bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR-21 in Substance P-induced exosomes promotes cell proliferation and migration in human colonic epithelial cells
Authors: Bakirtzi Kyriaki , Man Law Ivy Ka , Fang Kai , Iliopoulos Dimitrios , Pothoulakis Charalabos
Published: September 2019

Exosomes are cellular vesicles involved in intercellular communication via their specialized molecular cargo, such as miRNAs. Substance P (SP), a neuropeptide/hormone, and its high-affinity receptor, NK-1R, are highly expressed during colonic inflammation. Our previous studies show that SP/NK-1R signaling stimulates differential miRNA expression and promotes colonic epithelial cell proliferation. In this study, we examined whether SP/NK-1R signaling regulates exosome biogenesis and exosome-miRNA cargo sorting. Moreover, we examined the role of SP/NK-1R signaling in exosome-regulated cell proliferation and migration. Exosomes produced by human colonic NCM460 epithelial cells overexpressing NK-1R (NCM460-NK1R) were isolated from culture media. Exosome abundance and uptake were assessed by Western blot analysis (abundance) and Exo-Green fluorescence microscopy (abundance and uptake). Cargo-miRNA levels were assessed by RT-PCR. Cell proliferation and migration were assessed using xCELLigence technology. Colonic epithelial exosomes were isolated from mice pretreated with SP for 3 days. Cell proliferation in vivo was assessed by Ki-67 staining. SP/NK-1R signaling in human colonic epithelial cells (in vitro) and mouse colons (in vivo) increased 1) exosome production, 2) the level of fluorescence in NCM460s treated with Exo-Green-labeled exosomes, and 3) the level of miR-21 in exosome cargo. Moreover, our results showed that SP/NK-1R-induced cell proliferation and migration are at least in part dependent on intercellular communication via exosomal miR-21 in vitro and in vivo. Our results demonstrate that SP/NK-1R signaling regulates exosome biogenesis and induces its miR-21 cargo sorting. Moreover, exosomal miR-21 promotes proliferation and migration of target cells.

NEW & NOTEWORTHY Substance P signaling regulates exosome production in human colonic epithelial cells and colonic crypts in wild-type mice. MiR-21 is selectively sorted into exosomes induced by Substance P stimulation and promotes cell proliferation and migration in human colonocytes and mouse colonic crypts.
Metformin alters the duodenal microbiome and decreases the incidence of pancreatic ductal adenocarcinoma promoted by diet-induced obesity
Authors: Dong Tien S. , Chang Hui-Hua , Hauer Meg , Lagishetty Venu , Katzka William , Rozengurt Enrique , Jacobs Jonathan P. , Eibl Guido
Published: September 2019

Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. In previous work, we have shown that metformin can prevent the increased incidence of PDAC in a KrasG12D mouse model subjected to a diet high in fat and calories (HFCD). One potential way that metformin can affect the host is through alterations in the gut microbiome. Therefore, we investigated microbial associations with PDAC development and metformin use in the same mouse model. Lox-Stop-Lox Kras G12D/+ (LSL-Kras G12D/+); p48-Cre (KC) mice were given control diet, HFCD, or HFCD with 5 mg/mL metformin in drinking water for 3 mo. At the end of the 3 mo, 16S rRNA sequencing was performed to characterize microbiome composition of duodenal mucosal, duodenal luminal, and cecal luminal samples. KC mice on an HFCD demonstrated depletion of intact acini and formation of advanced pancreatic intraepithelial neoplasia. This effect was completely abrogated by metformin treatment. HFCD was associated with significant changes in microbial composition and diversity in the duodenal mucosa and lumen, much of which was prevented by metformin. In particular, Clostridium sensu stricto was negatively correlated with percent intact acini and seemed to be inhibited by the addition of metformin while on an HFCD. Administration of metformin eliminated PDAC formation in KC mice. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.

NEW & NOTEWORTHY Pancreatic ductal adenocarcinoma (PDAC)’s growing incidence has been linked to the rise in obesity and type 2 diabetes mellitus. Administration of metformin eliminated PDAC formation in KC mice with diet-induced obesity. This change was associated with significant microbial changes in both the mucosal and luminal microbiome of the duodenum. This suggests that the microbiome may be a potential mediator of the chemopreventive effects of metformin.
Enteric neuron density correlates with clinical features of severe gut dysmotility
Authors: Boschetti Elisa , Malagelada Carolina , Accarino Anna , Malagelada Juan R. , Cogliandro Rosanna F. , Gori Alessandra , Bonora Elena , Giancola Fiorella , Bianco Francesca , Tugnoli Vitaliano , Clavenzani Paolo , Azpiroz Fernando , Stanghellini Vincenzo , Sternini Catia , De Giorgio Roberto
Published: September 2019

