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Purpose: Stress urinary incontinence (SUI) is a key factor for post-prostatectomy (RP) quality of life. Current international guidelines struggle to find the adequate place for each kind of surgeries. The aim of this systematic review and meta-analysis considering updated evidence is to assess the efficacy and safety of proACT in treating male patients with post-RP SUI. Methods: A review of the literature was performed by searching the PubMed database. We narrowed included studies with adult male patients with SUI; outcomes included pads or pad weight per day and quality of life (QOL) questionnaires, as well as safety outcomes. Results: 18 studies involving 1570 patients mean age of 68.8 (EC 2.1) were included. The mean follow-up reported was 34.7 months (EC 17.7; median 38.5; range 1–128 months). An average of 60.7% (EC 27) and 40.4% of patients suffered from mild-to-moderate and severe incontinence, respectively. The overall dryness rate was 55.1% (EC 19.3) while respecting the definition of 0–1 pads per day, and the mean dryness rate was 53% (EC 0.2). The mean overall complication rate was 31.2% (EC 18.3%), including an explantation rate of 26.5% (EC 15.3) and a reoperation rate of 22.7% (EC 8.7). The methodological quality of the 18 studies was very heterogeneous. Conclusion: Implantation of proACT adjustable balloons is a minimally invasive technique that provides medium outcomes (53%) with a strict definition of dryness (0–1 PPD) and important complication rate (31.2%). Past of irradiation is a negative predictive factor for incontinence. [ABSTRACT FROM AUTHOR]

Peritoneal metastasis is the leading cause of death for gastrointestinal cancers. The native and therapy-induced ascites ecosystems are not fully understood. Here, we characterize single-cell transcriptomes of 191,987 ascites cancer/immune cells from 35 patients with/without gastric cancer peritoneal metastasis (GCPM). During GCPM progression, an increase is seen of monocyte-like dendritic cells (DCs) that are pro-angiogenic with reduced antigen-presenting capacity and correlate with poor gastric cancer (GC) prognosis. We also describe the evolution of monocyte-like DCs and regulatory and proliferative T cells following therapy. Moreover, we track GC evolution, identifying high-plasticity GC clusters that exhibit a propensity to shift to a high-proliferative phenotype. Transitions occur via the recently described, autophagy-dependent plasticity program, paligenosis. Two autophagy-related genes (MARCKS and TXNIP) mark high-plasticity GC with poorer prognosis, and autophagy inhibitors induce apoptosis in patient-derived organoids. Our findings provide insights into the developmental trajectories of cancer/immune cells underlying GCPM progression and therapy resistance.Peritoneal metastasis is one of the most common forms of death for gastrointestinal cancers, however, its cell composition is incompletely understood. Here, the authors use single cell RNA-seq of peritoneal metastases from 35 patients and show diversity in immune cells, and plasticity in cancer cell phenotypes and autophagy related genes as biomarkers of prognosis. [ABSTRACT FROM AUTHOR]

Cardiovascular function is related to age, sex, and state of consciousness. We hypothesized that cardiovagal baroreflex sensitivity (BRS) demonstrates different patterns in both sexes before and after 50 years of age and that these patterns are associated with patterned changes during the sleep–wake cycle. We recruited 67 healthy participants (aged 20–79 years; 41 women) and divided them into four age groups: 20–29, 30–49, 50–69, and 70–79 years. All the participants underwent polysomnography and blood pressure measurements. For each participant, we used the average of the arterial pressure variability, heart rate variability (HRV), and BRS parameters during the sleep–wake stages. BRS and HRV parameters were significantly negatively correlated with age. The BRS indexes were significantly lower in the participants aged ≥ 50 years than in those aged < 50 years, and these age-related declines were more apparent during non-rapid eye movement sleep than during wakefulness. Only BRS demonstrated a significantly negative correlation with age in participants ≥ 50 years old. Women exhibited a stronger association than men between BRS and age and an earlier decline in BRS. Changes in BRS varied with age, sex, and consciousness state, each demonstrating a specific pattern. The age of 50 years appeared to be a crucial turning point for sexual dimorphism in BRS. Baroreflex modulation of the cardiovascular system during sleep sensitively delineated the age- and sex-dependent BRS patterns, highlighting the clinical importance of our results. Our findings may aid in screening for neurocardiac abnormalities in apparently healthy individuals. [ABSTRACT FROM AUTHOR]

