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OBJECTIVE: Despite the availability of pharmacological treatment for seizures, people with epilepsy (PwE) commonly experience impairments in quality of life (QoL). Given the limited access to psychosocial treatments for PwE, digital interventions could bridge treatment gaps and help improve QoL. The objective of this study was to examine the effectiveness of emyna, a fully automated digital intervention based on cognitive behavioral therapy (CBT) techniques, in improving health-related QoL among PwE who reported impairments in QoL. A previous trial showed that emyna was effective in improving depressive symptoms among PwE with a comorbid depressive disorder, but its effects on QoL among PwE without comorbid depression remain unknown. METHODS: A pragmatic randomized controlled trial was conducted with N = 438 PwE (mean age = 37.5, 70.3% women, physician-verified diagnoses) who were assigned to the intervention group (n = 216), which used emyna alongside treatment as usual (TAU), or the control group (n = 222), which received TAU only. QoL and secondary outcomes such as general self-efficacy, medication adherence, general distress, and epilepsy-related work and social adjustment were assessed at baseline, 3 months, and 6 months. The primary outcome was QoL assessed with the Quality of Life in Epilepsy [QOLIE-31] total score at 3 months post-randomization. RESULTS: Findings from the intent-to-treat analyses showed that after 3 months, participants in the intervention group experienced significant and clinically relevant improvements in health-related QoL compared to the control group (baseline-adjusted group difference = 4.5; 95% CI = [2.0, 6.9], p < 0.001; Cohen's d = 0.32). Effects on secondary outcomes did not reach statistical significance. SIGNIFICANCE: This study extends previous research by demonstrating that emyna facilitates improvements in QoL in a diverse group of PwE treated in routine care settings. This CBT-based digital intervention therefore presents a convenient and cost-effective addition to healthcare providers' treatment repertoire. PLAIN LANGUAGE SUMMARY: In our study, we tested a digital program called emyna, which conveys cognitive behavioral therapy (CBT) techniques to help improve the quality of life for people living with epilepsy. We found that those who used emyna alongside their usual treatments felt better about their quality of life compared to those who did not use the program. Emyna offers a new, convenient way for people with epilepsy to manage their condition, which can be used alongside currently available treatments.
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RNA interference (RNAi) is a gene-silencing mechanism triggered by the cytosolic entry of double-stranded RNAs (dsRNAs). Many animal cells internalize extracellular dsRNAs via endocytosis for RNAi induction. However, it is not clear how the endocytosed dsRNAs are translocated into the cytosol across the endo/lysosomal membrane. Herein, we show that in Drosophila S2 cells, endocytosed dsRNAs induce lysosomal membrane permeabilization (LMP) that allows cytosolic dsRNA translocation. LMP mediated by dsRNAs requires the lysosomal Cl-/H+ antiporter ClC-b/DmOstm1. In clc-b or dmostm1 knockout S2 cells, extracellular dsRNAs are endocytosed and reach the lysosomes normally but fail to enter the cytosol. Pharmacological induction of LMP restores extracellular dsRNA-directed RNAi in clc-b or dmostm1-knockout cells. Furthermore, clc-b or dmostm1 mutant flies are defective in extracellular dsRNA-directed RNAi and its associated antiviral immunity. Therefore, endocytosed dsRNAs have an intrinsic ability to induce ClC-b/DmOstm1-dependent LMP that allows cytosolic dsRNA translocation for RNAi responses in Drosophila cells.
