The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease

The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60?ml/min per 1.73?m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5?ml/min per 1.73?m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD.     

Comparison of Physical Activity Using Questionnaires (Leisure Time Physical Activity Instrument and Physical Activity at Home and Work Instrument) and Accelerometry in Fibromyalgia Patients: The Al-Ándalus Project

Objective

To compare the levels of physical activity (PA) assessed with questionnaires (Leisure Time Physical Activity Instrument [LTPAI], Physical Activity at Home and Work Instrument [PAHWI]) and accelerometry in patients with fibromyalgia; and to analyze the test-retest reliability of these questionnaires.

Design

Cross-sectional study.

Setting

Local fibromyalgia association.

Participants

Participants (N=99; 5 men) with fibromyalgia with a mean age of 50.2±9.5 years.

Interventions

Not applicable.

Main Outcome Measures

Participants carried an accelerometer for 1 week and completed the LTPAI and PAHWI twice (separated by a 1-wk interval). The LTPAI and PAHWI were summed to obtain overall values of PA.

Results

Time spent in total, moderate, and moderate-vigorous PA was higher (P<.01) when assessed by the LTPAI and PAHWI compared with accelerometry. The Bland-Altman method showed an absence of agreement between the LTPAI and PAHWI and the accelerometer for moderate, moderate-vigorous, and total PA. The test-retest reliability for the workplace subscale and total score of the PAHWI showed high and moderate intraclass correlation coefficients (ICCs), respectively, but also manifested high SE of measurements (up to 179min/d). The LTPAI showed low to moderate ICCs and high SE of measurements (up to 79min/d). For the LTPAI and PAHWI, the ICCs for total activity across the population were low to moderate, and the Bland-Altman method confirmed this lack of agreement.

Conclusions

The LTPAI and PAHWI and the accelerometer differ greatly when assessing PA. Furthermore, the LTPAI and PAHWI did not show good levels of test-retest reliability. Therefore, the self-administered LTPAI and PAHWI show questionable usefulness to assess PA in populations with fibromyalgia.     

RASAL2 activates RAC1 to promote triple-negative breast cancer progression

Patients with triple-negative breast cancer (TNBC) have a high incidence of early relapse and metastasis; however, the molecular basis for recurrence in these individuals remains poorly understood. Here, we demonstrate that RASAL2, which encodes a RAS-GTPase–activating protein (RAS-GAP), is a functional target of anti-invasive microRNA-203 and is overexpressed in a subset of triple-negative or estrogen receptor–negative (ER-negative) breast tumors. As opposed to luminal B ER-positive breast cancers, in which RASAL2 has been shown to act as a RAS-GAP tumor suppressor, we found that RASAL2 is oncogenic in TNBC and drives mesenchymal invasion and metastasis. Moreover, high RASAL2 expression was predictive of poor disease outcomes in patients with TNBC. RASAL2 acted independently of its RAS-GAP catalytic activity in TNBC; however, RASAL2 promoted small GTPase RAC1 signaling, which promotes mesenchymal invasion, through binding and antagonizing the RAC1-GAP protein ARHGAP24. Together, these results indicate that activation of a RASAL2/ARHGAP24/RAC1 module contributes to TNBC tumorigenesis and identify a context-dependent role of RASAL2 in breast cancer.     

Stenting of the superior vena cava and right pulmonary artery in a woman with a mediastinal mass and acute respiratory distress syndrome (ARDS)

We report the case of a woman with a mass in the anterior and middle mediastinum (a non-small-cell lung carcinoma), determining significant compression of both superior vena cava and right pulmonary artery. The patient developed acute respiratory distress syndrome , necessitating intubation and admission to the Intensive Care Unit . Radiotherapy sessions to reduce the mass effect were attempted, without significant clinical improvement. Due to the persistence of severe hypoxemia, stenting of the superior vena cava and the right pulmonary artery was performed, the latter resulting in a significant improvement of the arterial blood gas parameters, allowing extubation of the patient. In our opinion, stenting of the superior vena cava and the pulmonary artery (or its branches) is an effective and safe treatment; it should be considered in similar cases, especially if other - less invasive - treatments fail.     

Rational Control of Molecular Properties Is Mandatory to Exploit the Potential of PROTACs as Oral Drugs

To obtain new oral drugs in the beyond rule of five space, PROTACs among others, molecular properties should be optimized in early drug discovery. Degraders call for design strategies which focus on intramolecular interaction and chameleonicity. In parallel, tailored revalidation of permeability assessment and prediction methods becomes fundamental in this innovative chemical space.