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BACKGROUND AND OBJECTIVE: Although the mouse is a widely used animal model in biomedical research, there are few published studies on its nasal aerodynamics, potentially due to its small size. It is not appropriate to assume that mice and rats' nasal structure and airflow characteristics are the same because the ratio of nasal surface area to nasal volume and body weight is much higher in a mouse than in a rat. The aim of this work is to use anatomically accurate image-based computational fluid dynamic modeling to quantitatively reveal the characteristics of mouse nasal airflow and mass transport that haven't been detailed before and find key differences to that of rat nose, which will deepen our understanding of the mouse's physiological functions. METHODS: We created an anatomically accurate 3D computational nasal model of a B6 mouse using postmortem high-resolution micro-CT scans and simulated the airflow distribution and odor transport patterns under restful breathing conditions. The deposition pattern of airborne particles was also simulated and validated against experimental data. In addition, we calculated the gas chromatograph efficiency of odor transport in the mouse employing the theoretical plate concept and compared it with previous studies involving cat and rat models. RESULTS: Similar to the published rat model, respiratory and olfactory flow regimes are clearly separated in the mouse nasal cavity. A high-speed dorsal medial (DM) stream was observed, which enhances the delivery speed and efficiency of odor to the ethmoid (olfactory) recess (ER). The DM stream split into axial and secondary paths in the ER. However, the secondary flow in the mouse is less extensive than in the rat. The gas chromatograph efficiency calculations suggest that the rat may possess a moderately higher odorant transport efficiency than that of the mouse due to its more complex ethmoid recess structure and extensive secondary flow. However, the mouse's nasal structure seems to adapt better to varying airflow velocity. CONCLUSIONS: Due to the inherent structural disparities, the rat and mouse models exhibit moderate differences in airflow and mass transport patterns, potentially impacting their olfaction and other behavioral habits.
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Cavidade Nasal , Animais , Ratos , Camundongos , Cavidade Nasal/diagnóstico por imagem , Cavidade Nasal/fisiologia , Cavidade Nasal/anatomia & histologia , Microtomografia por Raio-X , Nariz/fisiologia , Nariz/anatomia & histologia , Simulação por Computador , Odorantes , Modelos Anatômicos , Hidrodinâmica , Camundongos Endogâmicos C57BL , Imageamento TridimensionalRESUMO
The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilised 1H-NMR spectroscopy-based metabolomics, in situ enzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: (1) the mini-Krebs-cycle, fuelled by glutamine and branched chain amino acids, generating N-acetylaspartate; (2) the alanine-generating Cahill-cycle; (3) the lactate-releasing Cori-cycle. Moreover, the metabolomics data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.
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Ciclo do Ácido Cítrico , Glicólise , Fosforilação Oxidativa , Retina , Animais , Camundongos , Retina/metabolismo , Metabolismo Energético , Metabolômica , Epitélio Pigmentado da Retina/metabolismo , Células Fotorreceptoras Retinianas Bastonetes/metabolismo , Camundongos Endogâmicos C57BL , Células Fotorreceptoras Retinianas Cones/metabolismoRESUMO
INTRODUCTION: Recent studies have defined pseudoparesis as limited active forward elevation between 45° and 90° and maintained passive range of motion (ROM) in the setting of a massive rotator cuff tear (RCT). Although pseudoparesis can be reliably reversed with reverse total shoulder arthroplasty (RSA) or superior capsular reconstruction (SCR), the optimal treatment for this indication remains unknown. The purpose of this study was to compare the clinical outcomes of RSA to SCR in patients with pseudoparesis secondary to massive, irreparable RCT (miRCT). METHODS: This was a retrospective cohort study of consecutive patients aged 40-70 years with pseudoparesis secondary to