Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Autocrine FGF1 signaling promotes glucose uptake in adipocytes.

Fibroblast growth factor 1 (FGF1) is an autocrine growth factor released from adipose tissue during over-nutrition or fasting to feeding transition. While local actions underlie the majority of FGF1's anti-diabetic functions, the molecular mechanisms downstream of adipose FGF receptor signaling are unclear. We investigated the effects of FGF1 on glucose uptake and its underlying mechanism in murine 3T3-L1 adipocytes and in ex vivo adipose explants from mice. FGF1 increased glucose uptake in 3T3-L1 adipocytes and epididymal WAT (eWAT) and inguinal WAT (iWAT). Conversely, glucose uptake was reduced in eWAT and iWAT of FGF1 knockout mice. We show that FGF1 acutely increased adipocyte glucose uptake via activation of the insulin-sensitive glucose transporter GLUT4, involving dynamic crosstalk between the MEK1/2 and Akt signaling proteins. Prolonged exposure to FGF1 stimulated adipocyte glucose uptake by MEK1/2-dependent transcription of the basal glucose transporter GLUT1. We have thus identified an alternative pathway to stimulate glucose uptake in adipocytes, independent from insulin, which could open new avenues for treating patients with type 2 diabetes.

Remote monitoring technologies in Alzheimer's disease: design of the RADAR-AD study.

BACKGROUND: Functional decline in Alzheimer's disease (AD) is typically measured using single-time point subjective rating scales, which rely on direct observation or (caregiver) recall. Remote monitoring technologies (RMTs), such as smartphone applications, wearables, and home-based sensors, can change these periodic subjective assessments to more frequent, or even continuous, objective monitoring. The aim of the RADAR-AD study is to assess the accuracy and validity of RMTs in measuring functional decline in a real-world environment across preclinical-to-moderate stages of AD compared to standard clinical rating scales. METHODS: This study includes three tiers. For the main study, we will include participants (n = 220) with preclinical AD, prodromal AD, mild-to-moderate AD, and healthy controls, classified by MMSE and CDR score, from clinical sites equally distributed over 13 European countries. Participants will undergo extensive neuropsychological testing and physical examination. The RMT assessments, performed over an 8-week period, include walk tests, financial management tasks, an augmented reality game, two activity trackers, and two smartphone applications installed on the participants' phone. In the first sub-study, fixed sensors will be installed in the homes of a representative sub-sample of 40 participants. In the second sub-study, 10 participants will stay in a smart home for 1 week. The primary outcome of this study is the difference in functional domain profiles assessed using RMTs between the four study groups. The four participant groups will be compared for each RMT outcome measure separately. Each RMT outcome will be compared to a standard clinical test which measures the same functional or cognitive domain. Finally, multivariate prediction models will be developed. Data collection and privacy are important aspects of the project, which will be managed using the RADAR-base data platform running on specifically designed biomedical research computing infrastructure. RESULTS: First results are expected to be disseminated in 2022. CONCLUSION: Our study is well placed to evaluate the clinical utility of RMT assessments. Leveraging modern-day technology may deliver new and improved methods for accurately monitoring functional decline in all stages of AD. It is greatly anticipated that these methods could lead to objective and real-life functional endpoints with increased sensitivity to pharmacological agent signal detection.

Hyperglycemia Induces Bioenergetic Changes in Adipose-Derived Stromal Cells While Their Pericytic Function Is Retained.

Diabetic retinopathy (DR) is a hyperglycemia (HG)-mediated microvascular complication. In DR, the loss of pericytes and subsequently endothelial cells leads to pathologic angiogenesis in retina. Adipose-derived stromal cells (ASC) are a promising source of therapeutic cells to replace lost pericytes in DR. To date, knowledge of the influence of HG on the bioenergetics and pericytic function of ASC is negligible. Human ASC were cultured in normoglycemia medium (5 mM d-glucose) or under HG (30 mM d-glucose) and assessed. Our data showed that HG increased the level of apoptosis and reactive oxygen species production in ASC, yet their proliferation rate was not affected. HG induced alterations in mitochondrial function and morphology in ASC. HG also strongly affected the bioenergetic status of ASC in which both the maximum oxygen consumption rate and extracellular acidification rate were decreased. This was corroborated by a reduced uptake of glucose under HG. In spite of these observations, in vitro, ASC promoted the formation of vascular-like networks of human umbilical vein endothelial cells on monolayers of ASC under HG with minimally affected.

Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder and is strongly associated with obesity and type 2 diabetes. Currently, there is no approved pharmacological treatment for this disease, but improvement of insulin resistance using peroxisome proliferator-activated receptor-γ (PPARγ) agonists, such as thiazolidinediones (TZDs), has been shown to reduce steatosis and steatohepatitis effectively and to improve liver function in patients with obesity-related NAFLD. However, this approach is limited by adverse effects of TZDs. Recently, we have identified fibroblast growth factor 1 (FGF1) as a target of nuclear receptor PPARγ in visceral adipose tissue and as a critical factor in adipose remodeling. Because FGF1 is situated downstream of PPARγ, it is likely that therapeutic targeting of the FGF1 pathway will eliminate some of the serious adverse effects associated with TZDs. Here we show that pharmacological administration of recombinant FGF1 (rFGF1) effectively improves hepatic inflammation and damage in leptin-deficient ob/ob mice and in choline-deficient mice, two etiologically different models of NAFLD. Hepatic steatosis was effectively reduced only in ob/ob mice, suggesting that rFGF1 stimulates hepatic lipid catabolism. Potentially adverse effects such as fibrosis or proliferation were not observed in these models. Because the anti-inflammatory effects were observed in both the presence and absence of the antisteatotic effects, our findings further suggest that the anti-inflammatory property of rFGF1 is independent of its effect on lipid catabolism. Our current findings indicate that, in addition to its potent glucose-lowering and insulin-sensitizing effects, rFGF1 could be therapeutically effective in the treatment of NAFLD.

Melphalan, prednisone, and lenalidomide versus melphalan, prednisone, and thalidomide in untreated multiple myeloma.

The combination of melphalan, prednisone, and thalidomide (MPT) is considered standard therapy for newly diagnosed patients with multiple myeloma who are ineligible for stem cell transplantation. Long-term treatment with thalidomide is hampered by neurotoxicity. Melphalan, prednisone, and lenalidomide, followed by lenalidomide maintenance therapy, showed promising results without severe neuropathy emerging. We randomly assigned 668 patients between nine 4-week cycles of MPT followed by thalidomide maintenance until disease progression or unacceptable toxicity (MPT-T) and the same MP regimen with thalidomide being replaced by lenalidomide (MPR-R). This multicenter, open-label, randomized phase 3 trial was undertaken by Dutch-Belgium Cooperative Trial Group for Hematology Oncology and the Nordic Myeloma Study Group (the HOVON87/NMSG18 trial). The primary end point was progression-free survival (PFS). A total of 318 patients were randomly assigned to receive MPT-T, and 319 received MPR-R. After a median follow-up of 36 months, PFS with MPT-T was 20 months (95% confidence interval [CI], 18-23 months) vs 23 months (95% CI, 19-27 months) with MPR-R (hazard ratio, 0.87; 95% CI, 0.72-1.04; P = .12). Response rates were similar, with at least a very good partial response of 47% and 45%, respectively. Hematologic toxicity was more pronounced with MPR-R, especially grades 3 and 4 neutropenia: 64% vs 27%. Neuropathy of at least grade 3 was significantly higher in the MPT-T arm: 16% vs 2% in MPR-R, resulting in a significant shorter duration of maintenance therapy (5 vs 17 months in MPR-R), irrespective of age. MPR-R has no advantage over MPT-T concerning efficacy. The toxicity profile differed with clinically significant neuropathy during thalidomide maintenance vs myelosuppression with MPR.

Fibroblast Growth Factor Signaling in Metabolic Regulation.

The prevalence of obesity is a growing health problem. Obesity is strongly associated with several comorbidities, such as non-alcoholic fatty liver disease, certain cancers, insulin resistance, and type 2 diabetes, which all reduce life expectancy and life quality. Several drugs have been put forward in order to treat these diseases, but many of them have detrimental side effects. The unexpected role of the family of fibroblast growth factors in the regulation of energy metabolism provides new approaches to the treatment of metabolic diseases and offers a valuable tool to gain more insight into metabolic regulation. The known beneficial effects of FGF19 and FGF21 on metabolism, together with recently discovered similar effects of FGF1 suggest that FGFs and their derivatives carry great potential as novel therapeutics to treat metabolic conditions. To facilitate the development of new therapies with improved targeting and minimal side effects, a better understanding of the molecular mechanism of action of FGFs is needed. In this review, we will discuss what is currently known about the physiological roles of FGF signaling in tissues important for metabolic homeostasis. In addition, we will discuss current concepts regarding their pharmacological properties and effector tissues in the context of metabolic disease. Also, the recent progress in the development of FGF variants will be reviewed. Our goal is to provide a comprehensive overview of the current concepts and consensuses regarding FGF signaling in metabolic health and disease and to provide starting points for the development of FGF-based therapies against metabolic conditions.

Langmuir-Blodgett films based on inorganic molecular complexes with magnetic or optical properties.

Langmuir and Langmuir-Blodgett (LB) films of a great variety of molecular metal complexes with interesting magnetic or optical properties have been prepared in the last few years. Some of the results obtained by our group and others are summarized in this article.