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Citosol , Proteínas de Drosophila , Endocitosis , Lisosomas , Interferencia de ARN , ARN Bicatenario , Animales , ARN Bicatenario/metabolismo , Lisosomas/metabolismo , Citosol/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Canales de Cloruro/metabolismo , Canales de Cloruro/genética , Línea Celular , Membranas Intracelulares/metabolismo , Permeabilidad , Drosophila/metabolismo , Drosophila/genéticaRESUMEN
BACKGROUND: To examine the pathological effect of a mesial temporal seizure onset zone (SOZ) on local and inter-regional response to faces in the amygdala and other structures of the temporal lobe. METHODS: Intracranial EEG data was obtained from the amygdala, hippocampus, fusiform gyrus and parahippocampal gyrus of nine patients with drug-refractory epilepsy during visual stimulation with faces and mosaics. We analyzed event-related potentials (ERP), gamma frequency power, phase-amplitude coupling and phase-slope-index and compared the results between patients with versus without a mesial temporal SOZ. RESULTS: In the amygdala and fusiform gyrus, faces triggered higher ERP amplitudes compared to mosaics in both patient groups and higher gamma power in patients without a mesial temporal SOZ. In the hippocampus, famous faces triggered higher gamma power for both groups combined but did not affect ERPs in either group. The differentiated ERP response to famous faces in the parahippocampal gyrus was more pronounced in patients without a mesial temporal SOZ. Phase-amplitude coupling and phase-slope-index results yielded bidirectional modulation between amygdala and fusiform gyrus, and predominately unidirectional modulation between parahippocampal gyrus and hippocampus. CONCLUSIONS: A mesial temporal SOZ was associated with an impaired response to faces in the amygdala, fusiform gyrus and parahippocampal gyrus in our patients. Compared to this, the response to faces in the hippocampus was impaired in patients with, as well as without, a mesial temporal SOZ. Our results support existing evidence for face processing deficits in patients with a mesial temporal SOZ and suggest the pathological effect of a mesial temporal SOZ on the amygdala to play a pivotal role in this matter in particular.
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Epilepsia del Lóbulo Temporal , Epilepsia , Electrocorticografía/métodos , Epilepsia del Lóbulo Temporal/patología , Potenciales Evocados , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética/métodos , Convulsiones/patologíaRESUMEN
PURPOSE: To assess clinical and demographic characteristics in two cohorts of elderly patients with drug-resistant focal epilepsy, undergoing resective epilepsy surgery (RES). Further, to determine seizure, neuropsychological, and mental health outcomes after RES and evaluate possible influencing factors. METHODS: Consecutive patients aged ≥50 years with temporal lobe epilepsy (TLE) who underwent curative RES in the Hamburg epilepsy surgery program (2004-2017) were identified. Data were retrospectively analyzed. Seizure outcome was classified according to ILAE and Engel outcome scales in patients with first-time surgeries and with reoperations. Previously reported predictors of the seizure outcome were evaluated using regression analyses. Changes in verbal memory were assessed for patients with complete pre- and postoperative datasets (n=30) using repeated-measures analysis of variance. For evaluation of possible predictors of psychopathologic changes after RES a regression analysis was conducted. RESULTS: Fifty-one elderly patients underwent RES of the temporal lobe, including twelve aged ≥60 years, and five with reoperations. After one year, 65% of the patients with first-time surgeries were seizure free and 91% had a favorable outcome. At last follow-up, 49% were seizure free since surgery. Three reoperated patients had an Engel I outcome. Seizure outcome was not dependent on age at surgery, duration of epilepsy, or other evaluated variables. There was no significant decline in the memory performance after surgery. Significant improvements in mental health were found. CONCLUSION: RES for drug-resistant TLE is safe, effective, and improves mental health also in patients aged ≥ 50 years. Thus, it should be evaluated as the treatment of choice also in this age group.
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Epilepsia del Lóbulo Temporal , Epilepsia , Trastornos Mentales , Anciano , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Estudios Retrospectivos , Convulsiones/cirugía , Resultado del TratamientoRESUMEN
Across the animal kingdom, macrophages are known for their functions in innate immunity, but they also play key roles in development and homeostasis. Recent insights from single cell profiling and other approaches in the invertebrate model organism Drosophila melanogaster reveal substantial diversity among Drosophila macrophages (plasmatocytes). Together with vertebrate studies that show genuine expression signatures of macrophages based on their organ microenvironments, it is expected that Drosophila macrophage functional diversity is shaped by their anatomical locations and systemic conditions. In vivo evidence for diverse macrophage functions has already been well established by Drosophila genetics: Drosophila macrophages play key roles in various aspects of development and organogenesis, including embryogenesis and development of the nervous, digestive, and reproductive systems. Macrophages further maintain homeostasis in various organ systems and promote regeneration following organ damage and injury. The interdependence and interplay of tissues and their local macrophage populations in Drosophila have implications for understanding principles of organ development and homeostasis in a wide range of species.