miRCT who were treated with either RSA or SCR by a single fellowship-trained shoulder surgeon from 2016 to 2021 with a minimum 12-month follow-up. Multivariate linear regression modeling was used to compare active ROM, visual analog pain scale (VAS), Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form (ASES) score between RSA and SCR while controlling for confounding variables. RESULTS: Twenty-seven patients were included in the RSA cohort and 23 patients were included in the SCR cohort with similar mean follow-up times (26.2 ± 21.1 vs. 21.9 ± 14.7 months, respectively). The patients in the RSA group were significantly older than those in the SCR group (65.2 ± 4.4 vs. 54.2 ± 7.8 years, P < .001) and had more severe arthritis (1.8 ± 0.9 vs. 1.2 ± 0.5 Samilson-Prieto, P = .019). The pseudoparesis reversal rate among the RSA and SCR cohorts was 96.3% and 91.3%, respectively. On univariate analysis, the RSA cohort demonstrated significantly greater mean improvement in active FF (89° ± 26° vs. 73° ± 30° change, P = .048), greater postoperative SSV (91 ± 8% vs. 69 ± 25%, P < .001), lower postoperative VAS pain scores (0.6 ± 1.2 vs. 2.2 ± 2.9, P = .020), and less postoperative internal rotation (IR; 4.6° ± 1.6° vs. 6.9° ± 1.8°, P = .004) compared with SCR. On multivariate analysis controlling for age and osteoarthritis, RSA remained a significant predictor of greater SSV (ß = 21.5, P = .021) and lower VAS scores (ß = -1.4, P = .037), whereas SCR was predictive of greater IR ROM (ß = 3.0, P = .043). CONCLUSION: Although both RSA and SCR effectively reverse pseudoparesis, patients with RSA have higher SSV and lower pain scores but less IR after controlling for age and osteoarthritis. The results of this study may inform surgical decision making for patients who are suitable candidates for either procedure.
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Artroplastia do Ombro , Amplitude de Movimento Articular , Lesões do Manguito Rotador , Humanos , Pessoa de Meia-Idade , Masculino , Feminino , Estudos Retrospectivos , Lesões do Manguito Rotador/cirurgia , Lesões do Manguito Rotador/complicações , Idoso , Artroplastia do Ombro/métodos , Adulto , Procedimentos de Cirurgia Plástica/métodos , Resultado do Tratamento , Cápsula Articular/cirurgiaRESUMO
The peripheral structures of mammalian sensory organs often serve to support their functionality, such as alignment of hair cells to the mechanical properties of the inner ear. Here, we examined the structure-function relationship for mammalian olfaction by creating an anatomically accurate computational nasal model for the domestic cat (Felis catus) based on high resolution microCT and sequential histological sections. Our results showed a distinct separation of respiratory and olfactory flow regimes, featuring a high-speed dorsal medial stream that increases odor delivery speed and efficiency to the ethmoid olfactory region without compromising the filtration and conditioning purpose of the nose. These results corroborated previous findings in other mammalian species, which implicates a common theme to deal with the physical size limitation of the head that confines the nasal airway from increasing in length infinitely as a straight tube. We thus hypothesized that these ethmoid olfactory channels function as parallel coiled chromatograph channels, and further showed that the theoretical plate number, a widely-used indicator of gas chromatograph efficiency, is more than 100 times higher in the cat nose than an "amphibian-like" straight channel fitting the similar skull space, at restful breathing state. The parallel feature also reduces airflow speed within each coil, which is critical to achieve the high plate number, while feeding collectively from the high-speed dorsal medial stream so that total odor sampling speed is not sacrificed. The occurrence of ethmoid turbinates is an important step in the evolution of mammalian species that correlates to their expansive olfactory function and brain development. Our findings reveal novel mechanisms on how such structure may facilitate better olfactory performance, furthering our understanding of the successful adaptation of mammalian species, including F. catus, a popular pet, to diverse environments.