Gastrointestinal (GI) symptoms can originate from severe dysmotility due to enteric neuropathies. Current methods used to demonstrate enteric neuropathies are based mainly on classic qualitative histopathological/immunohistochemical evaluation. This study was designed to identify an objective morphometric method for paraffin-embedded tissue samples to quantify the interganglionic distance between neighboring myenteric ganglia immunoreactive for neuron-specific enolase, as well as the number of myenteric and submucosal neuronal cell bodies/ganglion in jejunal specimens of patients with severe GI dysmotility. Jejunal full-thickness biopsies were collected from 32 patients (22 females; 16–77 yr) with well-characterized severe dysmotility and 8 controls (4 females; 47–73 yr). A symptom questionnaire was filled before surgery. Mann-Whitney U test, Kruskal-Wallis coupled with Dunn’s posttest and nonparametric linear regression tests were used for analyzing morphometric data and clinical correlations, respectively. Compared with controls, patients with severe dysmotility exhibited a significant increase in myenteric interganglionic distance ( P = 0.0005) along with a decrease in the number of myenteric ( P < 0.00001) and submucosal ( P < 0.0004) neurons. A 50% reduction in the number of submucosal and myenteric neurons correlated with an increased interganglionic distance and severity of dysmotility. Our study proposes a relatively simple tool that can be applied for quantitative evaluation of paraffin sections from patients with severe dysmotility. The finding of an increased interganglionic distance may aid diagnosis and limit the direct quantitative analysis of neurons per ganglion in patients with an interganglionic distance within the control range.

NEW & NOTEWORTHY Enteric neuropathies are challenging conditions characterized by a severe impairment of gut physiology, including motility. An accurate, unambiguous assessment of enteric neurons provided by quantitative analysis of routine paraffin sections may help to define neuropathy-related gut dysmotility. We showed that patients with severe gut dysmotility exhibited an increased interganglionic distance associated with a decreased number of myenteric and submucosal neurons, which correlated with symptoms and clinical manifestations of deranged intestinal motility.
Lipid mediators of insulin signaling in diabetic kidney disease
Authors: Mitrofanova Alla , Sosa Marie Anne , Fornoni Alessia
Published: September 2019

Diabetic kidney disease (DKD) affects ∼40% of patients with diabetes and is associated with high mortality rates. Among different cellular targets in DKD, podocytes, highly specialized epithelial cells of the glomerular filtration barrier, are injured in the early stages of DKD. Both clinical and experimental data support the role of preserved insulin signaling as a major contributor to podocyte function and survival. However, little is known about the key modulators of podocyte insulin signaling. This review summarizes the novel knowledge that intracellular lipids such as cholesterol and sphingolipids are major determinants of podocyte insulin signaling. In particular, the implications of these lipids on DKD development, progression, and treatment will be addressed.
Early suppression of peripheral mononuclear blood cells in sepsis in response to stimulation with cytomegalovirus, OKT3, and pokeweed mitogen
Authors: Malewicz N. M. , Walstein K. , Heine T. , Engler A. , Bick A. , Cox L. , Dötsch A. , Westendorf A. M. , Horn P. A. , Lindemann M. , Peters J. , Schäfer S. T.
Published: September 2019

Critically ill patients are at risk for sepsis, and immunosuppressive mechanisms may prevail. Whether functional tests are helpful to detect immune alterations is largely unknown. Therefore, we tested the hypotheses that reactivity of peripheral blood mononuclear cells (PBMCs) to secrete interferon-γ (IFNγ) following stimulation in vitro is decreased in patients with early sepsis compared with postoperative patients. IFNγ secretion [enzyme-linked immunospot (ELISpot)] in response to stimulation with cytomegalovirus (CMV), pokeweed mitogen (PWM), muromonab-anti-CD3 (OKT3), and human leukocyte antigen (HLA)-DRA-mRNA expression and serum cytokine concentrations were repeatedly [ days 1, 3, 5, and 7 after intensive care unit (ICU) admission] determined in patients with sepsis ( n = 7) and patients undergoing major abdominal surgery (radical prostatectomy, cystectomy, n = 10). In a second cohort, HLA-DRA expression was assessed in 80 patients with sepsis, 30 postoperative patients, and 44 healthy volunteers (German clinical trials database no. 00007694). In patients with sepsis, IFNγ secretion (ELISpot) was decreased compared with controls after stimulation with CMV ( P = 0.01), OKT3 ( P = 0.02), and PWM ( P = 0.02 on day 5), whereas unstimulated IFNγ secretion did not differ. HLA-DRA expression was also significantly decreased in patients with sepsis at all time points ( P = 0.004) compared with postoperative surgical patients, a finding confirmed in the larger cohort. Reactivity of PBMCs to stimulation with CMV, PWM, and OKT3 as well as HLA-DRA expression was already decreased upon ICU admission in patients with sepsis when compared with postoperative controls, suggesting early depression of acquired immunity. ELISpot assays may help to clinically characterize the time course of immunocompetence in patients with sepsis.

NEW & NOTEWORTHY We observed suppression of reactivity to stimulation with cytomegalovirus, muromonab-anti-CD3, and pokeweed mitogen in mononuclear blood cells of patients with early sepsis when compared with postoperative controls. Thus, there is early depression of acquired immunity in sepsis. Enzyme-linked immunospot assays may help to characterize immunocompetence in patients with sepsis.
Torque gains and neural adaptations following low-intensity motor nerve electrical stimulation training
Authors: Vitry Florian , Martin Alain , Papaiordanidou Maria
Published: September 2019

