Investigating the temporal dynamics of electroencephalogram (EEG) microstates using recurrent neural networks

Electroencephalogram (EEG) microstates that represent quasi‐stable, global neuronal activity are considered as the building blocks of brain dynamics. Therefore, the analysis of microstate sequences is a promising approach to understand fast brain dynamics that underlie various mental processes. Recent studies suggest that EEG microstate sequences are non‐Markovian and nonstationary, highlighting the importance of the sequential flow of information between different brain states. These findings inspired us to model these sequences using Recurrent Neural Networks (RNNs) consisting of long‐short‐term‐memory (LSTM) units to capture the complex temporal dependencies. Using an LSTM‐based auto encoder framework and different encoding schemes, we modeled the microstate sequences at multiple time scales (200–2,000 ms) aiming to capture stably recurring microstate patterns within and across subjects. We show that RNNs can learn underlying microstate patterns with high accuracy and that the microstate trajectories are subject invariant at shorter time scales (≤400 ms) and reproducible across sessions. Significant drop in the reconstruction accuracy was observed for longer sequence lengths of 2,000 ms. These findings indirectly corroborate earlier studies which indicated that EEG microstate sequences exhibit long‐range dependencies with finite memory content. Furthermore, we find that the latent representations learned by the RNNs are sensitive to external stimulation such as stress while the conventional univariate microstate measures (e.g., occurrence, mean duration, etc.) fail to capture such changes in brain dynamics. While RNNs cannot be configured to identify the specific discriminating patterns, they have the potential for learning the underlying temporal dynamics and are sensitive to sequence aberrations characterized by changes in metal processes. Empowered with the macroscopic understanding of the temporal dynamics that extends beyond short‐term interactions, RNNs offer a reliable alternative for exploring system level brain dynamics using EEG microstate sequences.     

Early onset demyelinating Charcot‐Marie‐Tooth disease caused by a novel in‐frame isoleucine deletion in peripheral myelin protein 2

Peripheral myelin protein 2 (PMP2) is a small protein located on the cytoplasmic side of compact myelin, involved in the lipids transport and in the myelination process. In the last years few families affected with demyelinating Charcot‐Marie‐Tooth neuropathy (CMT1), caused by PMP2 mutations, have been identified. In this study we describe the first case of a PMP2 in‐frame deletion. PMP2 was analyzed by direct sequencing after exclusion of the most frequent CMT‐associated genes by using a next generation sequencing (NGS) genes panel. Sanger sequencing was used for family's segregation analysis. Molecular modeling analysis was used to evaluate the mutation impact on the protein structure. A novel PMP2: p.I50del has been identified in a child with early onset CMT1 and in three affected family members. All family members show an early onset demyelinating neuropathy without other distinguish features. Molecular modeling analysis and in silico evaluations do not suggest a strong impact on the overall protein structure, but a most likely altered protein function. This study suggests the importance to add PMP2 in CMT NGS genes panels or, at most, to test it after major CMT1 genes exclusion, due to the lack of diagnostic‐addressing additional features.     

Early serum TARC reduction predicts prognosis in advanced-stage Hodgkin lymphoma patients treated with a PET-adapted strategy

Among patients with advanced-stage classical Hodgkin lymphoma (cHL) receiving ABVD chemotherapy, PET performed after the first two treatment cycles (PET-2) has prognostic value. However, 15% of patients with a negative PET-2 will experience treatment failure. Here we prospectively evaluated serum thymus and activation-regulated chemokine (TARC) levels, to improve risk assessment in patients treated according to HD0607 PET-driven trial (#NCT00795613). In 266 patients with available serum samples, who have agreed to participate in a sub-study for assessment of the role of TARC monitoring, serum TARC levels were measured at baseline and at time of PET-2 by commercially available ELISA test kits. The primary end-point was to evaluate the association between TARC after 2 ABVD cycles and PFS. Median TARC-2 values were significantly higher in PET-2-positive patients compared to PET-2-negative patients (P = .001), and in patients with treatment failure compared to those in continuous CR (P = .01). The 4-year PFS significantly differed between patients with TARC-2 >800 pg/mL vs ≤800 pg/mL (64% vs 86%, P = .0001). Moreover, among PET-2-negative patients, elevated TARC-2 identified those with a worse prognosis (74% vs 89%; P = .01). In multivariable analysis, TARC-2 >800 pg/mL was a significant independent predictor of PFS in the whole study population (HR 2.39, P = .004) and among the PET-2-negative patients (HR 2.49, P = .02). In conclusion, our results indicate that TARC-2 serum levels above 800 pg/mL suggest the need for a stringent follow-up in PET-2-negative patients, and the evaluation of new drugs in PET-2-positive, who will likely fail to respond to intensification with escalated BEACOPP.     

