RESUMO
PURPOSE: Our study compares perioperative outcomes between two-dimensional (2D) laparoscopic radical prostatectomy (LRP) and the 4th generation three-dimensional/high definition (3DHD) LRP. METHODS: Retrospectively acquired data from patients that underwent 2D LRP (n = 75) and 3DHD LRP (n = 75) from March 2013 to October 2015 were evaluated. Procedures were performed by a single surgeon. The extra-peritoneal approach with 5 trocars was utilized. Perioperative outcomes, potency, and continence were compared between groups. RESULTS: Patient characteristics were similar between the two groups in terms of age (p = 0.44), prostate-specific antigen (PSA) levels (p = 0.34), and Gleason scores (p = 0.14). Body mass index (BMI) was significantly higher in the 3DHD group (p = 0.0036). Postoperatively, no significant differences were observed in Hgb loss (p = 0.50), positive surgical margins (p = 1.00), and post-op Gleason scores (p = 0.30). Significant differences were observed for length of hospital stay (p < 0.001) and Jackson-Pratt (JP) drainage (p < 0.001). Regarding potency, 73.7% and 51.6% of the patients in the 3DHD and 2D groups regained potency at 6 months, respectively (p = 0.0025). Almost 43% of the patients in the 3DHD group regained continence at 1 month while for the 2D groups it was only 17.3% (p = 0.0008). CONCLUSION: 3DHD and 2D LRP have resulted in good outcomes in the perioperative periods. Our results show decreased JP drainage, shorter length of hospital stay, earlier return of urinary control, and earlier return of sexual function in the 3DHD LRP group. In lower volume centers where robotics equipment is not feasible due to economic barriers 3DHD can be safely performed as a minimally invasive alternative.
Assuntos
Laparoscopia , Neoplasias da Próstata , Masculino , Humanos , Estudos Retrospectivos , Neoplasias da Próstata/cirurgia , Resultado do Tratamento , Prostatectomia/métodos , Laparoscopia/métodosRESUMO
BACKGROUND: Organisms in the wild can acquire disease- and stress-resistance traits that outstrip the programs endogenous to humans. Finding the molecular basis of such natural resistance characters is a key goal of evolutionary genetics. Standard statistical-genetic methods toward this end can perform poorly in organismal systems that lack high rates of meiotic recombination, like Caenorhabditis worms. RESULTS: Here we discovered unique ER stress resistance in a wild Kenyan C. elegans isolate, which in inter-strain crosses was passed by hermaphrodite mothers to hybrid offspring. We developed an unbiased version of the reciprocal hemizygosity test, RH-seq, to explore the genetics of this parent-of-origin-dependent phenotype. Among top-scoring gene candidates from a partial-coverage RH-seq screen, we focused on the neuronally-expressed, cuticlin-like gene cutl-24 for validation. In gene-disruption and controlled crossing experiments, we found that cutl-24 was required in Kenyan hermaphrodite mothers for ER stress tolerance in their inter-strain hybrid offspring; cutl-24 was also a contributor to the trait in purebred backgrounds. CONCLUSIONS: These data establish the Kenyan strain allele of cutl-24 as a determinant of a natural stress-resistant state, and they set a precedent for the dissection of natural trait diversity in invertebrate animals without the need for a panel of meiotic recombinants.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis , Humanos , Animais , Caenorhabditis elegans/genética , Quênia , Fenótipo , Proteínas de Caenorhabditis elegans/genéticaRESUMO
OBJECTIVE: To compare acute treatment responses and long-term outcome in leucine-rich glioma-inactivated 1 (LGI1) antibody encephalitis. METHODS: Retrospective case series of 118 patients with LGI1 antibody encephalitis evaluated at Mayo Clinic across all US sites from 1 May 2008 to 31 March 2019. Patient clinical data were identified and analysed through the neuroimmunology laboratory and electronic medical record. LGI1 antibody detection was by cell-based indirect immunofluorescence assay of serum, cerebrospinal fluid or both. Clinical outcomes were faciobrachial dystonic seizure (FBDS) resolution, modified Rankin Scale (mRS) score, Kokmen Short Test of Mental Status (STMS) score (0-38 point scale) and neuropsychometric testing results. RESULTS: Compared with intravenous immunoglobulin (IVIg) (n=21), patients treated with single-agent acute corticosteroids (intravenous, oral or both) (n=49) were more likely to experience resolution of FBDS (61% vs 7%, p=0.002) and improvements in mRS score (ΔmRS score 2 vs 0, p=0.008) and median Kokmen STMS scores (ΔKokmen STMS score 5 points vs 0 points, p=0.01). In 54 patients with long-term follow-up (≥2 years), the median mRS score was 1 (range 0-6) and the median Kokmen STMS score was 36 (range 24-38) after all combinations of immunotherapy. Neuropsychometric testing in 32 patients with long-term follow-up (≥2 years) demonstrated short-term memory impairments in 37%. CONCLUSIONS: Corticosteroids appeared more effective acutely than IVIg in improving LGI1 antibody encephalitis in this retrospective comparison of immunotherapies. While improvement with immunotherapy is typical and long-term outcome is favourable, short-term memory deficits are noted in approximately a third of the patients.
