The superfamily of transforming growth factors‐beta (TGF‐beta) comprises an expanding list of multifunctional proteins serving as regulators of cell proliferation and differentiation. Prominent members of this family include the TGF‐beta s 1‐5, activins, bone morphogenetic proteins and a recently discovered glial cell line‐derived neurotrophic factor (GDNF). In the present study we demonstrate and compare the survival promoting and neuroprotective effects of TGF‐beta 1, ‐2 and ‐3, activin A and GDNF for midbrain dopaminergic neurons in vitro. All proteins increase the survival of tyrosine hydroxylase‐immunoreactive dopaminergic neurons isolated from the embryonic day (E) 14 rat mesencephalon floor to varying extents (TGF‐beta s 2.5‐fold, activin A and GDNF 1.6‐fold). TGF‐beta s, activin A and GDNF did not augment numbers of very rarely observed astroglial cells visualized by using antibodies to glial fibrillary acidic protein and had no effect on cell proliferation monitored by incorporation of BrdU. TGF‐beta 1 and activin A protected dopaminergic neurons against N‐methyl‐4‐phenylpiridinium ion toxicity. Reverse transcription‐polymerase chain reaction (RT‐PCR) analysis indicated that TGF‐beta 2 mRNA, but not GDNF mRNA, is expressed in the E14 rat midbrain floor and in mesencephalic cultures. We conclude that TGF‐beta s 1‐3, activin A and GDNF share a neurotrophic capacity for developing dopaminergic neurons, which is not mediated by astroglial cells and not accompanied by an increase in cell proliferation.

Transforming growth factor-betas (TGF-betas) constitute an expanding family of multifunctional cytokines with prominent roles in development, cell proliferation, differentiation, and repair. We have cloned, expressed, and raised antibodies against a distant member of the TGF-betas, growth/differentiation factor-15 (GDF-15). GDF-15 is identical to macrophage inhibitory cytokine-1 (MIC-1). GDF-15/MIC-1 mRNA and protein are widely distributed in the developing and adult CNS and peripheral nervous systems, including choroid plexus and CSF. GDF-15/MIC-1 is a potent survival promoting and protective factor for cultured and iron-intoxicated dopaminergic (DAergic) neurons cultured from the embryonic rat midbrain floor. The trophic effect of GDF-15/MIC-1 was not accompanied by an increase in cell proliferation and astroglial maturation, suggesting that GDF-15/MIC-1 probably acts directly on neurons. GDF-15/MIC-1 also protects 6-hydroxydopamine (6-OHDA)-lesioned nigrostriatal DAergic neurons in vivo. Unilateral injections of GDF-15/MIC-1 into the medial forebrain bundle just above the substantia nigra (SN) and into the left ventricle (20 microgram each) immediately before a 6-OHDA injection (8 microgram) prevented 6-OHDA-induced rotational behavior and significantly reduced losses of DAergic neurons in the SN. This protection was evident for at least 1 month. Administration of 5 microgram of GDF-15/MIC-1 in the same paradigm also provided significant neuroprotection. GDF-15/MIC-1 also promoted the serotonergic phenotype of cultured raphe neurons but did not support survival of rat motoneurons. Thus, GDF-15/MIC-1 is a novel neurotrophic factor with prominent effects on DAergic and serotonergic neurons. GDF-15/MIC-1 may therefore have a potential for the treatment of Parkinson's disease and disorders of the serotonergic system.

We have cloned a novel member of the transforming growth factor-beta (TGF-beta) superfamily from a human placental cDNA library. The sequence is identical to five very recently published sequences, of which only one (macrophage inhibitory cytokine-1, MIC-1) has been characterized in terms of function. In light of the present data demonstrating the wide distribution of the mRNA and putative multifunctionality, we propose to name this molecule growth/differentiation factor-15/MIC-1 (GDF-15/MIC-1). The deduced amino acid sequence reveals typical features of a secreted molecule. The epithelium of the choroid plexus is the only site in the adult brain expressing detectable levels of GDF-15/MIC-1 mRNA. Many epithelia of non-neural tissues including those of the prostate and intestinal mucosa, bronchi and bronchioli, secretory tubuli of the submandibular gland, and lactating mammary gland are prominent sites of GDF-15/MIC-1 synthesis. GDF-15/MIC-1 is also strongly expressed by macrophages in the adrenal gland. Thus, GDF-15/MIC-1, like many other members of the TGF-beta superfamily, is widely distributed in adult tissues, being most strongly expressed in epithelial cells and macrophages.

Healthcare providers all over the world are faced with a single challenge: the need to improve patient outcomes while containing costs. Drivers include an increasing demand for chronic disease management for an aging population, technological advancements and empowered patients taking control of their health experience. The digital transformation in healthcare, through the creation of a rich health data foundation and integration of technologies like the Internet of Things (IoT), advanced analytics, Machine Learning (ML) and Artificial Intelligence (AI), is recognized as a key component to tackle these challenges. It can lead to improvements in diagnostics, prevention and patient therapy, ultimately empowering care givers to use an evidence-based approach to improve clinical decisions. Real-time interactions allow a physician to monitor a patient ‘live’, instead of interactions once every few weeks. Operational intelligence ensures efficient utilization of healthcare resources and services provided, thereby optimizing costs. However, procedure-based payments, legacy systems, disparate data sources with the limited adoption of data standards, technical debt, data security and privacy concerns impede the efficient usage of health information to maximize value creation for all healthcare stakeholders. This has led to a highly-regulated, constrained industry. Ultimately, the goal is to improve quality of life and saving people’s lives through the creation of the intelligent healthcare provider, fully enabled to deliver value-based healthcare and a seamless patient experience. Information technologies that enable this goal must be extensible, safe, reliable and affordable, and tailored to the digitalization maturity-level of the individual organization.

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