Coronary thrombi neovascularization in patients with ST-elevation myocardial infarction - clinical and angiographic implications

Introduction

Coronary artery thrombosis in ST-elevation myocardial infarction (STEMI) is a dynamic process often preceded by episodes of silent plaque rupture and subocclusive thrombosis. Thrombus organization is achieved by ingrowth of endothelial and smooth muscle cells. Clinical significance and impact of thrombus neovascularization on primary percutaneous coronary intervention (pPCI) outcome remain unclear. Therefore we investigated composition and neovascularization of thrombi aspirated during pPCI and their association with clinical and angiographic parameters of STEMI patients.

Methods

Aspirated thrombi retrieved from 84 STEMI patients were classified as fresh (< 1 day), lytic (1-5 days) or organized (> 5 days). Thrombus neovascularization was evaluated immunohistochemically using CD34, CD31 and VEGF antibodies. CD34 and CD31 immunopositive (CD34/CD31 +) cells were organized as single, clusters and microvessels. VEGF positivity was graded as low or high, based on thrombus surface immunopositive area.

Results

CD34/CD31 + cells were present in 67% of all aspirated thrombi. Thrombus CD34/CD31 positivity was associated with previous history of angina pectoris (χ² = 6.142, p = 0.013) and lower myocardial blush grade (MBG < 3, χ² = 12.602, p < 0.001). Organization of CD34/CD31 + cells showed inverse association with the extent of VEGF positivity (χ² = 10.607, p = 0.005). Fresh thrombi were associated with shorter ischemic time (U = 237.5, p = 0.002) and MBG 3 (χ² = 6.379, p = 0.012).

Conclusions

Older thrombus age and neovascularization are associated with suboptimal myocardial perfusion in STEMI patients. Thrombus VEGF expression is inversely associated with degree of CD34 + cell organization. Therefore, neovascularization of aspirated thrombi may indicate the duration of thrombosis, coronary microcirculation status and outcome in STEMI patients.     

PDNF, a human parasite-derived mimic of neurotrophic factors, prevents caspase activation, free radical formation, and death of dopaminergic cells exposed to the Parkinsonism-inducing neurotoxin MPP+

The neuraminidase/trans-sialidase of Trypanosoma cruzi, the agent of Chagas' disease, promotes differentiation and survival of growth factor-deprived neuronal and glial cells. To gain further insights into the possible neuroprotection of this parasite-derived counterpart of neurotrophic factors (PDNF), we sought to determine whether it mimics growth factors in a cellular model of neurodegenerative diseases. Ascertaining cell viability by morphology, vital dye exclusion, mitochondrial reducing function, and absence of DNA fragmentation, we show here that PDNF rescues from death two dopaminergic neuronal cell lines and one differentiated immortalized mesencephalic neurons exposed to the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) and its toxic metabolite, 1-methyl-4-phenylpyridinium (MPP+), both widely used in models of Parkinson's disease. We further show that PDNF promoted survival at concentrations comparable to bona fide growth factors in a MAPK/Erk activation-dependent manner. PDNF also strongly suppresses the overproduction of MPTP-induced reactive oxygen species (ROS), and the activation of both initiator caspase-9 and effector caspase-3. This down-regulation of ROS and caspases explains, at least in part, the PDNF-induced salvaging of the dopaminergic cells from the Parkinsonism-promoting toxin, confirming the novel and striking functional mimicry by the trypanosome neuraminidase of host growth factors in a cellular model of neurodegeneration.     