Dimethyl sulfoxide (DMSO) is a highly utilized small molecule that serves many purposes in scientific research. DMSO offers unique polar, aprotic and amphiphilic features, which makes it an ideal solvent for a wide variety of both polar and nonpolar molecules. Furthermore, DMSO is often used as a cryoprotectant in cell-based research. However, recent reports suggest that DMSO, even at low concentration, might interfere with important cellular processes, and cause macromolecular changes to proteins where a shift from α-helical to β-sheet structure can be observed. To investigate how DMSO might influence current research, we assessed biochemical and cellular impacts of DMSO treatment on the structure of the aggregation-prone protein α-synuclein, which plays a central role in the etiology of Parkinson's disease, and other brain-related disorders, collectively termed the synucleinopathies. Here, we found that addition of DMSO increased the particle-size of α-synuclein, and accelerated the formation of seeding-potent fibrils in a dose-dependent manner. These fibrils made in the presence of DMSO were indistinguishable from fibrils made in pure PBS, when assessed by proteolytic digestion, cytotoxic profile and their ability to seed cellular aggregation of α-synuclein. Moreover, as evident through binding to the MJFR-14-6-4-2 antibody, which preferentially recognizes aggregated forms of α-synuclein, and a bimolecular fluorescence complementation assay, cells exposed to DMSO experienced increased aggregation of α-synuclein. However, no observable α-synuclein abnormalities nor differences in neuronal survival were detected after oral DMSO-treatment in either C57BL/6- or α-synuclein transgenic F28 mice. In summary, we demonstrate that low concentrations of DMSO makes α-synuclein susceptible to undergo aggregation both in vitro and in cells. This may affect experimental outcomes when studying α-synuclein in the presence of DMSO, and should call for careful consideration when such experiments are planned. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) and Alzheimer's disease (AD) are characterized by pathological accumulation and aggregation of different amyloidogenic proteins, α-synuclein (aSyn) in PD, and amyloid-β (Aβ) and Tau in AD. Strikingly, few PD and AD patients' brains exhibit pure pathology with most cases presenting mixed types of protein deposits in the brain. Bimolecular fluorescence complementation (BiFC) is a technique based on the complementation of two halves of a fluorescent protein, which allows direct visualization of protein–protein interactions. In the present study, we assessed the ability of aSyn and Tau to interact with each other. For in vitro evaluation, HEK293 and human neuroblastoma cells were used, while in vivo studies were performed by AAV6 injection in the substantia nigra pars compacta (SNpc) of mice and rats. We observed that the co-expression of aSyn and Tau led to the emergence of fluorescence, reflecting the interaction of the proteins in cell lines, as well as in mouse and rat SNpc. Thus, our data indicates that aSyn and Tau are able to interact with each other in a biologically relevant context, and that the BiFC assay is an effective tool for studying aSyn-Tau interactions in vitro and in different rodent models in vivo. [ABSTRACT FROM AUTHOR]

A letter to the editor of the European Spine Journal raises questions about a study conducted by Stewart et al. on the benefits of adding bilateral erector spinae plane blocks (ESPBs) to postoperative pain management after open lumbar laminectomy. The letter highlights concerns about the methodology and results of the study, including the use of standardized anesthetic and analgesic management, the assessment of postoperative pain levels, the achievement of pain control goals, and discrepancies in the reported results. The authors of the letter request clarification and responses from the original study authors. [Extracted from the article]

The pathological hallmark of Parkinson's disease (PD) is the formation of Lewy bodies containing aggregated alpha-synuclein (α-syn). Although PD is associated with these distinct histological changes, other pathological features such as microvascular alterations have been linked to neurodegeneration. These changes need to be investigated as they create a hostile brain microenvironment and may contribute to the development and progression of the disease. We use a human α-syn overexpression mouse model that recapitulates some of the pathological features of PD in terms of progressive aggregation of human α-syn, impaired striatal dopamine fiber density, and an age-dependent motor deficit consistent with an impaired dopamine release. We demonstrate for the first time in this model a compromised blood–brain barrier integrity and dynamic changes in vessel morphology from angiogenesis at earlier stages to vascular regression at later stages. The vascular alterations are accompanied by a pathological activation of pericytes already at an early stage without changing overall pericyte density. Our data support and further extend the occurrence of vascular pathology as an important pathophysiological aspect in PD. The model used provides a powerful tool to investigate disease-modifying factors in PD in a temporal sequence that might guide the development of new treatments. [ABSTRACT FROM AUTHOR]

