bluuebunny/crossref_metadata_2025 huggingface dataset:
Anti-Inflammatory and Healing Activity of the Hydroalcoholic Fruit Extract of Solanum diploconos (Mart.) Bohs
Authors: Benvenutti Larissa , Nunes Roberta , Venturi Ivonilce , Ramos Silvia Aparecida , Broering Milena Fronza , Goldoni Fernanda Capitanio , Pavan Sarah Eskelsen , Pastor Maria Verônica Dávila , Malheiros Angela , Quintão Nara Lins Meira , Fernandes Elizabeth Soares , Santin José Roberto
Published: July 2021

Background. Solanum diploconos (Mart.) Bohs is a native Brazilian plant belonging to the Solanaceae family, popularly known as “tomatinho do mato” and poorly investigated. Herein, we presented for the first time evidence for the anti-inflammatory and wound healing activities of S. diploconos fruit hydroalcoholic extract. Material and Methods. In vitro fMLP-induced chemotaxis, LPS-induced inflammatory mediator levels (cytokines by ELISA and NO release by Griess reaction), and adhesion molecule expression (CD62L, CD49d, and CD18, by flow-cytometry) were assessed in neutrophils treated with different concentrations of the extract. Inflammation resolution was measured by the efferocytosis assay and the healing activity by in vivo and in vitro assays. The air pouch model of carrageenan-induced inflammation in Swiss mice was used to investigate the in vivo anti-inflammatory effects of the extract. Leukocyte influx (by optical microscopy) and cytokine release were quantified in the pouch exudates. Additionally, the acute and subacute toxic and genotoxic effects of the extract were evaluated. Results. In vitro, the extract impaired neutrophil chemotaxis and its ability to produce and/or release cytokines (TNFα, IL-1β, and IL-6) and NO upon LPS stimuli (p<0.01). LPS-treated neutrophils incubated with the extract presented increased CD62L expression (p<0.01), indicating a reduced activation. An enhanced efferocytosis of apoptotic neutrophils by macrophages was observed and accompanied by higher IL-10 and decreased TNFα secretion (p<0.01). In vivo, similar results were noted, including reduction of neutrophil migration, protein exudation, and cytokine release (p<0.01). Also, the extract increased fibroblast proliferation and promoted skin wound healing (p<0.01). No signs of toxicity or genotoxicity were observed for the extract. Conclusion. S. diploconos fruit extract is anti-inflammatory by modulating neutrophil migration/activation as well macrophage-dependent efferocytosis and inflammatory mediator release. It also indicates its potential use as a healing agent. Finally, the absence of acute toxic and genotoxic effects reinforces its possible use as medicinal product.
Cerebral Venous Sinus Thrombosis due to Iron Deficiency Anemia in an Adolescent Girl
Authors: Matlik Hussein N. , Sagar Nivargi
Published: July 2021

Cerebral venous sinus thrombosis (CVST) is rare but now increasingly diagnosed in children. Early diagnosis is of prime importance as any delay leads to significant mortality and morbidity. It requires a high index of suspicion to diagnose CVST early as, often, the symptoms are vague and the signs are nonspecific. Varieties of aetiologies are described for generation of cerebral venous sinus thrombus. Iron deficiency anemia is one of the most important preventable causes of CVST. The most proposed mechanism in development of CVST in iron deficiency is secondary thrombocytosis. However, we describe a case of CVST due to iron deficiency in the absence of thrombocytosis.
A View on Polymerase Chain Reaction as an Outstanding Molecular Diagnostic Technique in Periodontology
Authors: Shirmohammadi Adileh , Babaloo Amirreza , Maleki Dizaj Solmaz , Lotfipour Farzaneh , Sharifi Simin , Ghavimi Mohammad Ali , Khezri Khadijeh
Published: July 2021

Objectives. This study presents a discussion on the fundamentals of polymerase chain reaction (PCR) and its use as a diagnostic tool in periodontology. Materials and Methods. A computer‐aided as well as hand‐made search in PubMed and Scopus indexed journals (relevant to the topic) was done by keywords of molecular technique in periodontology, PCR, applications of PCR, and PCR in periodontics. Only the papers in the English language and outlining PCR and its association with periodontology were collected and utilized to provide a succinct review. There was no limitation for publication time. Results. The results of our search showed that PCR has turned into a standard in diagnosis in the field of periodontology. A variety of researches has demonstrated that its sensitive, and specific characteristics make it a quick and effective technique of recognition, identification, and quantification of microorganisms. Identification of various immunoinflammatory markers at the mRNA expression level as well as ascertaining gene‐related polymorphisms can also be performed. Conclusions. The mechanisms of periodontal disease can further become clarified using PCR. Clinical Relevance. PCR as a diagnostic method can play a main part in the validation of the clinical diagnosis of periodontal disease indicating the reason, pathogenesis, clinical steps, progress, and prognosis of the disease.
TP53 Mutations with Low Variant Allele Frequency Predict Short Survival in Chronic Lymphocytic Leukemia
Authors: Bomben Riccardo , Rossi Francesca Maria , Vit Filippo , Bittolo Tamara , D'Agaro Tiziana , Zucchetto Antonella , Tissino Erika , Pozzo Federico , Vendramini Elena , Degan Massimo , Zaina Eva , Cattarossi Ilaria , Varaschin Paola , Nanni Paola , Berton Michele , Braida Alessandra , Polesel Jerry , Cohen Jared A. , Santinelli Enrico , Biagi Annalisa , Gentile Massimo , Morabito Fortunato , Fronza Gilberto , Pozzato Gabriele , D'Arena Giovanni , Olivieri Jacopo , Bulian Pietro , Pepper Chris , Hockaday Anna , Schuh Anna , Hillmen Peter , Rossi Davide , Chiarenza Annalisa , Zaja Francesco , Di Raimondo Francesco , Del Poeta Giovanni , Gattei Valter
Published: July 2021

Purpose:

In chronic lymphocytic leukemia (CLL), TP53 mutations are associated with reduced survival and resistance to standard chemoimmunotherapy (CIT). Nevertheless, the clinical impact of subclonal TP53 mutations below 10% to 15% variant allele frequency (VAF) remains unclear.