Assuntos
Corticosteroides/uso terapêutico , Autoanticorpos , Doenças Autoimunes/tratamento farmacológico , Imunoglobulinas Intravenosas/uso terapêutico , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Encefalite Límbica/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/imunologia , Feminino , Humanos , Encefalite Límbica/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Cellular conformation of reduced pyridine nucleotides NADH and NADPH sensed using autofluorescence spectroscopy is presented as a real-time metabolic indicator under pressurized conditions. The approach provides information on the role of pressure in energy metabolism and antioxidant defense with applications in agriculture and food technologies. Here, we use spectral phasor analysis on UV-excited autofluorescence from Saccharomyces cerevisiae (baker's yeast) to assess the involvement of one or multiple NADH- or NADPH-linked pathways based on the presence of two-component spectral behavior during a metabolic response. To demonstrate metabolic monitoring under pressure, we first present the autofluorescence response to cyanide (a respiratory inhibitor) at 32 MPa. Although ambient and high-pressure responses remain similar, pressure itself also induces a response that is consistent with a change in cellular redox state and ROS production. Next, as an example of an autofluorescence response altered by pressurization, we investigate the response to ethanol at ambient, 12 MPa, and 30 MPa pressure. Ethanol (another respiratory inhibitor) and cyanide induce similar responses at ambient pressure. The onset of non-two-component spectral behavior upon pressurization suggests a change in the mechanism of ethanol action. Overall, results point to new avenues of investigation in piezophysiology by providing a way of visualizing metabolism and mitochondrial function under pressurized conditions.
Assuntos
NADP/química , NADP/metabolismo , NAD/química , NAD/metabolismo , Pressão , Fluorescência , Conformação MolecularRESUMO
BACKGROUND: Longitudinally extensive transverse myelitis (LETM) accompanying systemic lupus erythematosus (SLE) is often due to coexisting aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder but has not been associated with myelin oligodendrocyte glycoprotein-IgG (MOG-IgG). OBJECTIVE AND METHODS: Case report at an academic medical center. RESULTS: A 32-year-old woman developed severe transverse myelitis (paraplegia) shortly after SLE onset in the post-partum period. Magnetic resonance imaging (MRI) revealed an LETM, cerebrospinal fluid showed marked inflammation, and testing for infections was negative. Serum live-cell-based assay for MOG-IgG was positive but aquaporin-4-IgG was negative. CONCLUSION: In patients with SLE and LETM, MOG-IgG testing should be considered, in addition to AQP4-IgG.