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Orelha Interna , Olfato , Gatos , Animais , Cabeça , Aclimatação , MamíferosRESUMO
Damage to long axons in white matter tracts is a major pathology in closed head traumatic brain injury (TBI). Acute TBI treatments are needed that protect against axon damage and promote recovery of axon function to prevent long term symptoms and neurodegeneration. Our prior characterization of axon damage and demyelination after TBI led us to examine repurposing of 4-aminopyridine (4-AP), an FDA-approved inhibitor of voltage-gated potassium (Kv) channels. 4-AP is currently indicated to provide symptomatic relief for patients with chronic stage multiple sclerosis, which involves axon damage and demyelination. We tested clinically relevant dosage of 4-AP as an acute treatment for experimental TBI and found multiple benefits in corpus callosum axons. This randomized, controlled pre-clinical study focused on the first week after TBI, when axons are particularly vulnerable. 4-AP treatment initiated one day post-injury dramatically reduced axon damage detected by intra-axonal fluorescence accumulations in Thy1-YFP mice of both sexes. Detailed electron microscopy in C57BL/6 mice showed that 4-AP reduced pathological features of mitochondrial swelling, cytoskeletal disruption, and demyelination at 7 days post-injury. Furthermore, 4-AP improved the molecular organization of axon nodal regions by restoring disrupted paranode domains and reducing Kv1.2 channel dispersion. 4-AP treatment did not resolve deficits in action potential conduction across the corpus callosum, based on ex vivo electrophysiological recordings at 7 days post-TBI. Thus, this first study of 4-AP effects on axon damage in the acute period demonstrates a significant decrease in multiple pathological hallmarks of axon damage after experimental TBI.
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Lesões Encefálicas Traumáticas , Esclerose Múltipla , Animais , Feminino , Masculino , Camundongos , 4-Aminopiridina/farmacologia , 4-Aminopiridina/uso terapêutico , Axônios/patologia , Lesões Encefálicas Traumáticas/patologia , Camundongos Endogâmicos C57BL , Esclerose Múltipla/patologiaRESUMO
Survival motor neuron (SMN) protein deficiency results in loss of alpha motor neurons and subsequent muscle atrophy in patients with spinal muscular atrophy (SMA). Reactive microglia have been reported in SMA mice and depleting microglia rescues the number of proprioceptive synapses, suggesting a role in SMA pathology. Here, we explore the contribution of lymphocytes on microglia reactivity in SMA mice and investigate how SMN deficiency alters the reactive profile of human induced pluripotent stem cell (iPSC)-derived microglia. We show that microglia adopt a reactive morphology in spinal cords of SMA mice. Ablating lymphocytes did not alter the reactive morphology of SMA microglia and did not improve the survival or motor function of SMA mice, indicating limited impact of peripheral immune cells on the SMA phenotype. We found iPSC-derived SMA microglia adopted an amoeboid morphology and displayed a reactive transcriptome profile, increased cell migration, and enhanced phagocytic activity. Importantly, cell morphology and electrophysiological properties of motor neurons were altered when they were incubated with conditioned media from SMA microglia. Together, these data reveal that SMN-deficient microglia adopt a reactive profile and exhibit an exaggerated inflammatory response with potential impact on SMA neuropathology.
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Células-Tronco Pluripotentes Induzidas , Atrofia Muscular Espinal , Deficiência de Proteína , Animais , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Microglia/metabolismo , Neurônios Motores/patologia , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/metabolismo , Atrofia Muscular Espinal/patologia , Deficiência de Proteína/metabolismo , Deficiência de Proteína/patologia , Proteína 1 de Sobrevivência do Neurônio Motor/genética , Proteína 1 de Sobrevivência do Neurônio Motor/metabolismoRESUMO
BACKGROUND: Very little is known about the long-term prevalence of severe venous obstruction and occlusion in patients with transvenous implantable cardioverter-defibrillator leads. The objective of the current investigation was to elucidate the incidence and prevalence and to identify predisposing conditions in an ICD cohort over a long follow-up period. METHODS: Based on a prospective database, we analyzed consecutive patients who received an ICD implantation in our hospital between 06/1988 and 2009 as well as all corresponding follow-up data until 02/2018. Cavographies were used for analysis, and all patients with at least one device replacement and one follow-up cavography were included. RESULTS: Over a mean follow-up period of 94 ± 50 months, severe venous obstruction was found in 147 (33%) of 448 patients. Kaplan-Meier analysis shows a severe obstruction or occlusion in 50% of patients after a period of 14.3 years. The total number of leads (p < .001, HR 2.01, CI 2.000-2.022), an advanced age (p = .004, HR 1.023 per year, CI 1.022-1.024) and the presence of dilated cardiomyopathy (p = .035, HR 1.49, CI 1.47-1.51) were predictive of venous obstruction whereas the presence of anticoagulation was not. CONCLUSION: Severe obstruction of the access veins after ICD implantation occurs frequently and its prevalence shows a nearly linear increase over long-time follow-up. Multiple leads, an advanced age and DCM as underlying disease are associated with an increased risk of venous obstruction while the role of anticoagulation to prevent venous obstruction in ICD patients is unclear.