[Secondary amyloidosis (AA) and renal disease]. / Amiloidosis secundaria (AA) y afectación renal.

Amyloidosis is a disease resulting from extracellular deposition of fibrillar protein in various organs. AA amyloidosis may complicate chronic inflammatory diseases, chronic infections and another chronic diseases. We review 31 patients (13 males and 18 females) with biopsy proven renal or rectal AA amyloidosis, referred to out hospital between january 1999 and november 2002. Renal failure was defined as serum creatinine > or = 1.5 mg/dl. Mean age was 58.4 +/- 15.7 years. The causes of AA amyloidosis were an underlying chronic rheumatologic disease (51.6%), chronic infection (41.9%) and a chronic inflammatory intestinal disorder (6.5%). Renal failure (RF) was detected in 20 patients (61.2%) and proteinuria and hematuria were found in 90.3% and 45.5 respectively. Proteinuria at diagnosis was 5.2 +/- 3.9 g/24 h and mean serum creatinine 3.5 +/- 3.7 mg/dl. Survival of patients without dialysis was 66.8 (51.1% RF, 90.9% non-RF) and 53.4% (38.2 RF, 77.9% non-RF) at 12 and 24 months respectively (p = 0.017). End-stage renal disease developed in 13 patients (41.9%). Ten patients were maintained on hemodialysis and 3 on CAD. Survival in dialysis at 6 and 12 months was 68.3% and 42.7% respectively. Fifteen patients died and the main causes of death were: infections (46.6) haemorrhagic complications (33.3%), cardiovascular events (13.3%) and cachexia (6.6%).

Correlation of central venous pressure with Doppler waveform of the common femoral veins.

The objects of this prospective study were to determine the nature of the flow in the right femoral vein and to correlate the flow velocity with the venous pressure measured in the right atrium. We performed 236 pulsed Doppler ultrasonographic examinations in 1 year on patients with a venous catheter with the distal tip in the right atrium. In the Doppler wave readouts we analyzed wave frequency, velocity components, and relationships among them and the existence of pulsatile flow. These parameters were then compared to the right atrium pressure. We investigated the correlation between the atrium pressure and the flow velocity obtained from the Doppler waveforms of the common femoral veins, obtaining a significant correlation (P<0.0001) with the following: the atrium systolic wave a, the atrium diastolic wave v, the pulsatility ratio (PR = Vmin/Vmax) and the pulsatility index (PI = [Vmax - Vmin] /Vavg). The receiver operating characteristic showed that the pulsed Doppler ultrasonography is not a sensitive technique in diagnosis high atrium pressures. In addition, both cardiac and respiratory phasicity of the venous wave was observed. A significant inverse relation was found between the pulsatile flow and high atrium pressure. Nonetheless, the low sensitivity of this technique does not allow the use of pulsatile Doppler ultrasonography in the common femoral vein for diagnosing increases of the atrium pressure.

The effect of avian uterine fluid on the growth behavior of calcite crystals.

Eggshell formation takes place on the eggshell membrane in an acellular medium, the uterine fluid that contains the inorganic minerals and precursors of the organic matrix. The high degree of eggshell structure could be due to an interaction between calcium carbonate and the organic matrix. The aim of this study was to demonstrate such an interaction by measuring the effect in vitro of uterine fluid collected at various phases of shell formation on precipitation kinetics, size, and morphology of calcite crystals. The SDS-PAGE profiles of the organic constituents differed between the different phases of eggshell formation. The predominant constituents were ovalbumin and ovotransferrin at the initial phase and lysozyme, ovocleidin-17, ovocalyxin-32, 36- and 21-kDa bands, and ovocleidin-116 at the growth phase. These proteins were numerous in the terminal phase and showed an increased staining of the 32- and 66-kDa bands and appearance of very low molecular weight bands. The precipitation lag time was shortened in proportion to the protein concentration at the initial stage. The effect was observed with a lower magnitude in the presence of constituents of growth and terminal phases. Crystal size was smaller in the presence of constituents from the three stages compared with the control. Components from the initial phase induced the formation of twinned crystals and of rounded corners in the rhombohedric crystals. The presence of components from the growth and terminal phases strongly modified the morphology of the calcite crystals. The majority of the corners became rough and developed curved faces. These observations confirm the interaction of the uterine fluid with calcite and its contribution to eggshell structure.

[Cervical synovial sarcoma: a case report]. / Sarcoma sinovial cervical. Aportación de un caso.

Synovial sarcomas of the head and neck are rare, fewer than 80 cases having been reported in the literature. A synovial sarcoma of cervical soft tissues presented as a lateral mass in a 51-year-old male and was treated by cervical dissection and radiotherapy. After 24 months the patient is recurrence-free. The histology and origin of synovial sarcomas is discussed.