The purpose of the study was to assess neural adaptations of the plantar-flexors induced by an electrical stimulation training applied over the motor nerve at low intensity using two different stimulation frequencies. Thirty subjects were randomly assigned into 3 groups: 20 Hz, 100 Hz, and control group. The training consisted of 15 sessions of 25 stimulation trains applied over the tibial nerve and delivered at an intensity evoking 10% maximal voluntary isometric contraction (MVIC). Before and after training, MVIC was assessed and neural adaptations were evaluated by the voluntary activation level (VAL) and the V-wave (normalized by the superimposed muscle compound action potential, V/MSUP). H-reflex and motor-evoked potential (MEP) recorded during MVIC were studied to assess spinal and corticospinal excitabilities [i.e., maximal H-reflex during maximal voluntary isometric contraction (HSUP)/MSUPand maximal motor-evoked potential during maximal voluntary isometric contraction (MEPSUP)/MSUP]. MVIC significantly increased after training only for the two training groups ( P = 0.017). This increase was accompanied by a significant increase of VAL only for these groups ( P = 0.014), whereas statistical analysis revealed a time effect for V/MSUP( P = 0.022). HSUP/MSUPand MEPSUP/MSUPwere significantly increased at post conditions only for the 100 Hz group ( P = 0.021 and P = 0.029). Results show that low-intensity electrical stimulation training applied over the motor nerve can induce torque gains, accompanied by neural adaptations. Stimulation frequency differentially affected spinal and corticospinal excitabilities, indicating that neural adaptations could have a supraspinal origin for the 20-Hz protocol, whereas spinal and supraspinal mechanisms were implicated in the torque increases after the 100-Hz training.

NEW & NOTEWORTHY This study brings new insights into the neurophysiological mechanisms responsible for torque gains after electrical stimulation training using wide pulse duration and low stimulation intensity applied over the motor nerve. Stimulation frequency had a distinct impact on spinal and/or supraspinal origins of the observed neural adaptations. The use of the aforementioned stimulation parameters in rehabilitation settings can be proved beneficial in terms of strength gains while avoiding any serious discomfort because of stimulation.
LncRNA IUR downregulates ZEB1 by upregulating miR-200 to inhibit prostate carcinoma
Authors: Sun Lingjun , Chen Taowei , Li Tao , Yu Jianda
Published: September 2019

We in this study investigated the role of imatinib-upregulated lncRNA (IUR) in prostate carcinoma (PC). We observed that IUR was downregulated in PC, and its expression levels decreased with the increase of clinical stages. In PC tissues, microRNA (miR)-200 was positively, while ZEB1 was inversely correlated with IUR. In PC cells, IUR and miR-200 overexpression mediated the downregulated ZEB1. IUR overexpression mediated the upregulation of miR-200, while IUR expression was not significantly affected by miR-200 overexpression. Cell invasion and migration analysis showed that IUR and miR-200 overexpression resulted in decreased invasion and migration rates. ZEB1 overexpression played an opposite role and attenuated the effects of IUR and miR-200 overexpression. Therefore, IUR can downregulate ZEB1 by upregulating miR-200 to inhibit PC cell invasion and migration.
Cross talk between mineral metabolism and meat quality: a systems biology overview
Authors: Diniz Wellison J. da Silva , Banerjee Priyanka , Regitano Luciana C. A.
Published: September 2019

Meat quality has an inherent complexity because of the multiple interrelated causative factors and layers of feedback regulation. Understanding the key factors and their interactions has been challenging, despite the availability of remarkable high-throughput tools and techniques that have provided insights on muscle metabolism and the genetic basis of meat quality. Likewise, we have deepened our knowledge about mineral metabolism and its role in cell functioning. Regardless of these facts, complex traits like mineral content and meat quality have been studied under reductionist approaches. However, as these phenotypes arise from complex interactions among different biological layers (genome, transcriptome, proteome, epigenome, etc.), along with environmental effects, a holistic view and systemic-level understanding of the genetic basis of complex phenotypes are in demand. Based on the state of the art, we addressed some of the questions regarding the interdependence of meat quality traits and mineral content. Furthermore, we sought to highlight potential regulatory mechanisms arising from the genes, miRNAs, and mineral interactions, as well as the pathways modulated by this interplay affecting muscle, mineral metabolism, and meat quality. By answering these questions, we did not intend to give an exhaustive review but to identify the key biological points, the challenges, and benefits of integrative genomic approaches.
Dynamic Compression Damage Energy Consumption and Fractal Characteristics of Shale
Authors: Yang Guoliang , Bi Jingjiu , Ma Linian
Published: September 2019

Studying the relationship between energy consumption and crushed size of shale under different loading conditions is the key to efficient shale cracking. The split Hopkinson pressure bar system was used to study the dynamic mechanical properties of shale under parallel‐ and vertical‐bedding loading, and energy dissipation in the impact tests was calculated. Relationships between the average crushed size of shale fracture products and energy dissipation and between the fractal dimension and dissipated energy were studied using fractal theory. The experimental results showed that the dynamic compressive strength of shale under parallel‐ and vertical‐bedding conditions had an obvious positive correlation with the strain rate. Dissipative energy of the shale samples under loading in both directions increased with the increase of strain rate. The increase of the strain rate enhanced crushing of the sample. The vertical‐bedding shale samples had stronger ability to absorb energy and more internal crack propagation. Dissipative energies of the shale samples in the parallel‐ and vertical‐bedding impact tests were positively related to the fractal dimension. The fractal dimension increased with the increase of dissipative energy during sample failure; with further increase in the dissipative energy, its effect on the change of fractal dimension gradually weakened.
Sensitivity of Importance Metrics for Critical Digital Services Graph to Service Operators’ Self-Assessment Errors
Authors: Kamola Mariusz
Published: September 2019