Experimental Design:

Using a training/validation approach, we retrospectively analyzed the clinical and biological features of TP53 mutations above (high-VAF) or below (low-VAF) the previously reported 10.0% VAF threshold, as determined by deep next-generation sequencing. Clinical impact of low-VAF TP53 mutations was also confirmed in a cohort (n = 251) of CLL treated with fludarabine-cyclophosphamide-rituximab (FCR) or FCR-like regimens from two UK trials.

Results:

In the training cohort, 97 of 684 patients bore 152 TP53 mutations, while in the validation cohort, 71 of 536 patients had 109 TP53 mutations. In both cohorts, patients with the TP53 mutation experienced significantly shorter overall survival (OS) than TP53 wild-type patients, regardless of the TP53 mutation VAF. By combining TP53 mutation and 17p13.1 deletion (del17p) data in the total cohort (n = 1,220), 113 cases were TP53 mutated only (73/113 with low-VAF mutations), 55 del17p/TP53 mutated (3/55 with low-VAF mutations), 20 del17p only, and 1,032 (84.6%) TP53 wild-type. A model including low-VAF cases outperformed the canonical model, which considered only high-VAF cases (c-indices 0.643 vs. 0.603, P < 0.0001), and improved the prognostic risk stratification of CLL International Prognostic Index. Clinical results were confirmed in CIT-treated cases (n = 552) from the retrospective cohort, and the UK trials cohort.

Conclusions:

TP53 mutations affected OS regardless of VAF. This finding can be used to update the definition of TP53 mutated CLL for clinical purposes.
Improving Risk Stratification for Pediatric Patients with Rhabdomyosarcoma by Molecular Detection of Disseminated Disease
Authors: Lak Nathalie S.M. , Voormanns Timon L. , Zappeij-Kannegieter Lily , van Zogchel Lieke M.J. , Fiocco Marta , van Noesel Max M. , Merks Johannes H.M. , van der Schoot C. Ellen , Tytgat Godelieve A.M. , Stutterheim Janine
Published: July 2021

Purpose:

Survival of children with rhabdomyosarcoma that suffer from recurrent or progressive disease is poor. Identifying these patients upfront remains challenging, indicating a need for improvement of risk stratification. Detection of tumor-derived mRNA in bone marrow (BM) and peripheral blood (PB) using reverse-transcriptase qPCR (RT-qPCR) is a more sensitive method to detect disseminated disease. We identified a panel of genes to optimize risk stratification by RT-qPCR.

Experimental Design:

Candidate genes were selected using gene expression data from rhabdomyosarcoma and healthy hematologic tissues, and a multiplexed RT-qPCR was developed. Significance of molecular disease was determined in a cohort of 99 Dutch patients with rhabdomyosarcoma (72 localized and 27 metastasized) treated according to the European pediatric Soft tissue sarcoma Study Group (EpSSG) RMS2005 protocol.

Results:

We identified the following 11 rhabdomyosarcoma markers: ZIC1, ACTC1, MEGF10, PDLIM3, SNAI2, CDH11, TMEM47, MYOD1, MYOG, and PAX3/7-FOXO1. RT-qPCR was performed for this 11-marker panel on BM and PB samples from the patient cohort. Five-year event-free survival (EFS) was 35.5% [95% confidence interval (CI), 17.5%–53.5%] for the 33/99 RNA-positive patients, versus 88.0% (95% CI, 78.9%–97.2%) for the 66/99 RNA-negative patients (P < 0.0001). Five-year overall survival (OS) was 54.8% (95% CI, 36.2%–73.4%) and 93.7% (95% CI, 86.6%–100.0%), respectively (P < 0.0001). RNA panel positivity was negatively associated with EFS (Hazard Ratio = 9.52; 95% CI, 3.23–28.02), whereas the RMS2005 risk group stratification was not, in the multivariate Cox regression model.

Conclusions:

This study shows a strong association between PCR-based detection of disseminated disease at diagnosis with clinical outcome in pediatric patients with rhabdomyosarcoma, also compared with conventional risk stratification. This warrants further validation in prospective trials as additional technique for risk stratification.
Bidirectional Regulatory Cross-Talk between Cell Context and Genomic Aberrations Shapes Breast Tumorigenesis
Authors: Kumar Brijesh , Bhat-Nakshatri Poornima , Maguire Calli , Jacobsen Max , Temm Constance J. , Sandusky George , Nakshatri Harikrishna
Published: July 2021