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PURPOSE: It is unknown which patient education strategy before epilepsy surgery or stereotactic electrode implantation is best for patients. This prospective and randomized clinical study investigates whether the use of the mixed reality tool "VSI Patient Education" (VSI PE) running on HoloLens® glasses is superior to the use of a rubber brain model as a 3-dimensional tool for patient education before epilepsy surgery and stereotactic electrode implantation. MATERIAL AND METHODS: 17 patients with indication for epilepsy surgery or stereotactic electrode implantation were included in the study and randomized into two groups. All patients were informed with both comparative tools VSI PE (apoQlar®) and a rubber brain model (3B Scientific®) in a chronological order depending on group assignment. Afterwards, the patient and, if present, a relative (12) each filled out a questionnaire. For statistical analysis, Wilcoxon rank-sum tests were performed. RESULTS: Patients found their patient education highly significantly more comprehensible (p = 0.001**, r = 0.84) and almost significantly more imaginable (p=0.020, r = 0.57), when their doctor used VSI PE compared to the rubber brain model. The patients felt significantly less anxious as a result of VSI PE (p = 0.008*, r = 0.64). Highly significantly more patients chose VSI PE as the preferred patient education tool (p < 0.001**, r = 0.91), and almost significantly more patients decided VSI PE to be the future standard tool (p = 0.020, r = 0.56). Significantly more relatives chose VSI PE as the preferred patient education tool (p = 0.004*, r = 0.83), and significantly more relatives decided VSI PE to be the future standard tool (p = 0.002*, r = 0.91). CONCLUSION: VSI Patient Education is a promising new mixed reality tool for informing patients before epileptic surgery or stereotactic electrode implantation in order to enhance comprehension and imagination and reduce fear and worries. It might strengthen patient commitment and have a positive influence on patients' decisions in favor of medically indicated surgical operations.
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Encéfalo/cirugía , Estimulación Encefálica Profunda , Electrodos Implantados , Epilepsia/cirugía , Educación del Paciente como Asunto , Adulto , Realidad Aumentada , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
The use of adult Drosophila melanogaster as a model for hematopoiesis or organismal immunity has been debated. Addressing this question, we identify an extensive reservoir of blood cells (hemocytes) at the respiratory epithelia (tracheal air sacs) of the thorax and head. Lineage tracing and functional analyses demonstrate that the majority of adult hemocytes are phagocytic macrophages (plasmatocytes) from the embryonic lineage that parallels vertebrate tissue macrophages. Surprisingly, we find no sign of adult hemocyte expansion. Instead, hemocytes play a role in relaying an innate immune response to the blood cell reservoir: through Imd signaling and the Jak/Stat pathway ligand Upd3, hemocytes act as sentinels of bacterial infection, inducing expression of the antimicrobial peptide Drosocin in respiratory epithelia and colocalizing fat body domains. Drosocin expression in turn promotes animal survival after infection. Our work identifies a multi-signal relay of organismal humoral immunity, establishing adult Drosophila as model for inter-organ immunity.
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Células Sanguíneas/metabolismo , Hematopoyesis/fisiología , Macrófagos/metabolismo , Mucosa Respiratoria/metabolismo , Animales , Drosophila/metabolismo , Hemocitos/metabolismo , Inmunidad Celular/inmunología , Inmunidad Innata/inmunología , Quinasas Janus/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Microbial cell components from the intestinal microbiota spread systemically in a healthy host, posing the threat of inappropriate immune activation. In this issue of Immunity, Troha et al. identify a key role for renal function in the clearance of circulating Lys-type peptidoglycan, revealing a mechanism that keeps these inflammatory triggers in check to maintain systemic immune homeostasis.