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Desfibriladores Implantáveis/efeitos adversos , Doenças Vasculares Periféricas/etiologia , Extremidade Superior/irrigação sanguínea , Constrição Patológica/epidemiologia , Constrição Patológica/etiologia , Feminino , Alemanha/epidemiologia , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Doenças Vasculares Periféricas/epidemiologia , Estudos ProspectivosRESUMO
While offering high-precision control of neural circuits, optogenetics is hampered by the necessity to implant fiber-optic waveguides in order to deliver photons to genetically engineered light-gated neurons in the brain. Unlike laser light, X-rays freely pass biological barriers. Here we show that radioluminescent Gd2(WO4)3:Eu nanoparticles, which absorb external X-rays energy and then downconvert it into optical photons with wavelengths of â¼610 nm, can be used for the transcranial stimulation of cortical neurons expressing red-shifted, â¼590-630 nm, channelrhodopsin ReaChR, thereby promoting optogenetic neural control to the practical implementation of minimally invasive wireless deep brain stimulation.
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Nanopartículas , Optogenética , Luz , Neurônios , FótonsRESUMO
PURPOSE: To observe the technical and clinical outcome as well as safety of CT fluoroscopy-guided drain placement in the multimodal clinical complication management of superinfected gastric leakage after sleeve gastrectomy. MATERIALS AND METHODS: All consecutive patients who underwent CT fluoroscopy-guided drain placement to treat superinfected postoperative leakage after sleeve gastrectomy in our department between 2007 and 2014 were included in this retrospective study. All interventions were performed on a 16- or 128-row CT scanner under intermittent CT fluoroscopy guidance (15-25âmAs, 120âkV). The technical and clinical success rates as well as complications, additional therapies and patient radiation dose were analyzed. RESULTS: 14 patients (mean age: 43.8â±â11.3 years, mean BMI: 52.9â±â13.5, 7 women) who underwent a total of 31 CT fluoroscopy-guided drain placement procedures were included. 30 of 31 interventions (96.8â%) were technically successful. 7 patients underwent more than one intervention due to drain obstruction or secondary dislocation or as further treatment. During and after the intervention no procedure-associated complications occurred. In all patients, inflammation parameters decreased within days after the CT-guided intervention. The total interventional dose length product (DLP) was 1561â±â1035 mGy*cm. CONCLUSION: CT fluoroscopy-guided drain placement has been shown to be a safe minimally invasive procedure that rarely leads to complications for treating superinfected gastric leakage occurring after sleeve gastrectomy. We assume that operative revisions in a high-risk patient group can be avoided using this procedure. KEY POINTS: · CT fluoroscopy-guided drain placement in obese - often medically highly complex - patients is a technically feasible procedure.. · Multimodal treatment (CT intervention, endoscopy and surgery) is required to successfully treat gastric leakage after bariatric surgery.. · High-risk surgery might be avoided by the CT-guided drain placement.. CITATION FORMAT: · Schwarz J, Strobl FF, Paprottka PM etâal. CT Fluoroscopy-Guided Drain Placement to Treat Infected Gastric Leakage after Sleeve Gastrectomy: Technical and Clinical Outcome of 31 Procedures. Fortschr Röntgenstr 2020; 192: 163â-â170.