Assuntos
Autoanticorpos/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Glicoproteína Mielina-Oligodendrócito/imunologia , Mielite Transversa/diagnóstico , Transtornos Puerperais/diagnóstico , Adulto , Aquaporina 4/imunologia , Feminino , Humanos , Imunoglobulina G , Imageamento por Ressonância Magnética , Mielite Transversa/sangue , Mielite Transversa/imunologia , Mielite Transversa/patologia , Transtornos Puerperais/sangue , Transtornos Puerperais/imunologia , Transtornos Puerperais/patologiaRESUMO
Bitopic integral membrane proteins with a single transmembrane helix play diverse roles in catalysis, cell signaling, and morphogenesis. Complete monospanning protein structures are needed to show how interaction between the transmembrane helix and catalytic domain might influence association with the membrane and function. We report crystal structures of full-length Saccharomyces cerevisiae lanosterol 14α-demethylase, a membrane monospanning cytochrome P450 of the CYP51 family that catalyzes the first postcyclization step in ergosterol biosynthesis and is inhibited by triazole drugs. The structures reveal a well-ordered N-terminal amphipathic helix preceding a putative transmembrane helix that would constrain the catalytic domain orientation to lie partly in the lipid bilayer. The structures locate the substrate lanosterol, identify putative substrate and product channels, and reveal constrained interactions with triazole antifungal drugs that are important for drug design and understanding drug resistance.
Assuntos
Domínio Catalítico/genética , Sistema Enzimático do Citocromo P-450/química , Bicamadas Lipídicas/metabolismo , Modelos Moleculares , Conformação Proteica , Proteínas de Saccharomyces cerevisiae/química , Cromatografia de Afinidade , Cromatografia em Gel , CristalizaçãoRESUMO
Antisense oligonucleotides (ASOs) conjugated to triantennary N-acetyl galactosamine (GalNAc) ligands represent an emerging approach to antisense therapy. Our current generation of GalNAc-ASO conjugates link the GalNAc to the 5'-terminus of the ASO. The conjugation reaction can be accomplished using solution-phase or solid-phase techniques. Here we show a direct comparison of a solution-phase and a solid-phase conjugation strategy. The solution-phase approach, using amine-pentafluorophenyl (PFP) ester coupling, is higher yielding and gives material of slightly higher purity, but requires several additional unit operations and longer production time. The solid-phase approach, using a protected GalNAc ligand phosphoramidite, is more expedient, but results in lower yield and purity. Both strategies efficiently deliver conjugated material in excellent purity.
Assuntos
Acetilgalactosamina/química , Técnicas de Química Sintética/métodos , Oligonucleotídeos Antissenso/química , Técnicas de Síntese em Fase Sólida/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Estrutura Molecular , SoluçõesRESUMO
The acetyl capping reaction used throughout solid phase oligonucleotide synthesis is meant to minimize n-1 deletionmer impurities by terminating sequences that fail to couple to a phosphoramidite. However, the reaction is also responsible for the formation of a number of impurities. One capping-related impurity has an additional mass of 98amu from the parent oligonucleotide. The n+98 amu impurity was found to result from modification of an adenine nucleobase. The structure of the impurity was determined by preparation of an oligonucleotide enriched in n+98 amu, enzymatic digestion to individual nucleosides, isolation of the pure nucleoside+98 amu species, crystallization, and X-ray crystallographic analysis. The n+98 amu impurity is an oligonucleotide in which one adenine residue has been converted to 5-amino-4-pyrimidinylimidazole. The mechanism of formation of the impurity was investigated, and a mechanism is proposed.
Assuntos
Adenina/química , Imidazóis/química , Oligonucleotídeos/síntese química , Modelos Moleculares , Estrutura Molecular , Oligonucleotídeos/químicaRESUMO
The acetyl 'capping' reaction routinely employed during phosphorothioate oligonucleotide synthesis has been implicated in the formation of an impurity species with a mass 41 amu greater than the expected oligonucleotide molecule. The impurity has been found to arise by conversion of a protected guanine nucleobase to N(2)-acetyl-2,6-diaminopurine. A two-part mechanism is proposed consisting of transamidation of the protecting group on guanine and substitution of guanine's O(6) atom.