Breast cancers are classified into five intrinsic subtypes and 10 integrative clusters based on gene expression patterns and genomic aberrations, respectively. Although the cell-of-origin, adaptive plasticity, and genomic aberrations shape dynamic transcriptomic landscape during cancer progression, how interplay between these three core elements governs obligatory steps for a productive cancer progression is unknown. Here, we used genetic ancestry-mapped immortalized breast epithelial cell lines generated from breast biopsies of healthy women that share gene expression profiles of luminal A, normal-like, and basal-like intrinsic subtypes of breast cancers and breast cancer relevant oncogenes to develop breast cancer progression model. Using flow cytometry, mammosphere growth, signaling pathway, DNA damage response, and in vivo tumorigenicity assays, we provide evidence that establishes cell context–dependent effects of oncogenes in conferring plasticity, self-renewal/differentiation, intratumor heterogeneity, and metastatic properties. In contrast, oncogenic aberrations, independent of cell context, shaped response to DNA damage-inducing agents. Collectively, this study reveals how the same set of genomic aberration can have distinct effects on tumor characteristics based on cell-of-origin of tumor and highlights the need to utilize multiple “normal” epithelial cell types to decipher oncogenic properties of a gene of interest. In addition, by creating multiple isogenic cell lines ranging from primary cells to metastatic variants, we provide resources to elucidate cell-intrinsic properties and cell-oncogene interactions at various stages of cancer progression.

Implications:

Our findings demonstrate that how an interplay between the normal cell type that encountered genomic aberrations and type of genomic aberration influences heterogeneity, self-renewal/differentiation, and tumor properties including propensity for metastasis.
In vitro Immunomodulatory Effects of Human Umbilical Cord-Derived Mesenchymal Stem Cells on Peripheral Blood Cells from Warm Autoimmune Hemolytic Anemia Patients
Authors: Ma Chunya , Feng Yannan , Yang Lu , Wang Shufang , Sun Xiaolin , Tai Shengfei , Guan Xiaozhen , Wang Deqing , Yu Yang
Published: July 2021

Introduction: Autoimmune hemolytic anemia is a potentially lethal disease characterized by autoimmune hemolysis. Although human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been reported as a promising therapy, there is limited evidence regarding warm autoimmune hemolytic anemia (wAIHA) patients. This study aimed to investigate the potential therapeutic effects of hUC-MSCs via immune regulation in wAIHA patients. Methods: Peripheral blood mononuclear cells (PBMCs) from 10 wAIHA patients and 8 healthy controls were isolated from peripheral blood and cultured for 3 days with or without the presence of hUC-MSCs; PBMCs were co-cultured with hUC-MSCs using Transwell assays. The supernatant cytokine levels were measured after culture through AimPlex Multiple Immunoassays for Flow, including IL-2, IL-4, IL-10, IFN-γ, TNF-α, and IL-17A. The percentages of regulatory T cells, regulatory B cells, and Th1/Th2 in PBMCs were also assessed before and after culturing. Results: In the wAIHA group, hUC-MSCs could upregulate the Treg and Breg proportions after culturing for 3 days, and the Treg and Breg percentages increased after co-culturing with hUC-MSCs in the wAIHA group compared with PBMC cultured alone for 3 days (8.29 ± 8.59 vs. 6.82 ± 1.32, 3.82 ± 1.87 vs. 1.75 ± 1.20, respectively). Compared with the PBMC wAIHA group, the levels of TNF-α (2.13 ± 2.07 vs. 16.20 ± 21.13 pg/mL, p = 0.019) and IL-10 (10.51 ± 18.42 vs. 37.78 ± 44.20 pg/mL, p = 0.012) were significantly elevated in the PBMC + hUC-MSCs wAIHA group. Conclusion: The hUC-MSCs contributed to the increasing proportion of regulatory cell populations in PBMCs of wAIHA patients, thereby potentially regulating autoimmune response; thus, hUC-MSCs may be a promising approach for wAIHA treatment.
Urrets-Zavalia Syndrome Following Cataract Surgery
Authors: Kurtz Shimon , Fradkin Maayan
Published: July 2021

We describe a case of Urrets-Zavalia syndrome (UZS) in a healthy 56-year-old woman who underwent femtosecond-assisted phacoemulsification with intraocular lens implantation in both eyes. One month after an uneventful postoperative course in the left eye, the right eye was operated. Dilated pupil which was nonreactive to light appeared on day 21 postoperatively. This was discovered upon examination following anterior chamber inflammatory reaction which occurred 2 weeks following her surgery. Our case report emphasizes the importance and danger in developing UZS even if the reaction in the anterior chamber does not occur immediately after surgery. In addition, the importance of intraocular pressure follow-up in the period after UZS is acknowledged.
Metabolism and Sex Differentiation in Animals from a Starvation Perspective
Authors: Sakae Yuta , Tanaka Minoru
Published: July 2021

Animals determine their sex genetically (GSD: genetic sex determination) and/or environmentally (ESD: environmental sex determination). Medaka (Oryzias latipes) employ a XX/XY GSD system, however, they display female-to-male sex reversal in response to various environmental changes such as temperature, hypoxia, and green light. Interestingly, we found that 5 days of starvation during sex differentiation caused female-to-male sex reversal. In this situation, the metabolism of pantothenate and fatty acid synthesis plays an important role in sex reversal. Metabolism is associated with other biological factors such as germ cells, HPG axis, lipids, and epigenetics, and supplys substances and acts as signal transducers. In this review, we discuss the importance of metabolism during sex differentiation and how metabolism contributes to sex differentiation.
Partial Trisomy 13q/Monosomy 3p Resulting from a Paternal Reciprocal 3p;13q Translocation in a Boy with Facial Dysmorphism and Hypertrophic Cardiomyopathy
Authors: Martin-de Saro Monica , Compean Zyndia , Aguilar Karina , González-Huerta Luz María , Plaza-Benhumea Lautaro , Messina-Baas Olga , Cuevas-Covarrubiass Sergio Alberto
Published: July 2021