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Microbioma Gastrointestinal , Microbiota , Homeostasis , Inmunidad , PeptidoglicanoRESUMEN
OBJECTIVE: Depression and anxiety are highly prevalent among people with epilepsy (PwE) but often remain unrecognized and treated inadequately. Effective psychosocial treatments such as cognitive behavioral therapy (CBT) are rarely available to most PwE, which is one reason electronically delivered CBT (eCBT) is regarded as promising. This study examined an eCBT intervention, termed Emyna, that was tailored to suit the needs of PwE. It includes CBT-related content on depression, stress and anxiety, seizure triggers and auras, and lifestyle habits. The trial examined the efficacy of Emyna in reducing symptoms of depression (primary outcome) and anxiety as well as improving quality of life. METHODS: Participants (N = 200) with epilepsy, a diagnosis of a depressive disorder, and at least moderate depressive symptoms were randomized to Emyna or care as usual. At baseline and after 3, 6, and 9 months, participants were invited to complete online questionnaires. The primary outcome was improvement of depressive symptoms at 3 months. RESULTS: Relative to the control group, intervention group participants experienced significantly greater improvements in depression, anxiety, stress, social-occupational impairment, and epilepsy-related quality of life, in both intention-to-treat (ITT) and per-protocol analyses. In ITT analyses, effects of medium magnitude were observed, as measured by the Patient Health Questionnaire-9 items (Cohen d = 0.54, 95% confidence interval [CI] = 0.25-0.82, P < 0.001) and the Neurological Disorders Depression Inventory for Epilepsy (d = 0.51, 95% CI = 0.23-0.79, P < 0.01). At 3 months, intervention group participants also reported fewer illness-related days off work and fewer days hospitalized over the preceding months, compared to control group participants (P ≤ 0.05), whereas no such differences were present at baseline (P > 0.30). SIGNIFICANCE: These findings showed that Emyna, used adjunctively to usual care, could help improve mental health, social-occupational functioning, and quality of life among PwE. The program provides an additional treatment option that could produce clinically relevant symptom reductions and reduce key cost drivers (ie, hospitalization rates and illness-related inability to work).
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Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Epilepsia/psicología , Intervención basada en la Internet , Telemedicina/métodos , Adulto , Depresión/etiología , Epilepsia/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
An outstanding question in animal development, tissue homeostasis and disease is how cell populations adapt to sensory inputs. During Drosophila larval development, hematopoietic sites are in direct contact with sensory neuron clusters of the peripheral nervous system (PNS), and blood cells (hemocytes) require the PNS for their survival and recruitment to these microenvironments, known as Hematopoietic Pockets. Here we report that Activin-ß, a TGF-ß family ligand, is expressed by sensory neurons of the PNS and regulates the proliferation and adhesion of hemocytes. These hemocyte responses depend on PNS activity, as shown by agonist treatment and transient silencing of sensory neurons. Activin-ß has a key role in this regulation, which is apparent from reporter expression and mutant analyses. This mechanism of local sensory neurons controlling blood cell adaptation invites evolutionary parallels with vertebrate hematopoietic progenitors and the independent myeloid system of tissue macrophages, whose regulation by local microenvironments remain undefined.
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Proteínas de Drosophila/metabolismo , Drosophila melanogaster/crecimiento & desarrollo , Hematopoyesis , Sistema Hematopoyético/metabolismo , Hemocitos/metabolismo , Subunidades beta de Inhibinas/metabolismo , Larva/crecimiento & desarrollo , Células Receptoras Sensoriales/metabolismo , Animales , Carbacol/farmacología , Supervivencia Celular , Microambiente Celular , Agonistas Colinérgicos/farmacología , Proteínas de Drosophila/efectos de los fármacos , Drosophila melanogaster/efectos de los fármacos , Drosophila melanogaster/metabolismo , Sistema Hematopoyético/efectos de los fármacos , Hemocitos/efectos de los fármacos , Larva/efectos de los fármacos , Larva/metabolismo , Sistema Nervioso Periférico/efectos de los fármacos , Sistema Nervioso Periférico/metabolismo , Células Receptoras Sensoriales/efectos de los fármacosRESUMEN
BACKGROUND: Depression is common among persons with epilepsy (PwE), affecting roughly one in three individuals, and its presence is associated with personal suffering, impaired quality of life, and worse prognosis. Despite the availability of effective treatments, depression is often overlooked and treated inadequately in PwE, in part because of assumed concerns over drug interactions or proconvulsant effects of antidepressants. Internet-administered psychological interventions might complement antidepressant medication or psychotherapy, and preliminary evidence suggests that they can be effective. However, no trial has yet examined whether an Internet intervention designed to meet the needs of PwE can achieve sustained reductions in depression and related symptoms, such as anxiety, when offered as adjunct to treatment as usual. METHODS/DESIGN: This randomized controlled trial will include 200 participants with epilepsy and a current depressive disorder, along with currently at least moderately elevated depression (Patient Health Questionnaire (PHQ-9) sum score of at least 10). Patients will be recruited via epilepsy treatment centers and other sources, including Internet forums, newspaper articles, flyers, posters, and media articles or advertisements, in German-speaking countries. Main inclusion criteria are: self-reported diagnosis of epilepsy and a depressive disorder, as assessed with a phone-administered structured diagnostic interview, none or stable antidepressant medication, no current psychotherapy, no other major psychiatric disorder, no acute suicidality. Participants will be randomly assigned to either (1) a care-as-usual/waitlist (CAU/WL) control group, in which they receive CAU and are given access to the Internet intervention after 3 months (that is, a CAU/WL control group), or (2) a treatment group that may also use CAU and in addition immediately receives six-month access to the novel, Internet-administered intervention. The primary outcome measure is the PHQ-9, collected at three months post-baseline; secondary measures include self-reported anxiety, work and social adjustment, epilepsy symptoms (including seizure frequency and severity), medication adherence, potential negative treatment effects and health-related quality of life. Measurements are collected online at pre-treatment (T0), three months (T1), six months (T2), and nine months (T3). DISCUSSION: Results of this trial are expected to extend the body of knowledge with regard to effective and efficient treatment options for PwE who experience elevated depression and anxiety. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02791724 . Registered 01 June 2016.