α-Synucleinopathies are characterized by autonomic dysfunction and motor impairments. In the pure autonomic failure (PAF), α-synuclein (α-Syn) pathology is confined within the autonomic nervous system with no motor features, but mouse models recapitulating PAF without motor dysfunction are lacking. Here, we show that in TgM83+/− mice, inoculation of α-Syn preformed fibrils (PFFs) into the stellate and celiac ganglia induces spreading of α-Syn pathology only through the autonomic pathway to both the central nervous system (CNS) and the autonomic innervation of peripheral organs bidirectionally. In parallel, the mice develop autonomic dysfunction, featured by orthostatic hypotension, constipation, hypohidrosis and hyposmia, without motor dysfunction. Thus, we have generated a mouse model of pure autonomic dysfunction caused by α-Syn pathology. This model may help define the mechanistic link between transmission of pathological α-Syn and the cardinal features of autonomic dysfunction in α-synucleinopathy. Autonomic dysfunction is a feature of some α-synucleinopathies, but there are no models of pure autonomic dysfunction associated with α-synuclein. Here the authors describe a mouse model of pure autonomic dysfunction without motor dysfunciton by injection of pre-formed fibrils of α-synuclein to the stellate and celiac ganglia. [ABSTRACT FROM AUTHOR]

Background: Neoadjuvant therapy (NAT) before radical excision has become the preferred initial option for locally advanced digestive cancers such as esophageal cancer (EC), esophagogastric junction adenocarcinoma (EGJAC), gastric adenocarcinoma (GAC), rectal cancer (RC), and pancreatic cancer (PC). Although some patients reportedly achieve a pathologic complete response (pCR) after neoadjuvant therapy, the published data are inconsistent regarding whether pCR yields a survival benefit. The current meta-analysis was performed to assess the potential prognostic value of pCR after preoperative therapy for patients with digestive cancers. Methods: An extensive electronic search in PubMed, Web of Science, and the Cochrane Library was performed for relevant articles, from which data relative to independent correlations of pCR with overall survival (OS) and disease-free survival (DFS) were extracted for analysis. A random-effects model was used to calculate the pooled hazard ratios (HRs) with their corresponding 95% confidence intervals (CIs). Results: The study identified 6780 patients who met the inclusion and exclusion criteria. The results showed that pCR was significantly correlated with better OS (HR, 0.50; 95% CI, 0.43–0.58; P < 0.001) and DFS (HR, 0.49; 95% CI, 0.40–0.60; P < 0.001) for the digestive cancer patients who achieved pCR than for those who did not achieve pCR. Subgroup analysis showed that the correlation of pCR with OS was significant in EC (HR, 0.57; 95% CI, 0.47–0.69; P < 0.001), EGJAC/GAC (HR, 0.38; 95% CI, 0.17–0.86; P = 0.02), RC (HR, 0.48; 95% CI, 0.28–0.81; P = 0.006), and PC (HR, 0.41; 95% CI, 0.17–0.97; P = 0.04). In addition, the survival benefit for pCR patients was of similar magnitude, irrespective of the type of study, type of NAT, or ethnicity. Conclusions: A pCR is correlated with favorable survival outcomes compared with a non-pCR for digestive cancer patients after NAT. [ABSTRACT FROM AUTHOR]