Interdependency of critical digital services can be modeled in the form of a graph with exactly known structure but with edge weights subject to estimation errors. We use standard and custom centrality indexes to measure each service vulnerability. Vulnerability of all nodes in the graph gets aggregated in a number of ways into a single network vulnerability index for services whose operation is critical for the state. This study compares sensitivity of various centralities combined with various aggregation methods to errors in edge weights reported by service operators. We find that many of those combinations are quite robust and can be used interchangeably to reflect various perceptions of network vulnerability. We use graphs of source files’ dependencies for a number of open-source projects, as a good analogy for real critical services graph, which will remain confidential.
Integrated Analysis of mRNA Expression, CpG Island Methylation, and Polymorphisms in the MITF Gene in Ducks (Anas platyrhynchos)
Authors: Lin Ruiyi , Lin Weimin , Zhou Shiye , Chen Qiaohui , Pan Jiahua , Miao Yuanxin , Zhang Mengwen , Huang Zhongbin , Xiao Tianfang
Published: September 2019

Microphthalmia-associated transcription factor (MITF) is a key regulator for the development and function of melanocytes in skin, eye, and plumage pigmentations. Thus, the MITF was selected as a candidate gene associated with plumage coloration in ducks. This study analyzed the mRNA expression, promoter methylation, and polymorphisms in the MITF gene in ducks with different plumage colors (Putian Black, Putian White, Liancheng White, and Longsheng Jade-green). No expression of the MITF melanin-specific isoform (MITF-M) was detected in white feather bulbs. By contrast, the mRNA expression levels of MITF-M were high in black feather bulbs. Bioinformatics analysis showed that two CpG islands were present in the promoter region of the MITF gene. The methylation level of the second CpG island was significantly lower in black feather bulbs than in white feather bulbs. However, the methylation level of the first CpG island was not different among the feather bulbs with various colors except Liancheng White feather bulbs. The methylation status of the whole CpG island significantly and negatively correlated with the mRNA expression of MITF-M (P<0.05). Furthermore, four novel SNPs (single nucleotide polymorphisms) were identified in the 5′UTR, exon 4, intron 7, and intron 8 of the MITF gene. Allele T in g.39807T>G and allele G in g.40862G>A were the predominant alleles only found in Putian White, whereas the variant A allele in g.32813G>A exhibited a high allele frequency in Liancheng White. Collectively, these results contributed to the understanding of the function of the MITF gene in duck plumage coloration.
Effect of Colloidal Silicate on the Migration Behaviour of Strontium in Groundwater Environment of Geological Disposal Candidate Site
Authors: Zuo Rui , Han Kexue , Shi Rongtao , Ding Fei , Liu Li , Wang Jinsheng , Teng Yanguo , Yang Jie , Liu Xin
Published: September 2019

Various colloids are present in the natural groundwater environment, and colloids act on the processes involved when radionuclides leak from a repository in a high-level waste disposal site. This paper investigates the effect of colloidal silicate in natural groundwater environments on the migration behaviour of Sr(II). Three different experimental cases have been designed: (1) effect in the presence of colloidal silicate, (2) effect in the presence of a porous medium, and (3) effect in the presence of both colloidal silicate and porous medium (referred to as CS, PM, and PC, respectively). Batch experiments were used to study the effect of influencing factors on Sr(II) migration behaviour, such as the amount of CS, solid-to-liquid ratio, pH, contact time, and initial concentration of Sr(II). The experiments showed that the effect of PC on the migration behaviour of Sr(II) was greatest, and the presence of CS enhanced the sorption. The colloid amount, pH, and solid-to-liquid ratio significantly affected the migration behaviour. The more the colloids were added, the better the adsorption effect. The optimal pH and solid-to-liquid ratio were 6 and 20 : 1, respectively. The alkaline environment is more conductive to colloid sorption. When the solid-to-liquid ratio was 20 : 1, the sorption percentage of PC is 0.5 times larger than PM. Although the PC has a longer adsorption equilibrium time, the percentage of adsorption can be larger than that in the other two cases. The kinetics and isotherms of Sr(II) were best described by the pseudo-second-order and Langmuir models. It was inferred that strong chemical interactions and/or surface complexation contributed primarily to Sr(II) sorption, and the process was on the monolayer adsorption of the outer surface. These findings provide valuable information for the migration behaviour of strontium in groundwater environments of geological disposal site. At the same time, it provides information for the implementation of permeable reactive barrier technology to control the transport of radioactive Sr(II) and its species in natural surface and groundwater.
Breast Cancer in San Francisco: Disentangling Disparities at the Neighborhood Level
Authors: Guan Alice , Lichtensztajn Daphne , Oh Debora , Jain Jennifer , Tao Li , Hiatt Robert A. , Gomez Scarlett Lin , Fejerman Laura
Published: September 2019

Background:

This study uses a novel geographic approach to summarize the distribution of breast cancer in San Francisco and aims to identify the neighborhoods and racial/ethnic groups that are disproportionately affected by this disease.

Methods:

Nine geographic groupings were newly defined on the basis of racial/ethnic composition and neighborhood socioeconomic status. Distribution of breast cancer cases from the Greater Bay Area Cancer Registry in these zones were examined. Multivariable logistic regression models were used to determine neighborhood associations with stage IIB+ breast cancer at diagnosis. Cox proportional hazards regression was used to estimate the hazard ratios for all-cause and breast cancer–specific mortality.