Assuntos
2-Aminopurina/análogos & derivados , Oligonucleotídeos/síntese química , 2-Aminopurina/síntese química , 2-Aminopurina/química , Estrutura Molecular , Oligonucleotídeos/químicaRESUMO
Visual search can be guided by biasing one's attention towards features associated with a target. Prior work has shown that high-fidelity, picture-based cues are more beneficial to search than text-based cues. However, typically picture cues provide both detailed form information and color information that is absent from text-based cues. Given that visual resolution deteriorates with eccentricity, it is not clear that high-fidelity form information would benefit guidance to peripheral objects - much of the picture benefit could be due to color information alone. To address this, we conducted a search task with eye-tracking that had four types of cues that comprised a 2 (text/pictorial cue) × 2 (no color/color) design. We hypothesized that color information would be important for efficient search guidance while high-fidelity form information would be important for efficient verification times. In Experiment 1 cues were a colored picture of the target, a gray-scaled picture of the target, a text-based cue that included color (e.g., "blue shoe"), or a text-based cue without color (e.g., "shoe"). Experiment 2 was a replication of Experiment 1, except that the color word in the text-based cue was presented in the precise color that was the dominant color in the target. Our results show that high-fidelity form information is important for efficient verifications times (with color playing less of a role) and color is important for efficient guidance, but form information also benefits guidance. These results suggest that different features of the cue independently contribute to different aspects of the search process.
RESUMO
The low-prevalence effect (LPE) is the finding that target detection rates decline as targets become less frequent in a visual search task. A major source of this effect is thought to be that fewer targets result in lower quitting thresholds, i.e., observers respond target-absent after looking at fewer items compared to searches with a higher prevalence of targets. However, a lower quitting threshold does not directly account for an LPE in searches where observers continuously monitor a dynamic display for targets. In these tasks there are no discrete "trials" to which a quitting threshold could be applied. This study examines whether the LPE persists in this type of dynamic search context. Experiment 1 was a 2 (dynamic/static) x 2 (10%/40% prevalence targets) design. Although overall performance was worse in the dynamic task, both tasks showed a similar magnitude LPE. In Experiment 2, we replicated this effect using a task where subjects searched for either of two targets (Ts and Ls). One target appeared infrequently (10%) and the other moderately (40%). Given this method of manipulating prevalence rate, the quitting threshold explanation does not account for the LPE even for static displays. However, replicating Experiment 1, we found an LPE of similar magnitude for both search scenarios, and lower target detection rates with the dynamic displays, demonstrating the LPE is a potential concern for both static and dynamic searches. These findings suggest an activation threshold explanation of the LPE may better account for our observations than the traditional quitting threshold model.
RESUMO
This case report delineates the clinical trajectory and management strategies of a 59-year-old Hispanic male diagnosed with a left ventricular pseudoaneurysm (LVPA) following a delayed presentation of ST-segment elevation myocardial infarction (STEMI), for which reperfusion treatment was not administered. Initially, an echocardiogram demonstrated an extensive anterolateral myocardial infarction, severe left ventricular systolic dysfunction, and an early-stage left ventricular apical aneurysm with thrombus, leading to the initiation of warfarin. Metabolic myocardial perfusion imaging via positron emission tomography indicated a substantial myocardial scar without viability, guiding the decision against revascularization. Post discharge, the patient, equipped with a wearable cardioverter defibrillator for sudden cardiac death prevention, experienced symptomatic ventricular tachycardia, which was resolved with defibrillator shocks. Subsequent imaging revealed an acute LVPA adjacent to the existing left ventricular aneurysm. Given the high surgical risk, conservative management was elected, resulting in thrombosis and closure of the pseudoaneurysm after two weeks. The patient eventually transitioned to home hospice, surviving an additional five months. This report underscores the complexities and therapeutic dilemmas in managing post-MI LVPA patients who are ineligible for surgical intervention.
RESUMO
Establishing novel therapies for rare central nervous system (CNS) tumors is arduous due to challenges in conducting clinical trials in rare tumors. Immunotherapy treatment has been a rapidly developing field and has demonstrated improvements in outcomes for multiple types of solid malignancies. In rare CNS tumors, the role of immunotherapy is being explored. In this article, we review the preclinical and clinical data of various immunotherapy modalities in select rare CNS tumors, including atypical meningioma, aggressive pituitary adenoma, pituitary carcinoma, ependymoma, embryonal tumor, atypical teratoid/rhabdoid tumor, and meningeal solitary fibrous tumor. Among these tumor types, some studies have shown promise; however, ongoing clinical trials will be critical for defining and optimizing the role of immunotherapy for these patients.