The purpose of this observational study was to investigate the feasibility, initial safety, and efficacy of the SeQuent® Please DCB (B. Braun Melsungen, Germany) for patients with de novo coronary lesions in vessels exceeding 3.0 mm in a consecutive series of all comer percutaneous coronary intervention. A total of 120 patients (135 lesions) with de novo coronary lesions in vessels ≥ 3.0 mm treated with DCB were enrolled in this single-centre prospective observational study. The primary endpoint was target lesion failure (TLF), a composite endpoint of cardiac death, target vessel-myocardial infarction (TV-MI), and clinically driven target vessel revascularization (TLR) at 12 months. Safety endpoints included cardiac death, TV-MI, and definite target vessel thrombosis. 45.9% of the lesions were classified as complex (type B2/C). The reference vessel diameter was 3.09 ± 0.31 mm measured via quantitative coronary angiography analysis. Coronary dissections occurred in 42 patients (35.0%; Type A-B 14.1%; Type C 19.1%; Type D: 1.6%), two of which [1.6%; (type D dissection)] underwent bail-out stent implantation. 12-month follow-up was completed in 100% patients. The 12-month incidence of TLF was 3.4%. The clinically driven TLR occurred in four patients (3.4%). The incidence of TLR was low in patients without any detectable dissections, similar to those with dissections (3.8% vs. 2.5%; p = 0.146). No patient suffered cardiac death, TV-MI, or target vessel thrombosis. The study shows the feasibility, initial safety, and efficacy of coronary intervention using SeQuent® Please DCB for the treatment of patients with de novo lesion in vessels exceeding 3 mm. The study highlights that the coronary dissection (Type A-C) post DCB treatment occurs frequently but is safe at follow up. [ABSTRACT FROM AUTHOR]

The enteric nervous system (ENS) controls the function of the gastrointestinal tract and has been implicated in various diseases, including Parkinson's disease (PD). PD is a neurodegenerative disease with Lewy bodies (LBs) and Lewy neurites (LNs) as the main pathological features. In addition to the typical motor symptoms in PD, attention has been drawn to non-motor symptoms, such as constipation, implying dysfunction of the ENS. In the present study, we characterized the age-dependent morphological alterations and aggregation of α-synuclein (α-syn), the primary protein component in LBs and LNs, in the ENS in an α-syn transgenic mouse model. We found that the expression and accumulation of α-syn increased gradually in neurons of Meissner's and Auerbach's plexuses of the gastrointestinal tract with age (from 1 week to 2 years). In addition, α-syn was increasingly phosphorylated at the serine 129 residue, reflecting pathological alterations of the protein over time. Furthermore, α-syn was present in different subtypes of neurons expressing vasoactive intestinal polypeptide, neuronal nitric oxide synthase, or calretinin. The results indicated that BAC-α-Syn-GFP transgenic mice provide a unique model in which to study the relationship between ENS and PD pathogenesis. [ABSTRACT FROM AUTHOR]

Purpose: The frequency of breathing influences the spectral powers of heart rate variability (HRV) as well as the magnitudes of heart rate deceleration capacity (DC) and acceleration capacity (AC). We compared the strength of their relationships under different breathing frequencies.Methods: We studied 14 healthy young adults who breathed spontaneously and controlled their breathing rates to 0.1, 0.2, 0.3 and 0.4 Hz in a supine position. A 5-min R-R interval time series without movement artefacts or ectopic beats was obtained for each study period. Spectral indices were defined as the square roots of spectral powers in the very low frequency (0.01-0.04 Hz), low frequency (0.04-0.15 Hz), high frequency (0.15-0.4 Hz) and respiratory frequency bands. We also combined these frequency bands into LHF (0.04-0.4 Hz) and VLHF (0.01-0.4 Hz). DC and AC were obtained using phase rectified signal averaging.Results: DC and AC were significantly correlated with all indices of HRV. The within-subject correlation coefficients for the LHF index had the greatest absolute values (0.953 and -0.919, respectively). DC and AC had different strength of relationships with the LHF index, but became comparable (0.954 vs. -0.943) when the data obtained under 0.1-Hz breathing were excluded.Conclusion: DC is strongly correlated with the spectral index of the LHF band, indicating that they are controlled by similar influences under the conditions used in this study. AC is less related to the LHF index due to the fact that its magnitude deceases during 0.1-Hz breathing. [ABSTRACT FROM AUTHOR]