Results:

A total of 5,595 invasive primary breast cancers were diagnosed between January 1, 2006 and December 31, 2015. We found neighborhood and racial/ethnic differences in stage of diagnosis, molecular subtype, survival, and mortality. Patients in the Southeast (Bayview/Hunter's Point) and Northeast (Downtown, Civic Center, Chinatown, Nob Hill, Western Addition) areas were more likely to have stage IIB+ breast cancer at diagnosis, and those in the East (North Beach, Financial District, South of Market, Mission Bay, Potrero Hill) and Southeast were more likely to be diagnosed with triple-negative breast cancers (TNBC). Compared with other racial/ethnic groups, Blacks/African Americans (B/AA) experienced the greatest disparities in breast cancer–related outcomes across geographic areas.

Conclusions:

San Francisco neighborhoods with lower socioeconomic status and larger minority populations experience worse breast cancer outcomes.

Impact:

Our findings, which reveal breast cancer disparities at sub-county geographic levels, have implications for population-level health interventions.
FDA Approval Summary: Tagraxofusp-erzs For Treatment of Blastic Plasmacytoid Dendritic Cell Neoplasm
Authors: Jen Emily Y. , Gao Xin , Li Liang , Zhuang Luning , Simpson Natalie E. , Aryal Baikuntha , Wang Rong , Przepiorka Donna , Shen Yuan Li , Leong Ruby , Liu Chao , Sheth Christopher M. , Bowen Steven , Goldberg Kirsten B. , Farrell Ann T. , Blumenthal Gideon M. , Pazdur Richard
Published: September 2019

Tagraxofusp-erzs (Elzonris, Stemline) is a cytotoxin that targets CD123-expressing cells. On December 21, 2018, FDA approved tagraxofusp-erzs for the treatment of blastic plasmacytoid dendritic cell neoplasms (BPDCN) in adult and pediatric patients 2 years and older. Approval was based on the response rate in a single-arm trial, Study STML-401-0114; the pivotal cohort included 13 patients with treatment-naïve BPDCN who received tagraxofusp-erzs monotherapy. The complete response or clinical complete response (CR/CRc) rate in the pivotal cohort was 54% (95% CI: 25%–81%), and the median duration of CR/CRc was not reached with a median follow-up of 11.5 months (range: 0.2–12.7). In a separate exploratory cohort, a CR/CRc was achieved by 2 (13%) patients with R/R BPDCN. Safety was assessed in 94 patients with myeloid neoplasms treated with tagraxofusp-erzs at the approved dose and schedule. The major toxicity was capillary leak syndrome (CLS), which occurred in 55% of patients and was fatal in 2%. Hepatotoxicity and hypersensitivity reactions were reported in 88% and 46% of patients, respectively. Other common (≥30%) adverse reactions were nausea, fatigue, peripheral edema, pyrexia, and weight increase. A high proportion of patients (85%) developed neutralizing antidrug antibodies. Tagraxofusp-erzs is the first FDA-approved treatment for BPDCN.
Precision Medicine and the Practice of Trichiatry: Adapting the Concept
Authors: Trüeb Ralph M. , Jolliffe Vicky M.L. , Régnier Antonia Fellas , Dutra Rezende Hudson , Vañó-Galván Sergio , Kopera Daisy , Ioannides Demetrios , Gavazzoni Dias Maria Fernanda Reis , Macpherson Melanie , Gadzhigoroeva Aida , Ovcharenko Julya , Lee Won-Soo , Murugusundram Sundaram , Kurata Sotaro , Chang Mimi , Tanglertsampan Chuchai
Published: September 2019

Evidence-based medicine (EBM) aims for the ideal that healthcare professionals make conscientious, explicit, and judicious use of the best available evidence gained from the scientific method to clinical decision-making. It seeks to assess the strength of the evidence for benefits of diagnostic tests and treatments, using techniques from science, engineering, and statistics, such as the systematic review of medical literature, meta-analysis, risk-benefit analysis, and randomized controlled trials. The limited success rate of EBM therapies suggests that the complex nature of hair loss may be inadequately served by the present levels of evidence, and that physicians treating hair loss may have fallen short of adequately researching a robust evidence to underpin their practices. Against this backdrop, the concept of precision medicine (PM) is evolving. PM refers to the customization of medical care to the patient’s individual characteristics based on the patient’s genetic background and other molecular or cellular analysis, while classifying patients into subpopulations that differ in their susceptibility to a particular medical condition, in the biology or prognosis of those medical conditions, or in their response to a specific treatment. With the advances in hair research, the powerful tools of molecular biology and genetics, and innovative technologies, we have the robust scientific data and tools to adapt the concept of PM to the practice of trichiatry. Finally, databases pertaining to the development and efficacy of PM must be analyzed and be used to form the basis of evidence-based personalized trichiatry.
Ophthalmic Research Lecture 2018: DARC as a Potential Surrogate Marker
Authors: Yap Timothy E. , Shamsher Ehtesham , Guo Li , Cordeiro M. Francesca
Published: September 2019