Individuals with 3p deletion show a great clinical variability. Apparently, a 1.5-Mb terminal deletion, including the CRBN and CNTN4 genes, is sufficient to cause this syndrome. Partial trisomy 13q is a rare chromosomal abnormality with a variable phenotypic expression, but in most cases, patients have a phenotype resembling complete trisomy 13. The aim of the present study is to describe a 9-month-old Mexican male patient with 3p deletion/13q duplication and a novel clinical finding. He presented with facial dysmorphism and multiple congenital alterations. Echocardiogram revealed cardiac insufficiency with hypertrophic cardiomyopathy and pulmonary hypertension, not previously reported. Karyotype from the patient and his father were 46,XY,add(3)(p26) and 46,XY,t(3;13), respectively. Microarray assay of the proband exhibited an approximately 2.6-Mb loss at terminal 3p26.3 and a 27.7-Mb gain of the long arm in terminal chromosome 13 at q31.1q34. A chromosomal imbalance with a partial trisomy 13q31.1q34 and monosomy 3p26.3 of paternal origin were detected. Microarray assay of both parents were normal. The proband has a cardiomyopathy not previously reported. These data enrich the spectrum of clinical manifestations in 3p deletion/3q duplication chromosomopathy.
Fluid-Attenuated Inversion Recovery Hyperintense Ischemic Stroke Predicts Less Favorable 90-Day Outcome after Intravenous Thrombolysis
Authors: Kim Yongwoo , Luby Marie , Burkett Nina-Serena , Norato Gina , Leigh Richard , Wright Clinton B. , Kern Kyle C. , Hsia Amie W. , Lynch John K. , Adil Malik M. , Latour Lawrence L.
Published: July 2021

Introduction: The absence of an ischemic lesion on MRI fluid-attenuated inversion recovery (FLAIR) is helpful in predicting stroke onset within 4.5 h. However, some ischemic strokes become visible on FLAIR within 4.5 h. We hypothesized that the early lesion visibility on FLAIR may predict stroke outcome 90 days after intravenous (IV) thrombolysis, independent of time. Materials and Methods: We analyzed data from acute ischemic stroke patients presenting over the last 10 years who were screened with MRI and treated with IV thrombolysis within 4.5 h from onset. Three independent readers assessed whether ischemic lesions seen on diffusion-weighted imaging were also FLAIR positive based on visual inspection. Multivariable regression analyses were used to obtain an adjusted odds ratio of favorable clinical and radiological outcomes based on FLAIR positivity. Results: Of 297 ischemic stroke patients, 25% had lesion visibility on initial FLAIR. The interrater agreement for the FLAIR positivity assessment was 84% (κ = 0.604, 95% CI: 0.557–0.652). Patients with FLAIR-positive lesions had more right hemispheric strokes (57 vs. 41%, p = 0.045), were imaged later (129 vs. 104 min, p = 0.036), and had less frequent favorable 90-day functional outcome (49 vs. 63%, p = 0.028), less frequent early neurologic improvement (30 vs. 58%, p = 0.001), and more frequent contrast extravasation to the cerebrospinal fluid space (44 vs. 26%, p = 0.008). Conclusions: Early development of stroke lesion on FLAIR within 4.5 h of onset is associated with reduced likelihood of favorable 90-day outcome after IV thrombolysis.
Beyond Functional Impairment: Redefining Favorable Outcome in Patients with Subarachnoid Hemorrhage
Authors: Custal Christina , Koehn Julia , Borutta Matthias , Mrochen Anne , Brandner Sebastian , Eyüpoglu Ilker Y. , Lücking Hannes , Hoelter Philip , Kuramatsu Joji B. , Kornhuber Johannes , Schwab Stefan , Huttner Hagen B. , Gerner Stefan T.
Published: July 2021

Background: For outcome assessment in patients surviving subarachnoid hemorrhage (SAH), the modified Rankin scale (mRS) represents the mostly established outcome tool, whereas other dimensions of outcome such as mood disorders and impairments in social life remain unattended so far. Objective: The aim of our study was to correlate 12-month functional and subjective health outcomes in SAH survivors. Methods: All SAH patients treated over a 5-year period received outcome assessment at 12 months, including functional scores (mRS and Barthel Index [BI]), subjective health measurement (EQ-5D), and whether they returned to work. Analyses – including utility-weighted mRS – were conducted to detect associations and correlations among different outcome measures, especially in patients achieving good functional outcome (i.e., mRS 0-2) at 12 months. Results: Of 351 SAH survivors, 287 (81.2%) achieved favorable functional outcome at 12 months. Contrary to the BI, the EQ-5D visual analog scale (VAS) showed a strong association with different mRS grades, accentuated in patients with favorable functional outcome. Despite favorable functional outcome, patients reported a high rate of impairments in activities (24.0%), pain (33.4%), and anxiety/depression (42.5%). Further, multivariable analysis revealed (i) impairments in activities (odds ratio [OR] [95% confidence interval {CI}]: 0.872 [0.817–0.930]), (ii) presence of depression or anxiety (OR [95% CI]: 0.836 [0.760–0.920]), and (iii) return to work (OR [95% CI]: 1.102 [0.1.013–1.198]) to be independently associated with self-reported subjective health. Conclusion: Established stroke scores mainly focusing on functional outcomes do poorly reflect the high rate of subjective impairments reported in SAH survivors, specifically in those achieving good functional outcome. Further studies are needed to investigate whether psychoeducational approaches aiming at improving coping mechanisms and perceived self-efficacy may result in higher subjective health in these patients.
Recurrent Glomerular Diseases in Renal Transplantation with Focus on Role of Electron Microscopy
Authors: Seshan Surya V. , Salvatore Steven P.
Published: July 2021

