, and prediction of response to therapy. Functional proteomics seeks to decipher protein-protein interactions and biochemical pathways involved in disease biology and targeted by newer molecular therapeutics. Advanced spectrometry technologies and new protein array formats have improved these analyses and are now being applied prospectively in clinical trials. Further advancement of proteomics technology could usher in an era of personalized molecular medicine, where diseases are diagnosed at earlier stages and where therapies are more effective because they are tailored to the protein expression of a patient's malignancy.     

The challenge of cross-cultural clinical trials research: case report from the Tibetan Autonomous Region, People's Republic of China

Efforts to conduct Western clinical research in non-Western medical settings with little or no familiarity with such methodologies are on the rise, but documented accounts of the ways that biomedical science requires negotiation and translation across cultures are not plentiful. This article adds to this literature through analysis of an NICHD-funded collaborative research effort in women's health carried out in the Tibetan Autonomous Region of the People's Republic of China. The research involved a feasibility study for an eventual clinical trial comparing Tibetan medicine with misoprostol for preventing postpartum hemorrhage in delivering women. It explores strategies of negotiation and translation in and around notions of the scientific method, informed consent procedures, randomization, blinding, placebo, and concepts of medical standardization.     

Adipose-derived stromal cells: Their identity and uses in clinical trials, an update

In adults, adipose tissue is abundant and can be easily sampled using liposuction. Largely involved in obesity and associated metabolic disorders, it is now described as a reservoir of immature stromal cells. These cells, called adipose-derived stromal cells (ADSCs) must be distinguished from the crude stromal vascular fraction (SVF) obtained after digestion of adipose tissue. ADSCs share many features with mesenchymal stem cells derived from bone marrow, including paracrine activity, but they also display some specific features, including a greater angiogenic potential. Their angiogenic properties as well as their paracrine activity suggest a putative tumor-promoting role for ADSCs although contradictory data have been published on this issue. Both SVF cells and ADSCs are currently being investigated in clinical trials in several fields (chronic inflammation, ischemic diseases, etc. ). Apart from a phase Ⅲ trial on the treatment of fistula,most of these are in phaseⅠand use autologous cells. In the near future, the end results of these trials should provide a great deal of data on the safety of ADSC use.     

Improving design and analysis of research: lessons from clinical research

There is a clear need to optimise the use of animals in research and to ensure that the studies that are done make a worthwhile contribution to scientific knowledge. Research that has an inappropriate study design, or is improperly analysed or interpreted, may mislead and is not defensible. Published reviews of the quality of design and analysis in clinical studies are used to see what lessons can be drawn in respect of animal research. The need for clear and full reporting of research is discussed.     

Chemistry and clinical uses of the protein components involved in blood clotting

Recent advances in the chemistry of the clotting process include:

1. 1)
   The preparation of highly purified prothrombin and thrombin from beef blood by Seegers and his associates.     
   
   

Heritability: uses and abuses

This paper begins with a brief summary of the history of the development of ideas in the field of quantitative genetics. Next there is discussion of the controversy surrounding the contention that IQ tests validly estimate some highly heritable general intelligence factor. The validity of the reasoning supporting this contention is questioned. The theory of correlation between relatives has been of vast importance in plant and animal breeding because it is possible to design and carry out experiments to estimate variance components in expressions for covariances between relatives. However, data on humans is observational and individuals are not randomly assigned to environments, so that estimation of heritability from such data is not on the same firm foundation as it is in plant and animal breeding contexts. This revised version was published online in August 2006 with corrections to the Cover Date.     

Data analysis strategies for reducing the influence of the bias in cross-cultural research

In cross-cultural research, researchers have to adjust the constructs and associated measurement instruments that have been developed in one culture and then imported for use in another culture. Importing concepts from other cultures is often simply reduced to language adjustment of the content in the items of the measurement instruments that define a certain (psychological) construct. In the context of cross-cultural research, test bias can be defined as a generic term for all nuisance factors that threaten the validity of cross-cultural comparisons. Bias can be an indicator that instrument scores based on the same items measure different traits and characteristics across different cultural groups. To reduce construct, method and item bias,the researcher can consider these strategies: (1) simply comparing average results in certain measuring instruments; (2) comparing only the reliability of certain dimensions of the measurement instruments, applied to the "target" and "source" samples of participants, i.e. from different cultures; (3) comparing the "framed" factor structure (fixed number of factors) of the measurement instruments, applied to the samples from the "target" and "source" cultures, using explorative factor analysis strategy on separate samples; (4) comparing the complete constructs ("unframed" factor analysis, i.e. unlimited number of factors) in relation to their best psychometric properties and the possibility of interpreting (best suited to certain cultures, applying explorative strategy of factor analysis); or (5) checking the similarity of the constructs in the samples from different cultures (using structural equation modeling approach). Each approach has its advantages and disadvantages. The advantages and lacks of each approach are discussed.     

Neuroproteomics and microRNAs studies in multiple sclerosis: transforming research and clinical knowledge in biomarker research

Multiple sclerosis (MS) is a complex disease characterized by extensive phenotypic variability. Biomarkers to capture the different aspects of MS heterogeneity, and to help make a diagnosis and monitor disease progression, while providing insights into etiopathogenesis and response to treatment, are urgently needed. Omics technologies and research efforts with microRNAs have provide unparalleled opportunities for exploring altered protein profiles associated with molecular mechanisms of disease, substantially expanding the list of candidate biomarkers for MS. This review presents evidence from proteomic studies that have focused on identification of biomarkers released in biofluids as a result of the different pathophysiological processes of MS. Also discussed is the emerging role of miRNAs as complementary biomarkers related to cellular processes occurring in MS patients. Also provided is an overview of candidate biomarkers that have been proposed for elucidating pathophysiological processes and disease activity and for guiding clinical diagnosis and/or therapeutic interventions in MS.