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Terapia Cognitivo-Conductual/métodos , Depresión/terapia , Epilepsia/psicología , Internet , Psicoterapia/métodos , Adulto , Antidepresivos/uso terapéutico , Protocolos Clínicos , Depresión/psicología , Epilepsia/complicaciones , Femenino , Servicios de Salud , Humanos , Masculino , Persona de Mediana Edad , Calidad de Vida , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
OBJECTIVE: Selective amygdalohippocampectomy (sAHE) is a well-established treatment for temporal lobe epilepsy, commonly with favorable neuropsychological outcome. Yet, it is still unknown if subsequent resection of the anteromesial temporal lobe (AMTLR), when necessary, deteriorates neuropsychological performance in this selected group of patients. Thus, we evaluated the clinical and neuropsychological data of patients who, due to insufficient seizure control after sAHE, received a subsequent ipsilateral AMTLR and compared these findings with patients who did not receive a second resection (control group). METHODS: Patients' characteristics and neuropsychological data were assessed and analyzed in the reoperated as well as in the control group at each step of treatment. Experienced neuropsychologists conducted the standardized examination focusing on verbal, figural and working memory, speech fluency and attention. Preoperative diagnostics included further continuous video-electroencephalography monitoring, high-resolution magnetic resonance imaging and functional transcranial Doppler sonography. RESULTS: Eighty patients having received sAHE in our center from 11/2007 to 02/2013 were included in this study. Seventeen of these patients underwent subsequent AMTLR. Thirteen of these were available for follow-up after the second surgery and twelve had a comprehensive neuropsychological testing at all three steps. Analyzing the neuropsychological data revealed no significant differences compared with controls. On the individual level, the data demonstrated that improvement in a subdomain was more frequent than decline, if the performance had already deteriorated after the first procedure. Seizure control improved significantly (p < 0.001) in all patients after subsequent AMTLR resulting in seven patients being seizure-free at follow-up. SIGNIFICANCE: Subsequent AMTLR following sAHE can be a safe procedure to improve seizure outcome in selected patients. In our series the risk for further neuropsychological deterioration after the second procedure was low. The neuropsychological performance after the sAHE can be a valuable criterion to advise patients who are eligible for a second surgery on their risk of further cognitive decline.
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Amígdala del Cerebelo/cirugía , Lobectomía Temporal Anterior/efectos adversos , Trastornos del Conocimiento/etiología , Epilepsia del Lóbulo Temporal/cirugía , Hipocampo/cirugía , Adolescente , Adulto , Anciano , Amígdala del Cerebelo/diagnóstico por imagen , Trastornos del Conocimiento/diagnóstico , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Femenino , Hipocampo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas , Estudios Retrospectivos , Adulto JovenRESUMEN
Apoptosis-induced proliferation (AiP) is a compensatory mechanism to maintain tissue size and morphology following unexpected cell loss during normal development, and may also be a contributing factor to cancer and drug resistance. In apoptotic cells, caspase-initiated signaling cascades lead to the downstream production of mitogenic factors and the proliferation of neighboring surviving cells. In epithelial cells of Drosophila imaginal discs, the Caspase-9 ortholog Dronc drives AiP via activation of Jun N-terminal kinase (JNK); however, the specific mechanisms of JNK activation remain unknown. Here we show that caspase-induced activation of JNK during AiP depends on an inflammatory response. This is mediated by extracellular reactive oxygen species (ROSs) generated by the NADPH oxidase Duox in epithelial disc cells. Extracellular ROSs activate Drosophila macrophages (hemocytes), which in turn trigger JNK activity in epithelial cells by signaling through the tumor necrosis factor (TNF) ortholog Eiger. We propose that in an immortalized ("undead") model of AiP, signaling back and forth between epithelial disc cells and hemocytes by extracellular ROSs and TNF/Eiger drives overgrowth of the disc epithelium. These data illustrate a bidirectional cell-cell communication pathway with implication for tissue repair, regeneration, and cancer.