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Fístula Anastomótica/cirurgia , Drenagem/métodos , Fluoroscopia/métodos , Gastrectomia , Cirurgia Assistida por Computador/métodos , Infecção da Ferida Cirúrgica/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adulto , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
Human induced pluripotent stem (iPS) cell-derived neurons and astrocytes are attractive cellular tools for nervous system disease modeling and drug screening. Optimal utilization of these tools requires differentiation protocols that efficiently generate functional cell phenotypes in vitro. As nervous system function is dependent on networked neuronal activity involving both neuronal and astrocytic synaptic functions, we examined astrocyte effects on the functional maturation of neurons from human iPS cell-derived neural stem cells (NSCs). We first demonstrate human iPS cell-derived NSCs can be rapidly differentiated in culture to either neurons or astrocytes with characteristic cellular, molecular and physiological features. Although differentiated neurons were capable of firing multiple action potentials (APs), few cells developed spontaneous electrical activity in culture. We show spontaneous electrical activity was significantly increased by neuronal differentiation of human NSCs on feeder layers of neonatal mouse cortical astrocytes. In contrast, co-culture on feeder layers of isogenic human iPS cell-derived astrocytes had no positive effect on spontaneous neuronal activity. Spontaneous electrical activity was dependent on glutamate receptor-channel function and occurred without changes in INa , IK , Vm , and AP properties of iPS cell-derived neurons. These data demonstrate co-culture with neonatal mouse cortical astrocytes but not human isogenic iPS cell-derived astrocytes stimulates glutamatergic synaptic transmission between iPS cell-derived neurons in culture. We present RNA-sequencing data for an immature, fetal-like status of our human iPS cell-derived astrocytes as one possible explanation for their failure to enhance synaptic activity in our co-culture system.
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Astrócitos/fisiologia , Córtex Cerebral/fisiologia , Células Alimentadoras/fisiologia , Células-Tronco Pluripotentes Induzidas/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Potenciais de Ação , Animais , Astrócitos/citologia , Linhagem Celular , Córtex Cerebral/citologia , Técnicas de Cocultura , Células Alimentadoras/citologia , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Camundongos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/fisiologia , Neurônios/citologia , Receptores de Glutamato/metabolismo , TranscriptomaRESUMO
As a lightweight metal with mechanical properties similar to natural bone, Mg and its alloys are great prospects for biodegradable, load bearing implants. However, rapid degradation and H2 gas production in physiological media has prevented widespread use of Mg alloys. Surface heterogeneities in the form of intermetallic particles dominate the corrosion response. This research shows that surface homogenization significantly improved the biological corrosion response observed during immersion in simulated body fluid (SBF). The laser processed Mg alloy exhibited a 50% reduction in mass loss and H2 evolution after 24 h of immersion in SBF when compared to the wrought, cast alloy. The laser processed samples exhibited increased wettability as evident from wetting angle studies, further suggesting improved biocompatibility. Electrochemical analysis by potentiodynamic polarization measurements showed that the anodic and cathodic kinetics were reduced following laser processing and are attributed to the surface chemical homogeneity.
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Ligas/química , Líquidos Corporais/química , Lasers , Corrosão , HumanosRESUMO
The surface area of the maxilloturbinals and fronto-ethmoturbinals is commonly used as an osteological proxy for the respiratory and the olfactory epithelium, respectively. However, this assumption does not fully account for animals with short snouts in which these two turbinal structures significantly overlap, potentially placing fronto-ethmoturbinals in the path of respiratory airflow. In these species, it is possible that anterior fronto-ethmoturbinals are covered with non-sensory (respiratory) epithelium instead of olfactory epithelium. In this study, we analyzed the distribution of olfactory and non-sensory, respiratory epithelia on the turbinals of two domestic cats (Felis catus) and a bobcat (Lynx rufus). We also conducted a computational fluid dynamics simulation of nasal airflow in the bobcat to explore the relationship between epithelial distribution and airflow patterns. The results showed that a substantial amount of respiratory airflow passes over the anterior fronto-ethmoturbinals, and that contrary to what has been observed in caniform carnivorans, much of the anterior ethmoturbinals are covered by non-sensory epithelium. This confirms that in short-snouted felids, portions of the fronto-ethmoturbinals have been recruited for respiration, and that estimates of olfactory epithelial coverage based purely on fronto-ethmoturbinal surface area will be exaggerated. The correlation between the shape of the anterior fronto-ethmoturbinals and the direction of respiratory airflow suggests that in short-snouted species, CT data alone are useful in assessing airflow patterns and epithelium distribution on the turbinals.
