Functional Structure of Spontaneous Sleep Slow Oscillation Activity in Humans

Background During non-rapid eye movement (NREM) sleep synchronous neural oscillations between neural silence (down state) and neural activity (up state) occur. Sleep Slow Oscillations (SSOs) events are their EEG correlates. Each event has an origin site and propagates sweeping the scalp. While recent findings suggest a SSO key role in memory consolidation processes, the structure and the propagation of individual SSO events, as well as their modulation by sleep stages and cortical areas have not been well characterized so far. Methodology/Principal Findings We detected SSO events in EEG recordings and we defined and measured a set of features corresponding to both wave shapes and event propagations. We found that a typical SSO shape has a transition to down state, which is steeper than the following transition from down to up state. We show that during SWS SSOs are larger and more locally synchronized, but less likely to propagate across the cortex, compared to NREM stage 2. Also, the detection number of SSOs as well as their amplitudes and slopes, are greatest in the frontal regions. Although derived from a small sample, this characterization provides a preliminary reference about SSO activity in healthy subjects for 32-channel sleep recordings. Conclusions/Significance This work gives a quantitative picture of spontaneous SSO activity during NREM sleep: we unveil how SSO features are modulated by sleep stage, site of origin and detection location of the waves. Our measures on SSOs shape indicate that, as in animal models, onsets of silent states are more synchronized than those of neural firing. The differences between sleep stages could be related to the reduction of arousal system activity and to the breakdown of functional connectivity. The frontal SSO prevalence could be related to a greater homeostatic need of the heteromodal association cortices

Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery

Borbély AN, Figueras Agustí E, Martins A, et al. Conjugates of Cryptophycin and RGD or isoDGR Peptidomimetics for Targeted Drug Delivery. ChemistryOpen. 2019;8(6):737-742.RGD-cryptophycin and isoDGR-cryptophycin conjugates were synthetized by combining peptidomimetic integrin ligands and cryptophycin, a highly potent tubulin-binding antimitotic agent across lysosomally cleavable Val-Ala or uncleavable linkers. The conjugates were able to effectively inhibit binding of biotinylated vitronectin to integrin alphavbeta3, showing a binding affinity in the same range as that of the free ligands. The antiproliferative activity of the novel conjugates was evaluated on human melanoma cells M21 and M21-L with different expression levels of integrin alphavbeta3, showing nanomolar potency of all four compounds against both cell lines. Conjugates containing uncleavable linker show reduced activity compared to the corresponding cleavable conjugates, indicating efficient intracellular drug release in the case of cryptophycin-based SMDCs. However, no significant correlation between the in vitro biological activity of the conjugates and the integrin alphavbeta3 expression level was observed, which is presumably due to a non-integrin-mediated uptake. This reveals the complexity of effective and selective alphavbeta3 integrin-mediated drug delivery

Association of kidney disease measures with risk of renal function worsening in patients with type 1 diabetes

Background: Albuminuria has been classically considered a marker of kidney damage progression in diabetic patients and it is routinely assessed to monitor kidney function. However, the role of a mild GFR reduction on the development of stage 653 CKD has been less explored in type 1 diabetes mellitus (T1DM) patients. Aim of the present study was to evaluate the prognostic role of kidney disease measures, namely albuminuria and reduced GFR, on the development of stage 653 CKD in a large cohort of patients affected by T1DM. Methods: A total of 4284 patients affected by T1DM followed-up at 76 diabetes centers participating to the Italian Association of Clinical Diabetologists (Associazione Medici Diabetologi, AMD) initiative constitutes the study population. Urinary albumin excretion (ACR) and estimated GFR (eGFR) were retrieved and analyzed. The incidence of stage 653 CKD (eGFR < 60 mL/min/1.73 m2) or eGFR reduction > 30% from baseline was evaluated. Results: The mean estimated GFR was 98 \ub1 17 mL/min/1.73m2 and the proportion of patients with albuminuria was 15.3% (n = 654) at baseline. About 8% (n = 337) of patients developed one of the two renal endpoints during the 4-year follow-up period. Age, albuminuria (micro or macro) and baseline eGFR < 90 ml/min/m2 were independent risk factors for stage 653 CKD and renal function worsening. When compared to patients with eGFR > 90 ml/min/1.73m2 and normoalbuminuria, those with albuminuria at baseline had a 1.69 greater risk of reaching stage 3 CKD, while patients with mild eGFR reduction (i.e. eGFR between 90 and 60 mL/min/1.73 m2) show a 3.81 greater risk that rose to 8.24 for those patients with albuminuria and mild eGFR reduction at baseline. Conclusions: Albuminuria and eGFR reduction represent independent risk factors for incident stage 653 CKD in T1DM patients. The simultaneous occurrence of reduced eGFR and albuminuria have a synergistic effect on renal function worsening