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Apoptosis , Proliferación Celular , Drosophila melanogaster/metabolismo , Macrófagos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Caspasas/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimología , Drosophila melanogaster/crecimiento & desarrollo , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , LarvaRESUMEN
In vertebrates, hematopoiesis is regulated by inductive microenvironments (niches). Likewise, in the invertebrate model organism Drosophila melanogaster, inductive microenvironments known as larval Hematopoietic Pockets (HPs) have been identified as anatomical sites for the development and regulation of blood cells (hemocytes), in particular of the self-renewing macrophage lineage. HPs are segmentally repeated pockets between the epidermis and muscle layers of the larva, which also comprise sensory neurons of the peripheral nervous system. In the larva, resident (sessile) hemocytes are exposed to anti-apoptotic, adhesive and proliferative cues from these sensory neurons and potentially other components of the HPs, such as the lining muscle and epithelial layers. During normal development, gradual release of resident hemocytes from the HPs fuels the population of circulating hemocytes, which culminates in the release of most of the resident hemocytes at the beginning of metamorphosis. Immune assaults, physical injury or mechanical disturbance trigger the premature release of resident hemocytes into circulation. The switch of larval hemocytes between resident locations and circulation raises the need for a common standard/procedure to selectively isolate and quantify these two populations of blood cells from single Drosophila larvae. Accordingly, this protocol describes an automated method to release and quantify the resident and circulating hemocytes from single larvae. The method facilitates ex vivo approaches, and may be adapted to serve a variety of developmental stages of Drosophila and other invertebrate organisms.
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Ectopic calcification is a driving force for a variety of diseases, including kidney stones and atherosclerosis, but initiating factors remain largely unknown. Given its importance in seemingly divergent disease processes, identifying fundamental principal actors for ectopic calcification may have broad translational significance. Here we establish a Drosophila melanogaster model for ectopic calcification by inhibiting xanthine dehydrogenase whose deficiency leads to kidney stones in humans and dogs. Micro X-ray absorption near edge spectroscopy (µXANES) synchrotron analyses revealed high enrichment of zinc in the Drosophila equivalent of kidney stones, which was also observed in human kidney stones and Randall's plaques (early calcifications seen in human kidneys thought to be the precursor for renal stones). To further test the role of zinc in driving mineralization, we inhibited zinc transporter genes in the ZnT family and observed suppression of Drosophila stone formation. Taken together, genetic, dietary, and pharmacologic interventions to lower zinc confirm a critical role for zinc in driving the process of heterogeneous nucleation that eventually leads to stone formation. Our findings open a novel perspective on the etiology of urinary stones and related diseases, which may lead to the identification of new preventive and therapeutic approaches.