Background: The common causes of renal transplant complications include active or chronic rejection process, infections, and toxicity but also recurrent or de novo diseases, which play an important role in affecting long-term graft function or graft loss. Summary: Recurrent disease in renal transplantation is defined as recurrence of the original kidney disease leading to end-stage kidney disease. They comprise a heterogeneous group of predominantly glomerular and some tubulointerstitial and vascular lesions, which include primary kidney diseases (e.g., focal segmental glomerulosclerosis, membranous glomerulonephritis, and IgA nephropathy) or those secondary to systemic autoimmune, metabolic, and infectious processes that can range from subclinical to clinically overt acute, subacute, or chronic clinical presentations. In addition to the knowledge of prior renal disease and routine/periodic serum and urine testing for kidney function, a complete transplant renal biopsy examination is essential in the identification and differentiation of these diseases. The time of onset and severity of these diseases depend on the underlying etiopathogenetic mechanisms and the varied rates of recurrence in the early or late posttransplant period, often being modified by the current immunosuppressive protocols and other donor and recipient predisposing characteristics. Key Messages: Transplant kidney biopsy findings provide diagnostic accuracy and prognostic information regarding the potential for reversibility along with detection of unsuspected or clinically symptomatic recurrent diseases, with any concomitant rejection process or toxicity, for appropriate therapeutic decision-making. Routine electron microscopy in transplant kidney biopsies is a valuable tool in recognizing fully developed or early/subtle features of evolving recurrent diseases, often during the subclinical phases, in for cause or surveillance allograft biopsies.
“You Are Older, although You Do Not Know That”: Time, Consciousness, and Memory in “A Kind of Alaska” by Harold Pinter (1930–2008)
Authors: Brigo Francesco , Martini Mariano , Lorusso Lorenzo ,   on behalf of the Study Group on the History of Neurology of the Italian Neurological Society
Published: July 2021

“A Kind of Alaska” is a one-act play by the British playwright and Nobel Prize winner Harold Pinter (1930–2008), based on the book Awakenings by the neurologist Oliver Sacks (1933–2015). This play, first performed in 1982, is centered around the character of Deborah, a middle-aged woman, struck by encephalitis lethargica (“sleeping sickness”) at the age of 16, who wakes up after 29 years of apparent sleep following the injection of an unnamed drug. This article analyzes how Pinter’s drama investigated the mysterious and fascinating relationship between time, memory, and consciousness. The term “awakenings,” chosen by Sacks himself, clearly refers to the restoration of voluntary motor function in patients with postencephalitic parkinsonism who responded to levodopa. However, it also suggests that these patients had an impairment of awareness. Actually, beyond the acute phase, subjects with postencephalitic parkinsonism were not sleeping but severely akinetic and therefore probably aware of the passage of time. Oliver Sacks probably did not entirely recognize the intrinsic contradiction between prolonged sleep (with consequent impairment of awareness and subjective “time gap”) of the acute lethargic phase and the severe akinesia with preserved awareness of the time-passing characteristic of postencephalitic parkinsonism. This confusion was further compounded by Harold Pinter in his play.
Coming to Terms with a Conundrum: A Case of Primary Progressive Apraxia of Speech due to Corticobasal Degeneration?
Authors: Karantzoulis Aristotelis , Susani Emanuela , Ferrarese Carlo , Appollonio Ildebrando , Tremolizzo Lucio
Published: July 2021

Primary progressive apraxia of speech (PPAOS) is a progressive disorder impairing the motor speech act leaving linguistic function unattained. Although apraxia of speech frequently co-occurs with other neurodegenerative conditions, PPAOS defines a clinical syndrome where apraxia of speech is the sole or prominent symptom for much of the disease’s natural history. Mounting evidence is beginning to fully define this disease as the epiphenomenon of 4-repeat (4R) tau pathology although other pathologic signatures have been reported. Indeed, PPAOS patients generally present a parkinsonian syndrome late into their natural history mostly qualifying for either corticobasal syndrome (CBS) or progressive supranuclear palsy (PSP). This is starting to be reflected in diagnostic criteria for PSP, namely, in the PSP speech and language (SL) subcategory; however, this inclusion is not reflected for CBS. Here, we present a single case of a patient with PPAOS and her clinical follow-up lasting 6 years, from the time she sought our attention to her death which occurred 8 years into the disease. PPAOS was the only and prominent symptom for most of the illness with extrapyramidal signs overtly presenting in the last months of its course. Clinical evaluation, imaging, genetic, and cerebrospinal fluid biomarkers all pointed toward an underlying CBD pathology, albeit the eventual anatomopathological confirmation was not performed. Had her clinical course been more suggestive of PSP, she would have qualified for criteria as PSP-SL. Our case therefore suggests the hypothetic need to discuss the broadening of the existing CBS criteria to encompass isolated PPAOS.
Warning Signs in the Era of Unruptured Intracranial Aneurysms: Report on 2 Cases of Fatal Aneurysmal Hemorrhage
Authors: Wójtowicz Katarzyna , Kunert Przemysław , Przepiórka Łukasz , Marchel Andrzej
Published: July 2021