Assuntos
Neoplasias do Sistema Nervoso Central , Neoplasias Embrionárias de Células Germinativas , Tumor Rabdoide , Humanos , Neoplasias do Sistema Nervoso Central/terapia , Imunoterapia , Tumor Rabdoide/patologiaRESUMO
Torsades de pointes (TdP) is a life-threatening cardiac arrhythmia that can result from QT interval prolongation, sometimes secondary to medication adverse effects and electrolyte derangements. We present a 95-year-old Hispanic male with advanced chronic kidney disease (CKD) that was evaluated for dizziness and progressive weakness. The diagnosis of severe symptomatic hypokalemia and QT prolongation was made, and the patient was admitted for telemetry monitoring and aggressive intravenous electrolyte replacements. While under observation, the patient experienced syncope due to ventricular tachycardia (VT) with episodes of torsades de pointes. Due to refractory potassium depletion and hypertension, workup for hyperaldosteronism revealed renal potassium wasting, inappropriately normal plasma renin levels, and almost undetectable aldosterone levels. Careful analysis revealed the excessive chronic daily ingestion of licorice-containing candy twists and tea, which may cause pseudohyperaldosteronism. Licorice is a commonly used natural product that is available in many forms. It is sometimes used as a natural supplement and as a sweetener that can be widely found in many food products. Excessive ingestion can lead to apparent mineralocorticoid excess, reduced plasma potassium, sodium retention, hypertension, and metabolic alkalosis. Hypokalemia can be severe in some patients and lead to fatal cardiac arrhythmias such as ventricular tachycardia and torsades de pointes. Careful analysis is essential in cases of refractive hypokalemia and renal potassium wasting, especially in elderly patients with underlying renovascular disease.
RESUMO
Background and Aims: Labels designed to communicate critical information are paramount for the safe and effective use of over-the-counter medications; in recognition of this, the content and formatting of over the counter (OTC) labels sold in interstate commerce has been regulated for decades. Yet, available studies suggest that consumers frequently rely on limited information during decision making, failing to access the information required in the Drug Facts Label. This is particularly important for older consumers, who are at greater risk for adverse reactions to medicines. In two experiments we objectively evaluate how novel label designs that employ highlighting and a warning label placed on the package's front impact older consumers' attention to, and use of, critical information. Methods: In Experiment 1, 68 OTC patients (65+) engaged with a computer-based task answering yes/no scenario-based questions about a drug's appropriateness. In Experiment 2, 63 OTC patients (65+) conducted a forced-choice task where one of two drugs presented on a computer screen was appropriate for a provided scenario while the other was not. Both tasks required participants to access and use critical label information (i.e., warnings or active ingredients) to respond correctly. Dependent variables analyzed were the proportion of correct responses and time to correct response. Results: Highlighting or placing critical information on the front of the package significantly improved response accuracy and time to correct response in Experiment 1 as compared to responses utilizing the standard label. For Experiment 2, participants were faster and more accurate when critical information was highlighted. Conclusions: Results provide direct measures of the efficacy of novel labeling strategies. This information is relevant for regulations which dictate label design in ways that enhance ease and safety of use of medications for older adults.
RESUMO
In this case study, we present the evaluation of an orthotopic heart transplant (OHT) patient who presented with persistent shortness of breath and dizziness upon standing. The investigation uncovered the presence of progressive hypertrophic cardiomyopathy (HCM) in the transplanted heart, a condition first detected 11 years after the transplantation. Utilizing echocardiography with global longitudinal strain (GLS), we determined that the HCM likely originated from genetic predominance inherited from the heart donor rather than hypertensive disease. This finding highlights the significance of genetic factors in post-transplant complications and warrants further investigation into the long-term effects of heart transplantation on recipient health.