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Proteínas de Transporte de Catión/metabolismo , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Cálculos Renales/metabolismo , Xantina Deshidrogenasa/metabolismo , Zinc/metabolismo , Alopurinol/farmacología , Animales , Proteínas de Transporte de Catión/antagonistas & inhibidores , Proteínas de Transporte de Catión/genética , Quelantes/farmacología , Proteínas en la Dieta/farmacología , Modelos Animales de Enfermedad , Perros , Proteínas de Drosophila/antagonistas & inhibidores , Proteínas de Drosophila/genética , Drosophila melanogaster/genética , Etilenodiaminas/farmacología , Expresión Génica , Humanos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Cálculos Renales/genética , Cálculos Renales/patología , Cálculos Renales/prevención & control , Túbulos de Malpighi/química , Túbulos de Malpighi/efectos de los fármacos , Túbulos de Malpighi/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Espectroscopía de Absorción de Rayos X , Xantina Deshidrogenasa/antagonistas & inhibidores , Xantina Deshidrogenasa/genéticaRESUMEN
In multicellular organisms, cell number is typically determined by a balance of intracellular signals that positively and negatively regulate cell survival and proliferation. Dissecting these signaling networks facilitates the understanding of normal development and tumorigenesis. Here, we study signaling by the Drosophila PDGF/VEGF Receptor (Pvr) in embryonic blood cells (hemocytes) and in the related cell line Kc as a model for the requirement of PDGF/VEGF receptors in vertebrate cell survival and proliferation. The system allows the investigation of downstream and parallel signaling networks, based on the ability of Pvr to activate Ras/Erk, Akt/TOR, and yet-uncharacterized signaling pathway/s, which redundantly mediate cell survival and contribute to proliferation. Using Kc cells, we performed a genome wide RNAi screen for regulators of cell number in a sensitized, Pvr deficient background. We identified the receptor tyrosine kinase (RTK) Insulin-like receptor (InR) as a major Pvr Enhancer, and the nuclear hormone receptors Ecdysone receptor (EcR) and ultraspiracle (usp), corresponding to mammalian Retinoid X Receptor (RXR), as Pvr Suppressors. In vivo analysis in the Drosophila embryo revealed a previously unrecognized role for EcR to promote apoptotic death of embryonic blood cells, which is balanced with pro-survival signaling by Pvr and InR. Phosphoproteomic analysis demonstrates distinct modes of cell number regulation by EcR and RTK signaling. We define common phosphorylation targets of Pvr and InR that include regulators of cell survival, and unique targets responsible for specialized receptor functions. Interestingly, our analysis reveals that the selection of phosphorylation targets by signaling receptors shows qualitative changes depending on the signaling status of the cell, which may have wide-reaching implications for other cell regulatory systems.
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Drosophila melanogaster/citología , Hemocitos/citología , Animales , Apoptosis , Línea Celular , Supervivencia Celular , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Estudio de Asociación del Genoma Completo , Hemocitos/metabolismo , Insulina/metabolismo , Interferencia de ARN , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores de Esteroides/metabolismo , Transducción de SeñalRESUMEN
The invertebrate Drosophila melanogaster has been a powerful model for understanding blood cell development and immunity. Drosophila is a holometabolous insect, which transitions through a series of life stages from embryo, larva and pupa to adulthood. In spite of this, remarkable parallels exist between Drosophila and vertebrate macrophages, both in terms of development and function. More than 90% of Drosophila blood cells (hemocytes) are macrophages (plasmatocytes), making this highly tractable genetic system attractive for studying a variety of questions in macrophage biology. In vertebrates, recent findings revealed that macrophages have two independent origins: self-renewing macrophages, which reside and proliferate in local microenvironments in a variety of tissues, and macrophages of the monocyte lineage, which derive from hematopoietic stem or progenitor cells. Like vertebrates, Drosophila possesses two macrophage lineages with a conserved dual ontogeny. These parallels allow us to take advantage of the Drosophila model when investigating macrophage lineage specification, maintenance and amplification, and the induction of macrophages and their progenitors by local microenvironments and systemic cues. Beyond macrophage development, Drosophila further serves as a paradigm for understanding the mechanisms underlying macrophage function and cellular immunity in infection, tissue homeostasis and cancer, throughout development and adult life.
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Drosophila melanogaster/citología , Drosophila melanogaster/inmunología , Inmunidad Celular , Macrófagos/inmunología , Animales , Células Sanguíneas/inmunología , Linaje de la Célula , Macrófagos/citologíaRESUMEN
OBJECTIVE: Depression is the most prevalent psychiatric disorder in persons with epilepsy (PWEs). Despite its major impact on quality of life and risk of suicide, most PWEs are not treated for depression. A current challenge in mental health care is how to close this treatment gap and increase access to psychological services. Psychological online interventions (POIs) have shown efficacy in improving depression among individuals without neurologic disorders. This pilot study aimed to assess the feasibility and efficacy of a psychological online intervention for depression (Deprexis) in PWEs who have symptoms of depression. METHODS: Participants with self-reported epilepsy and subjective complaints of depressive symptoms were randomized to an intervention condition (Deprexis) or to a waiting list control (WLC) condition. After 9 weeks, participants were invited to complete an online reassessment. RESULTS: Relative to the waiting list group, program users experienced a significant symptom decline on the Beck Depression Inventory - I (BDI-I, primary outcome) with a moderate effect size in the complete observations analysis and a small effect size in the intention-to-treat analysis. Furthermore, there was a significant improvement with a moderate effect size on the "energy/fatigue" subscale of the Quality of Life In Epilepsy Inventory - 31 (QOLIE-31). SIGNIFICANCE: The results of this trial suggest that POIs may be a feasible and beneficial tool for PWEs who have comorbid depressive symptoms.