Glaucoma is a progressive, neurodegenerative disease that is increasing in prevalence worldwide. There is a need to develop ways in which to diagnose the disease sooner and more reliably in order to prevent irreversible visual loss and meet the growing demands on healthcare services. Research into neuroprotective therapies in glaucoma is lacking a reliable surrogate marker in order to show treatment efficacy in a meaningful and cost-effective manner. The detection of apoptosing retinal cells (DARC) is a new technique that has promise in providing a solution to this unmet clinical need. Multiple animal studies have demonstrated its use as a biomarker in quantifying the effect of retinal neuroprotection methods, and it has recently been translated into humans in phase I and II trials, with phase I demonstrating the visualisation of individual apoptosing retinal cells in healthy and glaucomatous patients, with good safety and tolerability. The future for this technique will now be identifying disease-specific characteristics of human disease that can be used in order to provide us with a much-needed surrogate marker in the field of retinal neurodegeneration.
Is Low Psychomotor Speed a Marker of Brain Vulnerability in Late Life? Digit Symbol Substitution Test in the Prediction of Alzheimer, Parkinson, Stroke, Disability, and Depression
Authors: Amieva Hélène , Meillon Céline , Proust-Lima Cécile , Dartigues Jean François
Published: September 2019

Background: Dementia, stroke, depression, and disability are frequent in late life and are major causes of quality of life disruption and family burden. Even though each of these disorders relies on specific pathogenic processes, a common clinical manifestation is psychomotor slowing. Objective: We assessed the relevance of a simple marker of low psychomotor speed in predicting several brain outcomes: dementia, Alzheimer’s disease (AD), Parkinson’s disease (PD), stroke, depressive symptoms, and disability in activities of daily living (ADL) and instrumental ADL (IADL). Methods: PAQUID is a population-based study involving 3,777 individuals aged 65 or older prospectively followed-up with repeated clinical evaluations. After 10 years, 437 participants developed dementia, 333 developed AD, 71 developed PD, 207 reported incident stroke, 404 developed disability in ADL, 994 in IADL, and 494 developed depressive symptomology. Psychomotor speed was measured with the digit symbol substitution test (DSST). Cox proportional hazards models controlled for several confounders assessed the risk of incident outcomes. Results: Participants with low DSST performance had increased risk of incident all-type dementia (hazard ratio [HR] 3.41, p < 0.0001) and AD-type dementia (HR 3.18, p < 0.0001). Higher risk for PD (HR 2.98, p = 0.04), IADL (HR 1.82, p < 0.0001), ADL disability (HR 1.95, p = 0.001), depressive symptoms (HR 1.53, p = 0.03), and a statistical trend for stroke (HR 1.88, p = 0.09) was also found. Conclusion: Low psychomotor speed is associated with an increased risk of developing various brain outcomes: dementia, AD, PD, disability, depressive symptoms, and marginally stroke. Low psychomotor speed may be the consequence of a number of discrete cerebral abnormalities and could be considered as a marker of brain vulnerability. In clinical practice, a low score in DSST should be seen as a warning sign of possible negative evolution.
Critical Factors for Binaural Hearing in Children with Bilateral Sequential Cochlear Implantation: First Implant Performance and Inter-Implant Interval
Authors: Jang Jeong Hun , Roh Ji-Min , Choo Oak Sung , Kim You-Jeong , Kim Hantai , Park Hun Yi , Choung Yun-Hoon
Published: September 2019

Objectives: This study evaluated the influence of the performance of the first cochlear implant (CI-1) on the second implant (CI-2) and the significance of inter-implant intervals in children with sequential cochlear implantation. Method: Thirty-four patients were included for speech perception outcome and 38 patients were included for subjective hearing satisfaction in daily life in this study. The patients were classified into 3 groups according to inter-implant interval: group I, <4 years; group II, 4–7 years; group III, >7 years. Open-set speech perception scores before and at 3, 6, 12, and 24 months after the second implantation was compared among the CI-1, CI-2, and bilateral CI conditions. Subjective hearing benefits in daily life were measured using a questionnaire of Speech, Spatial, and Qualities of Hearing Scale (SSQ) for parents of children with impaired hearing, and device use and preference were evaluated (by phone interview.) Results: The speech perception of children using the CI-2 only improved quickly within 3 months postoperatively and were similar to those using the CI-1 only. The results of monosyllabic and disyllabic word tests using CI-2 at 3 months after second implantation were not significantly different from those in patients using the CI-1 only. In the sentence test, the scores using the CI-2 only were not significantly different from those using the first implant only at 6 months after second implantation. SSQ scores were similar among groups and the worst score in each section was shown from the questions about performance under noisy conditions in each section. Device usage habits showed that 17 (44.7%) and 16 (42.1%) patients preferred bilateral and the CI-1, respectively. Only 5 (13.2%) patients wanted the CI-2 rather than the CI-1. While group I and II showed a prominent positive attitude to bilateral use, group III, for which the inter-implant interval was 7 years or more, showed a definite preference for the CI-1 (p < 0.01). Conclusions: Functional binaural benefits were achieved in patients who were good performers with the CI-1 after the second implantation irrespective of the inter-implant interval. Sequential CI should be strongly recommended for patients with unilateral CI showing a good performance.
Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma
Authors: Holmberg Leona A. , Green Damian , Libby Edward , Becker P.S.
Published: September 2019

Background: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT. Patients and Methods: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles. Results: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12–9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression. Conclusions: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.
Potential Food Availability Influences Social Interactions of Young Individuals in a Neotropical Primate (Alouatta palliata)
Authors: del Toro Cristina Jasso , Mondragón-Ceballos Ricardo , Gutiérrez-García Genaro
Published: September 2019