RESUMO
Here, we present the case of a 61-year-old veteran Hispanic male with recurrent aspiration pneumonitis, aerophagia, tympanic abdominal bloating, and a positive Ono's sign; symptoms present were secondary to diagnosed tracheoesophageal fistulas (TEFs). TEFs are abnormal connections between the esophagus and the trachea. In adult cases, several risk factors have been identified for acquired cases, which include infection, trauma, and cancer. Diagnosis of TEF can be challenging and, in most cases, requires high suspicion. Currently, there are no established guidelines for diagnosing and managing TEF. Clinical assessment and various imaging techniques are essential in the diagnostic process. This article will discuss the etiology, clinical presentation, diagnostic approaches, and management options for acquired TEFs.
RESUMO
Models of visual search posit that target absent responses occur when the quitting threshold for the trial is reached before a target is detected, and that feedback about missed targets allows the quitting threshold to be adaptively set to the difficulty of the search task. While these models may effectively capture processes in lab-based tasks, in real-world searches feedback is often impossible to provide. Instead, observers have little information about their errors, and may only be aware of when they successfully detect the target. We posit that in the absence of feedback the time required to find a target might influence quitting thresholds. In three experiments, we investigate how manipulating the mean time and the standard deviation of time to detect a target influence quitting thresholds in target absent trials. To vary target detection times while holding the search stimuli constant, we used an eye-movement contingent change to surreptitiously introduce a target near fixation at a particular time. Results show that decreasing the mean time to find a target also decreases the number of items inspected and reaction time in target absent trials, the hallmark of a shift in the quitting threshold. By contrast, varying the standard deviation around a fixed mean had no impact on target absent search times. These findings suggest that people are sensitive to the typical time required to find a target in a given task and use that information to flexibly adjust target absent quitting thresholds, but people are not sensitive to the variability.
Assuntos
Atenção , Movimentos Oculares , Humanos , Atenção/fisiologia , Tempo de Reação/fisiologia , Conscientização , Percepção Visual/fisiologiaRESUMO
Identifying underlying bleeding diathesis that is amenable to medical therapy must be determined to provide timely treatment and minimize morbidity. Nasal bleeding is viewed as an annoyance by most who suffer from its episodes. However, it can at times be a baleful ailment that can compromise a patient's airway, breathing, and circulation, which can result in death. A 75-year-old Hispanic man presented with life-threatening epistaxis and was ultimately diagnosed with multiple myeloma (MM). The patient suffered profuse bleeding and hemodynamic compromise, requiring endoscopic nasal packing, red cell transfusions, platelet transfusions, and right external carotid artery angiogram with maxillary arteries embolization prior to chemotherapy. Embolization of maxillary arteries helped to stabilize the patient to diagnose MM and start definitive management with chemotherapy. On data review, we could not find another case with severe epistaxis secondary to MM, which was controlled with endovascular embolization. This case highlights the difficulties in managing a rare condition and the importance of a multidisciplinary approach in patients who present with life-threatening epistaxis secondary to plasma cell dyscrasia.
RESUMO
Ion pair-reversed phase (IP-RP) HPLC is one of the most widely used methods for the analysis of oligonucleotide impurities. The method is compatible with mass spectrometry and has been used to guide the development of improved synthesis and purification approaches. The ability to detect and characterize impurities depends on the reagents and the IP buffer system employed, as each can directly affect the degree of chromatographic separation and the sensitivity of detection by MS. Previous work in our laboratory has shown that small alkyl amines are suitable IP reagents for the analysis of impurities in phosphate diester oligonucleotides and can be used to differentiate among individual members of composite impurity families. The addition of an alkyl acid often further enhances peak separation, but at the detriment of ion signal. An improved method with increased chromatographic performance and sensitivity of detection is presented here. Improvements were mainly realized through the use of lower concentrations of small alkyl amine (i.e., 5 mM) and acid (0.5 mM) IP reagents, and ammonium bicarbonate (20 mM) as a buffer. The improved capabilities of the new method are demonstrated by separation of the individual components of the composite n - 1 impurity in a set of four production-scale batches of a single oligonucleotide. Addition of the alkyl acid resulted in resolution of most individual n - 1 impurities. The observed enhanced sensitivity of detection allowed multiple reaction monitoring (MRM) experiments, which were used to differentiate among unresolved impurities.