Peritoneal dialysis discontinuation: to the root of the problem

: As the global burden of chronic kidney disease continues to increase, the use of peritoneal dialysis is often advocated as the preferred initial dialysis modality. Observational studies suggest a survival advantage for peritoneal dialysis over hemodialysis for the initial 2-3 years of dialysis. Peritoneal dialysis has been associated with better graft survival after kidney transplantation and has a reduced cost burden compared to hemodialysis. However, several medical and non-medical reasons may limit access to peritoneal dialysis, and less than 20% of patients with end-stage kidney disease are treated with peritoneal dialysis worldwide. In this narrative review, we sought to summarize the recent medical literature on risk factors for peritoneal dialysis discontinuation, distinguishing the early and the late phase after peritoneal dialysis initiation. Although the definition of clinically relevant outcomes varies among studies, we observed that center size, older age, and the presence of many comorbidities are risk factors associated with peritoneal dialysis discontinuation, regardless of the phase after peritoneal dialysis initiation. On the contrary, poor technique training and late referral to nephrology care, as opposed to the need for a caregiver, patient burnout and frequent hospitalizations, are related to early and late peritoneal dialysis drop-out, respectively. The aim of the review is to provide an overview of the most relevant parameters to be considered when advising patients in the selection of the most appropriate dialysis modality and in the clinical management of peritoneal dialysis patients. In addition, we wish to provide the readers with a critical appraisal of current literature and a call for a consensus on the definition of clinically relevant outcomes in peritoneal dialysis to better address patients' needs

Likeness-Based Detection of Sleep Slow Oscillations in Normal and Altered Sleep Conditions: Application on Low-Density EEG Recordings

Sleep slow oscillation (SSO) is a common EEG pattern of spontaneous activity during nonrapid eye movement sleep. A new method for detecting SSOs is presented and compared to previous canonical methods. The main result of this research is that for the first time an extensive SSO analysis is applied to clinical EEG montages, based on low-density EEG recordings. The proposed method gives positive indications about its effectiveness also for altered sleep, extending the SSO analysis to extreme cases, and thus, opening a new front for investigating pathophysiological correlates of sleep disorders

Low Glucose Concentrations Induce a Similar Inflammatory Response in Monocytes from Type 2 Diabetic Patients and Healthy Subjects

This study aims to assess the proinflammatory interleukin 1β (IL-1β) and anti-inflammatory IL-10 production by monocytes from 38 patients with type 2 diabetes and 31 controls in different glucose concentrations. Monocytes were incubated in low (2.5 mmol/L)-, normal (5.0 mmol/L)-, and high (20 mmol/L)-glucose conditions in the presence and absence of lipopolysaccharide (LPS). Monocytes from both patients and controls only produced a significant increase in IL-1β in low-glucose conditions (p<0.01), and this phenomenon was amplified in the presence of LPS, while it was not seen in normal- or high-glucose conditions, not even in the presence of LPS stimulation. There was no increase in IL-10 production by monocytes from either diabetic patients or controls using whatever glucose concentrations, except when treated with LPS in normal-glucose conditions. These findings seem to suggest that low-glucose conditions induce an inflammatory response in monocytes in all individuals, as an intrinsic capacity of this cell line. On the other hand, monocytes only retain their anti-inflammatory ability in response to known inflammatory stimuli such as LPS, under normal-glucose concentrations. In conclusion, human monocytes express an inflammatory pattern in low-glucose conditions in vitro. This response could contribute to explaining the higher cardiovascular risk induced by hypoglycemia in diabetic patients