Deforestation is widely recognised as an agent of human disturbance that causes widespread destruction of species habitats and can result in animals occupying forest patches with limited food resources. When animals are forced to change habitats, they must also adjust their diet, activity budgets and social behaviour in response to facing new ecological and environmental conditions. Only a few studies have analysed the influence of habitat conditions on social interactions of immature howler monkeys. In this study, we examined the effects of variation in food availability on social interactions of young howler monkeys (Alouatta palliata mexicana). This was accomplished by observing infant and juvenile members of two groups inhabiting a continuous forest habitat (640 ha) and three groups living in different-sized forest fragments (4, 42 and 93 ha) for a 15-month non-consecutive period. We quantified the Potential Food Availability Index (PFAI) for each habitat type based on the basal area, the Shannon-Wiener diversity index and abundance of food tree species. We used 15-min focal animal sampling to record the occurrence and/or duration of affiliative and agonistic behaviours. In habitats with higher PFAI, we observed more social play and proximity in infants aged 4–7 months, grooming in infants aged 8–14 months and social play in juveniles. Conversely, juveniles’ grooming rates and 0- to 3-month-old infants’ proximity rates decreased as PFAI increased. Our results suggest that food resource variation influences young howler monkeys’ social interactions. The reduction in social interactions due to low food availability may represent an energy-saving strategy to cope with limited resources in habitats disturbed by anthropogenic activities.
Clinical Characteristics of Jra Alloimmunization in Pregnancy: A Case Series
Authors: Kanagawa Takeshi , Fujikawa Eri , Mimura Kazuya , Endo Masayuki , Sasahara Jun , Kimura Tadashi , Mitsuda Nobuaki , Ishii Keisuke
Published: September 2019

Only few studies have reported on Jra alloimmunization in pregnancy, and its clinical course remains unclear. We reviewed our cases to clarify the change in the peak systolic velocity of the middle cerebral artery (MCA-PSV) during pregnancy and the critical anti-Jra antibody titer to predict fetal anemia. We collected the data of pregnant women with anti-Jra antibody from two hospitals between 2010 and 2017. We extracted data on maternal information, number of intrauterine blood transfusions (IUT), trend of anti-Jra antibody titer, changes of MCA-PSV, and neonatal outcome. We had 16 cases. IUTs were performed in 6 fetuses with severe anemia between 27 and 32 weeks’ gestation. The MCA-PSV did not increase more than 1.5 multiples of the median (MoM) after 32 weeks’ gestation. No significant difference was found in the maximum titer between cases with IUT and those without IUT. All pregnancies but one delivered at term. No neonates developed severe anemia or jaundice. MCA-PSV did not increase higher than 1.5 MoM later during the pregnancy. A critical titer to predict fetal anemia did not exist. Spontaneous term delivery could be expected even in fetuses who underwent IUT before 32 weeks’ gestation.
Feasibility and Safety of Intraoperative Optical Coherence Tomography-Guided Short-Term Posturing Prescription after Macular Hole Surgery
Authors: Lorusso Massimo , Micelli Ferrari Luisa , Cicinelli Maria Vittoria , Nikolopoulou Eleni , Zito Roberta , Bandello Francesco , Querques Giuseppe , Micelli Ferrari Tommaso
Published: September 2019

Purpose: To assess closure rate and visual outcome of a court of patients with macular hole (MH) who underwent surgical repair with intraoperative optical coherence tomography (iOCT)-confirmed MH closure and short-term postoperative face-down posturing (FDP). Secondary aim was to assess the correlation between iOCT and postoperative OCT at day 1. Methods: Retrospective clinical study conducted in the Miulli Hospital Acquaviva delle Fonti (Italy), enrolling patients with idiopathic MH who underwent 25-G pars plana vitrectomy plus internal limiting membrane peeling. During surgery, closure of MH was confirmed by iOCT and short-term FDP (12–24 h, until day-1 visit) was prescribed. All patients had measurement of best-corrected visual acuity (BCVA) and spectral domain-OCT before the surgery and during follow-up (at 1 day, 1 month, 3 months). Results: Twenty-nine eyes of 29 patients (14 males, 62.1%) were enrolled in the study. MH mean size was 451.7 ± 139.7 µm and baseline BCVA was 0.77 ± 0.26 logarithm of the minimum angle of resolution (LogMAR). MH was confirmed to be closed in 100% of patients intraoperatively (iOCT) and at OCT during early follow-up (1–3 days). Mean time of FDP was 18 ± 2.6 h. At 3 months, MH closure rate was 93%; 2 eyes ­underwent secondary MH repair surgery. Final BCVA was 0.39 ± 0.22 LogMAR (p < 0.0001). Conclusion: iOCT-based confirmation of MH closure could be a safe and useful tool for prescribing short-term FDP after surgery, with high closure rate and no additional complication. The execution of an OCT in the immediate postoperative days could be potentially unnecessary.
The Next Generation: Chatbots in Clinical Psychology and Psychotherapy to Foster Mental Health – A Scoping Review
Authors: Bendig Eileen , Erb Benjamin , Schulze-Thuesing Lea , Baumeister Harald
Published: September 2019