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Gatos/fisiologia , Lynx/fisiologia , Cavidade Nasal/fisiologia , Ventilação Pulmonar , Mucosa Respiratória/fisiologia , Animais , Masculino , Mucosa Olfatória/fisiologiaRESUMO
BACKGROUND: The possibilities of telemonitoring (TM) of patients with implantable cardioverter-defibrillators (ICD) have been rapidly improving over the last few years. Numerous studies have examined the effects of this development on the follow-up care of ICD patients. OBJECTIVES: Technical implementation and safety of ICD telemonitoring. Effects on the treatment of cardiac arrhythmias, the management of cardiac insufficiency patients and morbidity as well as mortality. Illustration of patient acceptance and cost-benefit assessment. MATERIALS AND METHODS: The current research situation regarding TM of ICDs is analyzed and the available evidence for the postulated advantages in the follow-up care of ICD patients are discussed. The current treatment guidelines and recommendations for implementation of TM in daily clinical praxis are presented. RESULTS AND CONCLUSIONS: TM offers the possibility of faster reaction times to arrhythmias, cardiac decompensation and ICD malfunctions. At the same time, the outpatient follow-ups can be reduced without negatively affecting safety, quality of life or patient acceptance. TM has the potential to cost-neutrally improve the safety of ICD therapy and could lead to optimized management of heart insufficiency patients, while reducing morbidity and mortality. Following the evidence of these benefits as shown in numerous studies, TM has already been included in the current therapy guidelines.
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Arritmias Cardíacas/mortalidade , Arritmias Cardíacas/prevenção & controle , Desfibriladores Implantáveis/estatística & dados numéricos , Telemetria/estatística & dados numéricos , Arritmias Cardíacas/diagnóstico , Medicina Baseada em Evidências , Humanos , Satisfação do Paciente , Prevalência , Medição de Risco , Taxa de Sobrevida , Telemedicina/estatística & dados numéricos , Resultado do TratamentoRESUMO
Implantable cardioverter-defibrillators are complex technical devices with a multitude of programming options for the physician. In recent years, numerous randomized trials have been performed to define the optimal programming strategies and have provided valuable insights, especially in primary prevention patients. This article provides an actual overview on the existing evidence on the most important programming features for accurate detection and therapy of ventricular arrhythmias.
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A woman presented with a solitary cardiac metastasis 5 months after curative surgery for endometrial adenocarcinoma (FIGO IB). The tumor was deemed inoperable and palliative ambulatory chemotherapy was initiated. We aimed at a palliative reduction of tumor mass after chemotherapy and atypical vascularization of the metastasis was demonstrated by coronary angiography. We identified two tumor vessels originating from the ramus circumflexus suitable to palliative percutaneous coronary intervention. Within 5 weeks, the initially mild dyspnea increased to New York Heart Association class III and readmission was planned. Regrettably, our patient died from congestive right heart failure only 2 months after diagnosis of tumor recurrence. This report illustrates the need for resolute action without delay even in cases of only mild right heart failure.