Introduction: The timing of treatment remains unresolved for patients with unruptured intracranial aneurysms (UIAs) and headaches, particularly when the pain is short term, localized, and related to the aneurysm site. We lack evidence to support the notion that when a headache accompanies an aneurysm, it elevates the risk of rupture. Results: We describe 2 cases of fatal subarachnoid hemorrhage in patients with a history of headache and known aneurysms. Both of these patients had good indications for treatment: a young age and an aneurysm >7 mm, and both were qualified for elective surgery. However, both patients died of fatal aneurysm ruptures before the planned surgery. Conclusion: These cases suggested that treatment should be started as soon as possible, when a UIA is diagnosed based on a short-term period of severe headaches or when a UIA is observed and then severe headaches appear. There is no straightforward guideline for treatment timing in these patients. However, in this era of UIAs, the significance of sentinel headaches should be reevaluated. Given the incidence of headaches in the general population and the very low risk of aneurysm rupture, there may be a tendency to neglect the role of headache as a possible warning sign.
A Relationship between the Characteristics of the Oval Nucleus of the Mesopallium and Parrot Vocal Response to Playback
Authors: Walløe Solveig , Chakraborty Mukta , Balsby Thorsten J.S. , Jarvis Erich D. , Dabelsteen Torben , Pakkenberg Bente
Published: July 2021

Correlations between differences in animal behavior and brain structures have been used to infer function of those structures. Brain region size has especially been suggested to be important for an animal’s behavioral capability, controlled by specific brain regions. The oval nucleus of the mesopallium (MO) is part of the anterior forebrain vocal learning pathway in the parrot brain. Here, we compare brain volume and total number of neurons in MO of three parrot species (the peach-fronted conure, Eupsittula aurea, the peach-faced lovebird, Agapornis roseicollis, and the budgerigar, Melopsittacus undulatus), relating the total neuron numbers with the vocal response to playbacks of each species. We find that individuals with the highest number of neurons in MO had the shortest vocal latency. The peach-fronted conures showed the shortest vocal latency and largest number of MO neurons, the peach-faced lovebird had intermediary levels of both, and the budgerigar had the longest latency and least number of neurons. These findings indicate the MO nucleus as one candidate region that may be part of what controls the vocal capacity of parrots.
The Effect of Shock Wave Lithotripsy on Male and Female Sexual Dysfunction in Patients with Proximal Ureteral Stones
Authors: Kalkanli Arif , Gezmis Cem Tugrul
Published: July 2021

Introduction: This study aims to investigate the effects of shock wave lithotripsy (SWL) treatment for proximal ureteral stones on the sexual functions of patients of both genders. Methods: In this prospective study, 30 female and 72 male patients who had received SWL treatment for proximal ureteral stones in our clinic between August 2019 and October 2020 were evaluated. CT, creatinine, urinary analysis, and culture were performed during the initial consultation for all patients. Information regarding the age, BMI, and stone burden of the patients was recorded. Male patients answered the International Index of Erectile Function-5 (IIEF-5) questionnaire, and female participants answered the Female Sexual Function Index (FSFI) 3 times: pre-procedural and post-procedural first and third month. CT was repeated on the first month, and any residues were noted. Results: The mean IIEF-5 scores of the male patients were 23.11 ± 8.11 prior to surgery, and it decreased to 19.74 ± 7.65 in the first month and 23.88 ± 9.23 in the third, p = 0.001. The mean FSFI scores of female patients were 18.2 ± 9.9, which decreased to 12.8 ± 6.12 in the first month and 17.8 ± 8.66 in the third, p = 0.001. Univariate analysis revealed that the patients’ age (male: p = 0.004 and female: p = 0.008) and BMI (male: p = 0.044 and female: p = 0.027) were related to the poorer scores for both genders. However, there were not any significant findings regarding stone burden (male: p = 0.054 and female: p = 0.078). Conclusions: The possibility of developing temporary sexual dysfunction should be taken into account for patients who are candidates for SWL treatment. As the patient’s age and BMI increase, SWL-related sexual dysfunction becomes more severe.
Fibroblast Growth Factor 23 Regulation and Acute Kidney Injury
Authors: Zhou Wen , Simic Petra , Rhee Eugene P.
Published: July 2021

Elevated fibroblast growth factor 23 (FGF23) levels are markers and potential mediators, of adverse outcomes in acute kidney injury (AKI). We recently identified glycerol-3-phosphate (G-3-P), a glycolysis byproduct, as a kidney-derived factor that circulates to bone and bone marrow and triggers FGF23 production in ischemic AKI. This kidney-to-bone signaling axis was further shown to require the conversion of G-3-P to lysophosphatidic acid (LPA) in bone marrow, followed by LPA signaling through the LPAR1 receptor. These findings highlight discrete steps potentially amenable to therapeutic targeting in conditions of FGF23 excess, although more work is required to determine the specificity and safety of targeting specific enzyme and receptor isoforms. Importantly, the initial metabolomic screen that identified a strong correlation between renal vein G-3-P and circulating FGF23 was conducted in human subjects undergoing elective catheterization, none with AKI. This raises the question of whether G-3-P might also modulate FGF23 homeostasis in patients with more mild or chronic decrements in kidney function, or under normal physiologic conditions – a question that is reinforced by a growing body of literature highlighting functional roles for a range of circulating metabolites traditionally thought to function exclusively inside cells.
Why Do Our Cancer Patients Sleep So Badly? Sleep Disorders in Cancer Patients: A Frequent Symptom with Multiple Causes
Authors: Strik Herwig , Cassel Werner , Teepker Michael , Schulte Thomas , Riera-Knorrenschild Jorge , Koehler Ulrich , Seifart Ulf
Published: July 2021