Background and Purpose: The present age of digitalization brings with it progress and new possibilities for health care in general and clinical psychology/psychotherapy in particular. Internet- and mobile-based interventions (IMIs) have often been evaluated. A fully automated version of IMIs are chatbots. Chatbots are automated computer programs that are able to hold, e.g., a script-based conversation with a human being. Chatbots could contribute to the extension of health care services. The aim of this review is to conceptualize the scope and to work out the current state of the art of chatbots fostering mental health. Methods: The present article is a scoping review on chatbots in clinical psychology and psychotherapy. Studies that utilized chatbots to foster mental health were included. Results: The technology of chatbots is still experimental in nature. Studies are most often pilot studies by nature. The field lacks high-quality evidence derived from randomized controlled studies. Results with regard to practicability, feasibility, and acceptance of chatbots to foster mental health are promising but not yet directly transferable to psychotherapeutic contexts. ­Discussion: The rapidly increasing research on chatbots in the field of clinical psychology and psychotherapy requires corrective measures. Issues like effectiveness, sustainability, and especially safety and subsequent tests of technology are elements that should be instituted as a corrective for future funding programs of chatbots in clinical psychology and psychotherapy.
New Cell Block Method to Enhance the Cellular Yield in Mucous and/or Bloody Samples
Authors: Hakso-Mäkinen Heli , Kholová Ivana
Published: September 2019

Objective: Cell blocks (CBs) are used to complement cytological diagnosis and for ancillary testing. Dissatisfaction with the cellular yield of the CB is widely recognized. Various techniques have been developed to increase the diagnostic utility of CBs. Study Design: We invented a new CB technique to increase cellular yield and diagnostic accuracy suitable especially for mucous and/or bloody cytological samples. Results: The new CB technique is described in detail with illustrations and cases, where it increased the cellular yield and diagnostic accuracy. CBs prepared by this method are suitable also for ancillary techniques, namely immunocytochemistry. Conclusions: The newly described method showed a better cellular yield in mucous and/or bloody cytological specimens.
A Brain Imaging-Based Diagnostic Biomarker for Periodic Catatonia: Preliminary Evidence Using a Bayesian Approach
Authors: Foucher Jack René , de Billy Clément , Jeanjean Ludovic Christophe , Obrecht Alexandre , Mainberger Olivier , Clauss Julie Marie Estelle , Schorr Benoit , Lupu Madalina Carmen , de Sousa Paulo Loureiro , Lamy Julien , Noblet Vincent , Sauleau Erik André , Landré Lionel , Berna Fabrice
Published: September 2019

Periodic catatonia (PC) is a psychomotor phenotype with a progressive-remitting course. While it can fit any disorder diagnosis of the schizoaffective spectrum, its core features consist of a mix of hypo- and hyperkinesias resulting in distortions of expressive movements such as grimacing and parakinesias. The replication of cerebral blood flow (CBF) increases in the left supplementary motor area (L-SMA) and lateral premotor cortex (L-LPM) in acute and remitting PC patients indicates that these increases could be used as diagnostic biomarkers. In this proof-of-concept study, 2 different MRI sequences were repeated on 3 separate days to get reliable measurement values of CBF in 9 PC and 26 non-PC patients during different cognitive tasks. Each patient was compared to 37 controls. In L-SMA [–9; +10; +60] and L-LPM [–46; –12; +43], a test was positive if the t value was >2.02 (α < 0.05; two tailed). The measurements had good analytical performance. Regarding the tests, their sensitivities and specificities were significantly different from the chance level on both measures, except for L-SMA sensitivities. When combining all the tests, among regions and methods, sensitivity was 98% (95% credible interval [CI] 76–100%) and specificity 88% (72–97%). Bayesian inferences of its negative predictive values for PC were >95% regardless of the context, while its positive predictive values reached 94% but only when used in combination with clinical criteria. The case-by-case analysis suggests that non-PC patients with neurological motor deficits are at risk to be false positive.
Social Status May Interfere in the Prognosis of Frontal Fibrosing Alopecia in Female Patients: An Observational Study
Authors: Papanikou Sofia , Xydeas-Kikemenis Anastasia , Nicolaidou Electra , Chatziioannou Argiro , Rigopoulos Dimitrios , Stratigos Alexandros , Chasapi Vasiliki
Published: September 2019

Introduction: Frontal fibrosing alopecia (FFA) is a cicatricial alopecia whose incidence has greatly increased worldwide over the last years. The main purpose of the study was to investigate the possible association of the social status of FFA patients with the prognosis of the disease. Methods: A total of 100 female patients with FFA, monitored at Andreas Sygros Hospital, Athens, Greece, during the last 3 years, were recruited in this observational study. The age of the women ranged from 29 to 92 years with a mean age of 61.2 years (SD = 10.3); 97% of them were Greek, with skin type II and III. Results: In total, 46% of the patients were intermediate graduates, and 42% had received tertiary education; 82% were married and 21% had 1 child. The duration of the disease ranged from 0.5 to 20 years with a mean duration of 5.2 years. In 53% of the women, the frontal hairline recession was <1 cm, in 26% it was 1–2 cm, and in 15% it was 3–4.99 cm. Overall, 55.6% of patients were professionals, 26% were technicians and associate professionals, 23% were office workers, 9% were service and sales workers, and 13% were at elementary occupations. The severity of the disease was higher in lower-educated patients, who belong to the category of unskilled or with elementary occupation. Conclusions: Women with high educational level and social status are more likely to be diagnosed earlier, resulting in sufficient therapeutic response.