We hypothesize that the time when age-related changes in autonomic functioning and in sleep structure occur are different and that autonomic functioning modulates sleep architecture differently before and after 50 years of age. Sixty-eight healthy subjects (aged 20 to 79 years old, 49 of them women) were enrolled. Correlation analysis revealed that wake after sleep onset, the absolute and relative value of stage 1 (S1; S1%), and relative value of stage 2 (S2) were positively correlated with age; however, sleep efficiency, stage 3 (S3), S3%, and rapid-eye-movement latency (REML) were negatively correlated with age. Significant degenerations of sleep during normal aging were occurred after 50 years of age; however, significant declines of autonomic activity were showed before 50 years of age. Before 50 years of age, vagal function during sleep was negatively correlated with arousal index; however, after 50 years of age, it was positively correlated with S1 and S1%. In addition, sympathetic activity during wake stage was positively related to S2% only after 50 years of age. Our results imply that the age-related changes in autonomic functioning decline promptly as individuals leave the younger part of their adult life span and that age-related changes in sleep slowly develop as individuals enter the older part of their adult life span. Furthermore, while various aspects of sleep architecture are modulated by both the sympathetic and vagal nervous systems during adult life span, the sleep quality is mainly correlated with the sympathetic division after 50 years of age. [ABSTRACT FROM AUTHOR]

The cellular hallmarks of Parkinson's disease (PD) are the loss of nigral dopaminergic neurons and the formation of α-synuclein-enriched Lewy bodies and Lewy neurites in the remaining neurons. Based on the topographic distribution of Lewy bodies established after autopsy of brains from PD patients, Braak and coworkers hypothesized that Lewy pathology primes in the enteric nervous system and spreads to the brain, suggesting an active retrograde transport of α-synuclein (the key protein component in Lewy bodies), via the vagal nerve. This hypothesis, however, has not been tested experimentally thus far. Here, we use a human PD brain lysate containing different forms of α-synuclein (monomeric, oligomeric and fibrillar), and recombinant α-synuclein in an in vivo animal model to test this hypothesis. We demonstrate that α-synuclein present in the human PD brain lysate and distinct recombinant α-synuclein forms are transported via the vagal nerve and reach the dorsal motor nucleus of the vagus in the brainstem in a time-dependent manner after injection into the intestinal wall. Using live cell imaging in a differentiated neuroblastoma cell line, we determine that both slow and fast components of axonal transport are involved in the transport of aggregated α-synuclein. In conclusion, we here provide the first experimental evidence that different α-synuclein forms can propagate from the gut to the brain, and that microtubule-associated transport is involved in the translocation of aggregated α-synuclein in neurons. [ABSTRACT FROM AUTHOR]

Summary: Huntington''s disease (HD) is a genetic neurodegenerative disorder. Since identification of the disease-causing gene in 1993, a number of genetically modified animal models of HD have been generated. The first transgenic mouse models, R6/1 and R6/2 lines, were established 8 years ago. The R6/2 mice have been the best characterized and the most widely used model to study pathogenesis of HD and therapeutic interventions. In the present review, we especially focus on the characteristics of R6 transgenic mouse models and, in greater detail, describe the different therapeutic strategies that have been tested in these mice. We also, at the end, critically assess the relevance of the HD mouse models compared with the human disease and discuss how they can be best used in the future. [Copyright &y& Elsevier]

A major neuropathological feature of Parkinson’s disease (PD) is the loss of nigrostriatal dopaminergic neuron. Patients exhibit motor symptoms, including bradykinesia, rigidity, and tremor. Neural grafting has been reported to restore striatial dopaminergic neurotransmission and induce symptomatic relief. The major limitation of cell replacement therapy for PD is the shortage of suitable donor tissue. The present review describes the possible sources of cells, including embryonic stem cells and somatic adult stem cells, both of which potentially could be used in cell therapy for PD, and discusses the advantages and disadvantages of each cell type. [ABSTRACT FROM AUTHOR]

This 'minireview' describes experiments in short term crush operated rat nerves, to study endogenous substances in anterograde and retrograde fast axonal transport. Immunofluorescence was used to recognize transported antigens, and cytofluorimetric scanning was employed to quantitate different antigens which had accumulated proximal and distal to the crushes. Vesicle membrane components p38 (synaptophysin) and SV2 accumulated on both sides of a crush. This was expected from a number of studies from different laboratories. Surface associated molecules, however, like synapsins and rab3a, have been studied by other groups with biochemical methods, and suggested to be transported with slow transport. The crush method, however, revealed that a considerable fraction of these two substances are transported with the fast transport system, and, thus, associated with fast transported organelles in the living neuron. Evidently, more than one technique is required to give a more complete picture of intraneuronal transport related events. [ABSTRACT FROM AUTHOR]