Introduction: On the one hand, sleep disorders in cancer patients are reported in 30–50% of cancer patients. On the other hand, specific causes for these sleep disorders are little known. This study was done to evaluate factors which may affect sleep of cancer patients. To our knowledge, this is the first study which includes return to work as one factor of sleep disturbance. Methods: 107 patients with various types of cancer treated in 2 hospitals were interviewed with a battery of questionnaires after having given informed consent. The questionnaires intended to detect abnormalities of sleep and related pain, breathing disorders, restless legs syndrome, depression, rumination, medication, and psychosocial distress. The study was approved by the ethics committee of the University of Marburg. Results: The analysis of the 6 sleep-related questionnaires indicated a sleep disorder of any kind in 68% of all patients. Insomnia symptoms were present in 48 patients (44.9%). Pain, depression, anxiety, and worries about the workplace were significantly related to sleep disorders. Conclusion: Sleep disorders are common in cancer patients. The causes are manifold and should be considered by caregivers during diagnosis, therapy, and aftercare of cancer patients. Tumour patients should actively be asked about sleep disorders. If these are present, they should be addressed, and as they have a large impact on quality of life, treatment options should be offered in cooperation with sleep specialists.
Associations of Genetically Predicted Lp(a) (Lipoprotein [a]) Levels With Cardiovascular Traits in Individuals of European and African Ancestry
Authors: Satterfield Benjamin A. , Dikilitas Ozan , Safarova Maya S. , Clarke Shoa L. , Tcheandjieu Catherine , Zhu Xiang , Bastarache Lisa , Larson Eric B. , Justice Anne E. , Shang Ning , Rosenthal Elisabeth A. , Shah Amy Sanghavi , Namjou-Khales Bahram , Urbina Elaine M. , Wei Wei-Qi , Feng QiPing , Jarvik Gail P. , Hebbring Scott J. , de Andrade Mariza , Manolio Teri A. , Assimes Themistocles L. , Kullo Iftikhar J.
Published: July 2021

Background:

Lp(a) (lipoprotein [a]) levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with (1) atherosclerotic cardiovascular disease subtypes: coronary heart disease, cerebrovascular disease, peripheral artery disease, and abdominal aortic aneurysm and (2) nonatherosclerotic cardiovascular disease phenotypes, stratified by ancestry.

Methods:

We performed (1) Mendelian randomization analyses for previously reported cardiovascular associations and (2) Mendelian randomization–phenome-wide association analyses for novel associations. Analyses were stratified by ancestry in electronic Medical Records and Genomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804 507 EA and 103 580 AA participants.

Results:

In Mendelian randomization analyses using the combined cohort, a 1-SD genetic increase in Lp(a) level was associated with atherosclerotic cardiovascular disease subtypes in EA—odds ratio and 95% CI for coronary heart disease 1.28 (1.16–1.41); cerebrovascular disease 1.14 (1.07–1.21); peripheral artery disease 1.22 (1.11–1.34); abdominal aortic aneurysm 1.28 (1.17–1.40); in AA, the effect estimate was lower than in EA and nonsignificant for coronary heart disease 1.11 (0.99–1.24) and cerebrovascular disease 1.06 (0.99–1.14) but similar for peripheral artery disease 1.16 (1.01–1.33) and abdominal aortic aneurysm 1.34 (1.11–1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34 (1.10–1.62), mitral valve disorders 1.18 (1.09–1.27), congestive heart failure 1.12 (1.05–1.19), and chronic kidney disease 1.07 (1.01–1.14). In AA, no significant associations were noted for aortic valve disorders 1.08 (0.94–1.25), mitral valve disorders 1.02 (0.89–1.16), congestive heart failure 1.02 (0.95–1.10), or chronic kidney disease 1.05 (0.99–1.12). Mendelian randomization–phenome-wide association analyses identified novel associations in EA with arterial thromboembolic disease, nonaortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension.

Conclusions:

Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with atherosclerotic cardiovascular disease in four major arterial beds in EA but only with peripheral artery disease and abdominal aortic aneurysm in AA. Additionally, novel cardiovascular associations were detected in EA.
Segment Length in Cine Strain Analysis Predicts Cardiac Resynchronization Therapy Outcome Beyond Current Guidelines
Authors: Zweerink Alwin , Friedman Daniel J. , Klem Igor , van de Ven Peter M. , Vink Caitlin , Biesbroek P. Stefan , Hansen Steen M. , Kim Raymond J. , van Rossum Albert C. , Atwater Brett D. , Allaart Cornelis P. , Nijveldt Robin
Published: July 2021

Background:

Patients with a class I recommendation for cardiac resynchronization therapy (CRT) are likely to benefit, but the effect of CRT in class II patients is more heterogeneous and additional selection parameters are needed in this group. The recently validated segment length in cine strain analysis of the septum (SLICE-ESS
sep
) measurement on cardiac magnetic resonance cine imaging predicts left ventricular functional recovery after CRT but its prognostic value is unknown. This study sought to evaluate the prognostic value of SLICE-ESS
sep
for clinical outcome after CRT.

Methods:

Two hundred eighteen patients with a left bundle branch block or intraventricular conduction delay and a class I or class II indication for CRT who underwent preimplantation cardiovascular magnetic resonance examination were enrolled. SLICE-ESS
sep
was manually measured on standard cardiovascular magnetic resonance cine imaging. The primary combined end point was all-cause mortality, left ventricular assist device, or heart transplantation. Secondary end points were (1) appropriate implantable cardioverter defibrillator therapy and (2) heart failure hospitalization.