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BACKGROUND: Imatinib is a tyrosine kinase inhibitor of BCR-ABL, ABL, PDGFR-α and -ß, KIT, and DDR. In solid tumors, it inhibits proliferation and invasiveness and facilitates higher intratumoral cytotoxic drug concentrations. Vinorelbine has good tolerability and efficacy in metastatic breast cancer (MBC). This study evaluates the safety and efficacy of imatinib and vinorelbine in combination. METHODS: In a prospective, open-label, phase I/II trial, 400 mg imatinib p.o. daily (corrected from 600 mg) was combined with an escalating dose of vinorelbine i.v. weekly in four dose levels of 10, 15, 20, and 25 mg/m(2) (each n ≥ 5) to treat patients with MBC (expressing PDGFR-α and/or -ß, and/or KIT). The last patient of each level was treated for >28 days, before enrolment for the next dose level started. Study endpoints were feasibility and tolerability, incidence of hematological and nonhematological toxicity, and clinical efficacy (data cutoff: November 18, 2011). A total of 33 patients have been enrolled, and all dose levels have been fully recruited. One patient is still on study medication. A translational subprotocol is ongoing. RESULTS: All 33 included patients are evaluable for safety (32 within the ITT population). Eleven patients were excluded early from the study (progressive disease, toxicity, and withdrawal of consent). Twenty-two patients participated in the study for >28 days ('ITT >28'). Within the ITT population, the response rate [complete response (CR) and partial response (PR)] was 9.4% (n = 3), the clinical benefit rate (CBR; CR+PR+stable disease) 50% (n = 16), and the median time to progression (TTP) 155 days. A total of 21.3% of the patients were on study medication for >6 months, and 15.2% for >12 months (mean 140 days, range 15-643). Within 'ITT >28', the response rate was 13.6%, CBR 72.7%, and median TTP 176 days. The response was independent of the receptor status (PDGFR-α, -ß, and KIT). Toxicities were as follows (safety population): 21.6% severe leukopenia, 9.1% severe neutropenia (with 1 febrile neutropenia), 1 case of bowel perforation, 36% diarrhea (3% severe), 84.8% nausea (severe 15.2%), 48.5% vomiting (severe 9.1%), 27.3% infections (severe 6.1%), 12.1% peripheral neuropathy (severe 9.1%), and 36.4% dyspnea (3% severe). Four patients on trial died (nondrug-related). CONCLUSION: The combination of imatinib and vinorelbine in MBC appeared to be feasible and tolerable. A CBR of 50% (ITT) in pretreated patients suggests that this combination may be active. Although toxicities were frequent, they appeared to be manageable.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Benzamidas/administração & dosagem , Benzamidas/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Metástase Neoplásica , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Estudos Prospectivos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Vimblastina/administração & dosagem , Vimblastina/efeitos adversos , Vimblastina/análogos & derivados , VinorelbinaRESUMO
The post-occipital sinus of the spinal vein is often used for the collection of blood samples from crocodilians. Although this sampling method has been reported for several crocodilian species, the technique and associated anatomy has not been described in detail in any crocodilian, including the Nile crocodile (Crocodylus niloticus). The anatomy of the cranial neck region was investigated macroscopically, microscopically, radiographically and by means of computed tomography. Latex was injected into the spinal vein and spinal venous sinus of crocodiles to visualise the regional vasculature. The spinal vein ran within the vertebral canal, dorsal to and closely associated with the spinal cord and changed into a venous sinus cranially in the post-occipital region. For blood collection, the spinal venous sinus was accessed through the interarcuate space between the atlas and axis (C1 and C2) by inserting a needle angled just off the perpendicular in the midline through the craniodorsal cervical skin, just cranial to the cranial borders of the first cervical osteoderms. The most convenient method of blood collection was with a syringe and hypodermic needle. In addition, the suitability of the spinal venous sinus for intravenous injections and infusions in live crocodiles was evaluated. The internal diameter of the commercial human epidural catheters used during these investigations was relatively small, resulting in very slow infusion rates. Care should be taken not to puncture the spinal cord or to lacerate the blood vessel wall using this route for blood collection or intravenous infusions.
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Jacarés e Crocodilos/anatomia & histologia , Canal Medular/irrigação sanguínea , AnimaisRESUMO
PURPOSE: Percutaneous endoscopic gastrostomy (PEG) or percutaneous endoscopic jejunostomy (PEJ) are substantial for patients with swallowing disorders to maintain enteral nutrition or to decompress palliatively intractable small bowel obstruction. Endoscopic placement can be impossible due to previous (gastric) operation, obesity, hepato-splenomegaly, peritoneal carcinosis, inadequate transillumination, or obstructed passage. Computed tomography (CT)-fluoroscopic guidance with or without endoscopy can enable placement of CT-PG/CT-PJ or CT-PEG/CT-PEJ if endoscopically guided placement fails. In this retrospective study, we will evaluate the feasibility and safety of this method. METHODS: A total of 101 consecutive patients were referred to our department for feeding support (n = 87) or decompression (n = 14). Reasons were: ENT tumor (n = 51), esophageal cancer (n = 19), mediastinal mass (n = 2), neurological disorder (n = 15). Decompression tubes were placed because of cancer (n = 13) or Crohn's disease (n = 1). The following approaches were chosen: CT fluoroscopy and simultaneous gastroscopy (n = 61), inflation of the stomach via nasogastric tube (n = 29), and direct puncture under CT-fluoroscopic guidance (n = 11). RESULTS: CT fluoroscopy-guided gastrostomy was feasible in 89 of 101 patients. No procedure-related mortality was observed. One tube was misplaced into the colon in a patient with a history of gastrectomy. No complication was seen after removal. Minor complications: dislodgement (n = 17), peristomal leakage (n = 7), wound infection (n = 1), superficial skin infection (n = 6), tube obstruction (n = 2). CONCLUSIONS: CT fluoroscopy-guided PG/PJ or PEG/PEJ is feasible and safe and provides adequate feeding support or decompression. It offers the benefits of minimally invasive therapy even in patients with contraindications to established endoscopic methods, combining the advantages of both techniques. Long-term complications-mainly tube-related problems-are easily treated.