The present minireview describes experiments carried out, in short-term crush-operated rat nerves, using immunofluorescence and cytofluorimetric scanning techniques to study endogenous substances in anterograde and retrograde fast axonal transport. Vesicle membrane components p38 (synaptophysin) and SV2 are accumulating on both sides of a crush, but a larger proportion of p38 (about 3/4) than of SV2 (about 1/2) is recycling toward the cell body, compared to the amount carried with anterograde transport. Matrix peptides, such as CGRP, ChrA, VIP, and DBH are recycling to a minor degree, although only 10-20% of surface-associated molecules, such as synapsins and kinesin, appear to recycle. The described methodological approach to study the composition of organelles in fast axonal transport, anterograde as compared to retrograde, is shown to be useful for investigating neurobiological processes. We make use of the 'in vivo chromatography' process that the fast axonal transport system constitutes. Only substances that are in some way either stored in, or associated with, transported organelles can be clearly observed to accumulate relative to the crush region. Emphasis in this paper was given to the synapsins, because of diverging results published concerning the degree of affiliation with various neuronal organelles. Our previously published results have indicated that in the living axons the SYN I is affiliated with mainly anterogradely fast transported organelles. Therefore, some preliminary, previously unpublished results on the accumulations of the four different synapsins (SYN Ia, SYN Ib, SYN IIa, and SYN IIb), using antisera specific for each of the four members of the synapsin family, are described. It was found that SYN Ib clearly has a stronger affiliation to anterogradely transported organelles than SYN Ia, and that both SYN IIa and SYN IIb are bound to some degree to transported organelles. [ABSTRACT FROM AUTHOR]

A hallmark of Parkinson's disease is the formation of large protein-rich aggregates in neurons, where α-synuclein is the most abundant protein. A standard approach to visualize aggregation is to fluorescently label the proteins of interest. Then, highly fluorescent regions are assumed to contain aggregated proteins. However, fluorescence brightness alone cannot discriminate micrometer-sized regions with high expression of non-aggregated proteins from regions where the proteins are aggregated on the molecular scale. Here, we demonstrate that 2-dimensional polarization imaging can discriminate between preformed non-aggregated and aggregated forms of α-synuclein, and detect increased aggregation in brain tissues of transgenic mice. This imaging method assesses homo-FRET between labels by measuring fluorescence polarization in excitation and emission simultaneously, which translates into higher contrast than fluorescence anisotropy imaging. Exploring earlier aggregation states of α-synuclein using such technically simple imaging method could lead to crucial improvements in our understanding of α-synuclein-mediated pathology in Parkinson's Disease. Camacho et al. show detection of non-aggregated and aggregated α-synuclein in brain tissue from a mouse model of Parkinson's disease using 2-dimensional polarization imaging. This fluorescence imaging method will allow for early detection of pathogenic α-synuclein aggregates associated with neurodegenerative illnesses. [ABSTRACT FROM AUTHOR]

By simultaneous coherent anti-Stokes Raman scattering (CARS) and 2-photon fluorescence microscopy of Thioflavin-S stained Alzheimer´s diseased human brain tissues, we show evidence of lipid deposits co-localizing with fibrillar β-amyloid (Aβ) plaques. Two lipid morphologies can be observed; lamellar structures and coalescing macro-aggregates of sub-micron sizes to ~25 μm. No significant lipid deposits were observed in non-fibrillar, diffuse plaques identified by Aβ immuno-staining. CARS microscopy of unlabeled samples confirms the lamellar and macro-aggregate lipid morphologies. The composition of the plaques was analyzed by CARS microspectroscopy and Raman microscopy; vibrational signatures of lipids with long acyl chains co-localize with the β-sheet vibrations. The lipid fluidity was evaluated from the CARS spectra, illustrating that the lipid composition/organization varies throughout the plaques. Altogether this indicates close amyloid-lipid interplay in fibrillar Aβ plaques, rendering them more dynamic compositions than previously believed and, hence, potential sources of toxic oligomers. [ABSTRACT FROM AUTHOR]