Results:

Two-thirds (65%) of patients had a positive SLICE-ESS
sep
≥0.9% (ie, systolic septal stretching). During a median follow-up of 3.8 years, 66 (30%) patients reached the primary end point. Patients with positive SLICE-ESS
sep
were at lower risk to reach the primary end point (hazard ratio 0.36;
P
<0.001) and heart failure hospitalization (hazard ratio 0.41;
P
=0.019), but not for implantable cardioverter defibrillator therapy (hazard ratio, 0.66;
P
=0.272). Clinical outcome of class II patients with a positive ESS
sep
was similar to those of class I patients (hazard ratio, 1.38 [95% CI, 0.66–2.88];
P
=0.396).

Conclusions:

Strain assessment of the septum (SLICE-ESS
sep
) provides a prognostic measure for clinical outcome after CRT. Detection of a positive SLICE-ESS
sep
in patients with a class II indication predicts improved CRT outcome similar to those with a class I indication whereas SLICE-ESS
sep
negative patients have poor prognosis after CRT implantation.
Translating Functional Connectivity After Stroke: Functional Magnetic Resonance Imaging Detects Comparable Network Changes in Mice and Humans
Authors: Blaschke Stefan J. , Hensel Lukas , Minassian Anuka , Vlachakis Susan , Tscherpel Caroline , Vay Sabine U. , Rabenstein Monika , Schroeter Michael , Fink Gereon R. , Hoehn Mathias , Grefkes Christian , Rueger Maria A.
Published: July 2021

Background and Purpose:

The translational roadblock has long impeded the implementation of experimental therapeutic approaches for stroke into clinical routine. Considerable interspecies differences, for example, in brain anatomy and function, render comparisons between rodents and humans tricky, especially concerning brain reorganization and recovery of function. We tested whether stroke-evoked changes in neural networks follow similar patterns in mice and patients using a systems-level perspective.

Methods:

We acquired resting-state functional magnetic resonance imaging data during the early poststroke phase in a sample of human patients and compared the observed network changes with data from 2 mouse stroke models, that is, photothrombosis and distal middle cerebral artery occlusion. Importantly, data were subjected to the same processing steps, allowing a direct comparison of global network changes using graph theory.

Results:

We found that network parameters computed for both mouse models of stroke and humans follow a similar pattern in the postacute stroke phase. Parameters indicating the global communication structure’s facilitation, such as small worldness and characteristic path length, were similarly changed in humans and mice in the first days after stroke. Additionally, small worldness correlated with concurrent motor impairment in humans. Longitudinal observation in the subacute phase revealed a negative correlation between initial small worldness and motor recovery in mice.

Conclusions:

We show that network measures based on resting-state functional magnetic resonance imaging data after stroke obtained in mice and humans share notable features. The observed network alterations could serve as therapeutic readout parameters for future translational studies in stroke research.
Residual Inflammatory Risk Predicts Poor Prognosis in Acute Ischemic Stroke or Transient Ischemic Attack Patients
Authors: Li Jiejie , Pan Yuesong , Xu Jie , Li Shiyu , Wang Mengxing , Quan Kehua , Meng Xia , Li Hao , Lin Jinxi , Wang Yilong , Zhao Xingquan , Liu Liping , Wang Yongjun ,   on behalf of the CNSR-III Investigators
Published: July 2021

Background and Purpose:

It is still unclear whether the residual cholesterol and inflammatory risk in the acute phase is associated with prognosis of stroke. We aimed to investigate the proportion and relative contribution of residual cholesterol and inflammatory risk, determined by baseline low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) levels, to the risk of recurrent stroke and poor functional outcome at 1 year.

Methods:

In this prospective multicenter cohort study, 10 499 consecutive acute ischemic stroke and transient ischemic attack patients with levels of LDL-C and hsCRP were enrolled. Patients were divided into 4 groups: residual cholesterol risk only (LDL-C ≥2.6 mmol/L and hsCRP <3 mg/L), residual inflammatory risk (RIR) only (LDL-C <2.6 mmol/L and hsCRP ≥3 mg/L), both risk (LDL-C ≥2.6 mmol/L and hsCRP ≥3 mg/L), and neither risk (LDL-C <2.6 mmol/L and hsCRP <3 mg/L). The primary outcomes consisted of stroke recurrence and a modified Rankin Scale score of 2 to 6 within 1 year.

Results:

The relative proportions of patients with RIR only, residual cholesterol risk only, both risk, and neither were 21.3%, 23.7%, 14.4%, and 40.6%, respectively. RIR only was independently associated with recurrent stroke (adjusted hazard ratio, 1.18 [95% CI, 1.00–1.40];
P
=0.05). The association was slightly attenuated after further adjusting for usage of antiplatelet agent and statin during 1-year follow-up in addition to the traditional risk factors (hazard ratio, 1.31 [95% CI, 0.99–1.76];
P
=0.07). When applying the LDL-C cutoff value of 1.8 mmol/L in the sensitivity analyses, such association in large-artery atherosclerosis subtype was more significant (adjusted hazard ratio, 1.69 [95% CI, 1.06–2.67];
P
=0.03). Patients with RIR only also had increased risk of poor functional outcome (adjusted odds ratio, 1.43 [95% CI, 1.24–1.64];
P
<0.0001).

Conclusions:

In the patients with acute ischemic stroke or transient ischemic attack, RIR only could be predictive for recurrent stroke, especially for those with large-artery atherosclerosis, and poor functional outcome.