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Endoscopia Gastrointestinal , Nutrição Enteral/métodos , Gastrostomia/métodos , Intubação Gastrointestinal , Jejunostomia/métodos , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Fluoroscopia , Gastroscopia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
Annual mortality events in Nile crocodiles (Crocodylus niloticus) in the Olifants River Gorge in Kruger National Park, South Africa, were experienced between 2008 and 2012, during which at least 216 crocodiles died. Live crocodiles were lethargic. Necropsy examination of 56 affected crocodiles showed dark yellow-brown firm nodules in both somatic fat and the abdominal fat body. In all of the 11 crocodiles submitted for histology, degenerative, necrotic, and inflammatory changes supported a diagnosis of steatitis in both fat types. Crocodiles are apex predators in this anthropogenically changed aquatic ecosystem that is used by humans upstream and downstream from the park for domestic, agricultural, fishing, and recreational purposes. This pathologic review of pansteatitis in crocodiles in the Olifants River system was part of a broad multidisciplinary research program. To date, no definitive causative agent has been identified. Epidemiologic evidence suggests that this event may have been a one-time event with long-standing repercussions on the health of the crocodiles. Pathologic findings are rarely documented in wild crocodilians. This study also reports on other conditions, including the presence of coccidian oocysts, capillarid and filaroid nematodes, digenetic trematodes, and pentastomes.
Assuntos
Jacarés e Crocodilos , Esteatite/mortalidade , Tecido Adiposo/patologia , Animais , Ecossistema , Feminino , Masculino , África do Sul/epidemiologia , Esteatite/epidemiologia , Esteatite/etiologia , TemperaturaRESUMO
INTRODUCTION: Implantable cardioverter-defibrillator (ICD) longevity is crucial for both patients and public health systems because it determines the number of surgical ICD replacements, which can generally be considered an additional risk factor for complications, and the cost-effectiveness of ICD therapy. Our objective was to obtain insight into the "real-world" longevities of implantable cardioverter-defibrillators, which quite often differ from those stated in the manufacturers' declarations. METHODS AND RESULTS: On the basis of a prospective database, we analyzed all ICD implantations performed in our hospital from June 1988 to June 2009. We studied 980 patients (follow-up 58 ± 51 months) with 1,502 ICDs and all respective data until August 2010. We compared the percentage of still operating ICDs at different points in time in relation to manufacturers, types of device (single chamber 623, dual chamber 588, cardiac resynchronization therapy ICDs [CRT-D] 291), and amount of right ventricular pacing (VP). We found distinct differences between the mean lifespans of ICDs of different manufacturers (Biotronik 4.3 years, Sorin 4.5 years, Guidant/Boston Scientific 4.7 years, St. Jude Medical 5 years, Medtronic 5.8 years). CRT-D devices (hazard ratio [HR] 1.778, P = 0.0005) were associated with an elevated annual relative risk for device replacement while a decrease in the proportion of VP (HR 0.934 for each 10% decrease in VP, P < 0.0001) and Medtronic ICDs were associated with a reduced risk of device replacement (HR 0.544, P < 0.0001). CONCLUSION: CRT-Ds and an elevated percentage of VP are associated with a significantly elevated risk for device replacement, while Medtronic ICDs showed the longest lifespans.