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Depresión/rehabilitación , Epilepsia/rehabilitación , Sistemas en Línea , Procesos Psicoterapéuticos , Adulto , Depresión/complicaciones , Depresión/psicología , Epilepsia/complicaciones , Epilepsia/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Escalas de Valoración Psiquiátrica , Calidad de Vida , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Fish, mice, and humans rely on two coexisting myeloid blood cell systems. One is sustained by hematopoietic progenitor cells, which reside in specialized microenvironments (niches) in hematopoietic organs and give rise to cells of the monocyte lineage. The other system corresponds to the independent lineage of self-renewing tissue macrophages, which colonize organs during embryonic development and are maintained during later life by proliferation in local tissue microenvironments. However, little is known about the nature of these microenvironments and their regulation. Moreover, many vertebrate tissues contain a mix of both tissue-resident and monocyte-derived macrophages, posing a challenge to the study of lineage-specific regulatory mechanisms and function. This review highlights how research in the simple model organism Drosophila melanogaster can address many of these outstanding questions in the field. Drawing parallels between hematopoiesis in Drosophila and vertebrates, we illustrate the evolutionary conservation of the two myeloid systems across animal phyla. Much like vertebrates, Drosophila possesses a lineage of self-renewing tissue-resident macrophages, which we refer to as tissue hemocytes, as well as a "definitive" lineage of macrophages that derive from hematopoiesis in the progenitor-based lymph gland. We summarize key findings from Drosophila hematopoiesis that illustrate how local microenvironments, systemic signals, immune challenges, and nervous inputs regulate adaptive responses of tissue-resident macrophages and progenitor-based hematopoiesis to maximize fitness of the animal.
Asunto(s)
Drosophila melanogaster/fisiología , Hematopoyesis , Células Mieloides/fisiología , Adaptación Fisiológica , Animales , Linaje de la Célula , Drosophila melanogaster/embriología , Células Madre Hematopoyéticas/fisiología , Macrófagos/fisiología , Modelos Animales , Nicho de Células MadreRESUMEN
OBJECTIVE: Epilepsy surgery is a standard treatment option for medically intractable temporal lobe epilepsy. Selective amygdalohippocampectomy (SAH) and anterior temporal lobectomy (ATL) are two of the standard surgical procedures in these cases. We conducted a retrospective analysis of patients treated with SAH via a modified transsylvian approach in our epilepsy center between 2008 and 2011, and we analyzed the impact of adjacent procedure-related infarctions on seizure outcome in these patients. METHODS: Infarctions were detected by magnetic resonance imaging (MRI) within the first week postoperatively and by a second MRI 9 months after surgical intervention. Neuropsychological testing was performed preoperatively. Evaluation of seizure outcome and postoperative neuropsychological testing were conducted approximately 1 year after epilepsy surgery. Correlative clinical data were analyzed by retrospective chart review. RESULTS: The postoperative MRI revealed temporal infarctions in 47.9% (n = 23/48) and frontal infarctions in 10.4% (n = 5/48) of the patients. These vascular events were asymptomatic in terms of focal neurologic deficits. Of the patients, 68.5% (n = 37/54) were free of disabling seizures (Engel class I) 1 year after the procedure. Patients with temporal infarctions were significantly more often free of disabling seizures (Engel class I, p = 0.046) than patients without temporal infarctions. Neuropsychological testing indicated a deterioration in verbal memory after SAH in patients with infarctions on the language-lateralized hemisphere compared to patients without infarction (p = 0.011). All other tested neuropsychological categories showed no significant differences between patients with or without infarctions. SIGNIFICANCE: Our results indicate a surprisingly high number of procedure-related temporal infarctions after transsylvian SAH. Hence, the volume of nonfunctional "eliminated" tissue is enlarged unintentionally, which is a possible explanation for better seizure outcome in these patients. This result supports the notion that ATL is the favorable procedure for temporal lobe epilepsy compared to SAH in the nondominant hemisphere, as neuropsychological deficits are rarely to be expected.