Current role of laser angioplasty of restenotic coronary stents

Treatment of in-stent restenosis (ISR) with conventional percutaneous transluminal coronary angioplasty (PTCA) causes significant recurrent neointimal tissue growth in 30-85%. Therefore, laser ablation of intrastent neointimal hyperplasia before balloon dilation can be an attractive alternative. However, the long-term outcomes of such treatment have not been studied thoroughly enough. This prospective case-control study evaluated angiographic and clinical outcomes of PTCA alone and a combination of excimer laser coronary angioplasty (ELCA) and adjunct PTCA in 125 patients with ISR. ELCA was performed before balloon dilation in 67 patients, PTCA alone was performed in 58 patients. Basic demographic and clinical data were comparable in both groups. Lesions included in ELCA group were longer (17.1+/-9.9 vs 13.6+/-9.1 mm; p = 0.034), more complex (36.5% type C stenoses vs 14.3%; p = 0.006), and more frequently had reduced distal blood flow (TIMI <3: 18.9% vs 4.8%; p = 0.025) compared to lesions in the PTCA group. Immediate angiographic results of PTCA and ELCA + PTCA appeared to be comparable. PTCA alone was successful in 57 patients (98.3%), ELCA + PTCA, in 66 patients (98.5%). The rates of hospital complications were comparable (3.0% in ELCA group vs 8.6% in PTCA group). The 1-year follow-up showed that the rates of major adverse cardiac events (MACE) were comparable in the 2 groups (37.3% in ELCA group vs 46.6% in PTCA group). The rates of target vessel revascularization (TVR) within 1 year after the intervention were also similar in the 2 groups (32.8% vs 34.5%). The data mean that ELCA in patients with complex ISR is efficient and safe. Despite a higher complexity of lesions in the ELCA group, no increase in the rate of complications was registered.     

Temporary hemodialysis catheters as a long-term vascular access in chronic hemodialysis patients

The objective was to review our experience with temporary, precurved, jugular catheters used for long-term vascular access in chronic hemodialysis patients. Thirty chronic hemodialysis patients, 14 men and 16 women, with an average age of 65.3 +/- 13.5 years (30-90 years), treated by dialysis for 1 month to 30 years (average +/- SD, 6.3 +/- 8.1 years), had single lumen, 'temporary' precurved non-tunneled jugular catheters placed into the right jugular vein as permanent vascular access, with 4% trisodium citrate as a locking solution and mupirocin at the exit site. Hemodialysis catheters were used for vascular access on average for 9.1 +/- 6.5 months, (1-22.7 months), and for a total of 271.7 months (8151 days). Average catheter functioning time was 3.1 +/- 1.9 months (0.5-10 months). The total number of side-effects was 55 (6.7/1000 catheter days), including 26 cases of thrombosis (3.2/1000 catheter days), 9 ruptures of the catheter (1.1/1000 catheter days), 15 catheter malfunctions (1.8/1000 catheter days), 2 exit site infections (0.2/1000 catheter days), 2 bacteremias (0.2/1000 catheter days), 1 avulsion of the catheter (0.1/1000 catheter days), and 2 catheters were removed because an AV fistula was successfully used. In 21 patients single-needle hemodialysis was performed, mean blood flow 251 +/- 16 mL/min (250-300), mean Kt/V 0.96 +/- 0.16 (0.72-1.27) and in 9 patients double-needle hemodialysis was performed (catheter and peripheral vein) with mean blood flow 252 +/- 14 mL/min (200-300), mean Kt/V 1.63 +/- 0.25 (1.21-1.96). 'Temporary' jugular single lumen non-tunneled hemodialysis catheters, with 4% citrate as locking solution and mupirocin ointment at the exit site provided good long-term vascular access with acceptable functioning time and low infection rate. The main reasons for catheter exchange or removal were malfunction and mechanical damage of the catheter.