A Transcriptomic Comparative Study of Cranial Vasculature.

In genetic studies of cerebrovascular diseases, the optimal vessels to use as controls remain unclear. Our goal is to compare the transcriptomic profiles among 3 different types of control vessels: superficial temporal artery (STA), middle cerebral arteries (MCA), and arteries from the circle of Willis obtained from autopsies (AU). We examined the transcriptomic profiles of STA, MCA, and AU using RNAseq. We also investigated the effects of using these control groups on the results of the comparisons between aneurysms and the control arteries. Our study showed that when comparing pathological cerebral arteries to control groups, all control groups presented similar responses in the activation of immunological processes, the regulation of intracellular signaling pathways, and extracellular matrix productions, despite their intrinsic biological differences. When compared to STA, AU exhibited upregulation of stress and apoptosis genes, whereas MCA showed upregulation of genes associated with tRNA/rRNA processing. Moreover, our results suggest that the matched case-control study design, which involves control STA samples collected from the same subjects of matched aneurysm samples in our study, can improve the identification of non-inherited disease-associated genes. Given the challenges associated with obtaining fresh intracranial arteries from healthy individuals, our study suggests that using MCA, AU, or paired STA samples as controls are feasible strategies for future large-scale studies investigating cerebral vasculopathies. However, the intrinsic differences of each type of control should be taken into consideration when interpreting the results. With the limitations of each control type, it may be most optimal to use multiple tissues as controls.

Somatic Variants in SVIL in Cerebral Aneurysms.

Background and Objectives: While somatic mutations have been well-studied in cancer, their roles in other complex traits are much less understood. Our goal is to identify somatic variants that may contribute to the formation of saccular cerebral aneurysms. Methods: We performed whole-exome sequencing on aneurysm tissues and paired peripheral blood. RNA sequencing and the CRISPR/Cas9 system were then used to perform functional validation of our results. Results: Somatic variants involved in supervillin (SVIL) or its regulation were found in 17% of aneurysm tissues. In the presence of a mutation in the SVIL gene, the expression level of SVIL was downregulated in the aneurysm tissue compared with normal control vessels. Downstream signaling pathways that were induced by knockdown of SVIL via the CRISPR/Cas9 system in vascular smooth muscle cells (vSMCs) were determined by evaluating changes in gene expression and protein kinase phosphorylation. We found that SVIL regulated the phenotypic modulation of vSMCs to the synthetic phenotype via Krüppel-like factor 4 and platelet-derived growth factor and affected cell migration of vSMCs via the RhoA/ROCK pathway. Discussion: We propose that somatic variants form a novel mechanism for the development of cerebral aneurysms. Specifically, somatic variants in SVIL result in the phenotypic modulation of vSMCs, which increases the susceptibility to aneurysm formation. This finding suggests a new avenue for the therapeutic intervention and prevention of cerebral aneurysms.

Impacto de un entrenamiento de simulación virtual remota sincrónica para el tratamiento inicial del accidente cerebrovascular isquémico en estudiantes de medicina / Impact of synchronous remote virtual simulation training, for the initial management of ischemic stroke in medical students

Introducción: El accidente cerebrovascular (ACV) es una patología prevalente y dependiente del tiempo. Su tratamiento completo inicial es competencia obligatoria del médico general en Chile. En el contexto de la enseñanza clínica tradicional, hay pocas oportunidades de práctica en ese momento de la evolución de los casos. El objetivo fue evaluar el efecto de un programa de simulación virtual remota sincrónica para el tratamiento inicial del ACV en estudiantes de quinto año de medicina.Sujetos y métodos.Estudio cuantitativo, cuasi experimental. Se realizaron cinco sesiones, en días separados, en grupos de tres estudiantes. Cada sesión consistió en tres escenarios de simulación virtual de complejidad creciente, administrada de manera remota, con registro de desempeño individual y debriefing grupal. Se calculó la confiabilidad y se utilizó la prueba de Wilcoxon para muestras relacionadas con p < 0,05 como estadísticamente significativa para comparar los cuestionarios pre- y poscurso.Resultados.Se observó una mejoría del diagnóstico y el tratamiento farmacológico inicial del ACV entre el primer y el tercer casos. Los participantes declararon que la experiencia con el simulador creó oportunidades para la práctica clínica simulada y promovió el desarrollo de la formación en comunicación (p < 0,005). La satisfacción con el programa medida después del término del curso mostró un alto grado de acuerdo promedio.Conclusiones.La simulación virtual aplicada en un programa de práctica deliberada, con debriefing guiado por un instructor, mejoró las competencias para el tratamiento inicial del ACV en estudiantes de grado de medicina y fue muy bien valorada por los estudiantes. (AU)

Introduction: Stroke is a prevalent and time-dependent pathology. Its complete initial management is a mandatory competence of the general practitioner in Chile. In the context of traditional clinical teaching, there are few opportunities for practice at that moment of the evolution of cases. The objective was to evaluate the effect of a remote virtual simulation program, synchronous with debriefing, for the initial management of stroke in fifth year medical students.Subjects and methods.Quantitative, quasi-experimental study. Five sessions were conducted on separate days in groups of three students. Each session consisted of three virtual simulation scenarios of increasing complexity, administered remotely, with individual performance recording and group debriefing. Reliability was calculated and the Wilcoxon test for related samples with p < 0.05 was used as statistically significant to compare pre and post course questionnaires.Results.Improvement in the diagnosis and initial pharmacological management of stroke was observed between the first and third cases. Participants stated that the simulator experience created opportunities for simulated clinical practice and promoted the development of communication training (p < 0.005). Satisfaction with the program measured after completion of the course showed a high degree of average agreement.Conclusions.Virtual simulation applied in a deliberate practice program, with instructor-guided debriefing has improved competencies for the initial management of stroke in undergraduate medical students and was highly valued by the students. (AU)

Diffusion Tensor Imaging and Tractography Utilized in the Resection of a Midbrain Cavernous Malformation.

Background: Diffusion tensor imaging (DTI) is a magnetic resonance-based imaging technique that can provide important information about the underlying structure and integrity of the white matter in the brain. Tractography, a DTI postprocessing technique, can provide a detailed model of individual white matter fiber tracts. Knowledge of these tracts may be beneficial in the surgical planning and execution for neurosurgical patients. Case Report: We review the basic principles behind DTI and present an illustrative case in which DTI was used to delineate the relationship of eloquent white matter tracts to a cavernous malformation in a patient undergoing resection. Conclusion: The use of DTI during preoperative planning allows the neurosurgeon to understand if a lesion is disrupting, infiltrating, or altering the course of local white matter tracts. With the combined use of DTI and intraoperative neuronavigation, the neurosurgeon can better identify and avoid white matter tracts, not only in the local area of resection but also during approach to the lesion, thereby reducing the risk of damage to vital cortical pathways and subsequent functional impairment.

Early entrapment of fourth ventricle following Pseudomonas meningitis in extreme prematurity: Case report.

Trapped fourth ventricle (TFV) as a complication of post-hemorrhagic hydrocephalus (PHH) is widely reported in the pediatric population with a prior history of ventriculo-peritoneal (VP) shunt placement. Characterized by disproportionate dilatation of the fourth ventricle on serial neuro-imaging, it is rarely encountered in the early course of preterm infants and the differentiating clinical features are subtle and non-specific. Clinical alertness and sonographic correlation hold the key to early diagnosis. We report an early emergence of TFV in an extremely low gestational age newborn (ELGAN) following fulminant Pseudomonas aeruginosa meningitis, approach to management, and the neurological outcome. Fourth ventricle entrapment as a complication of perinatally acquired Pseudomonas aeruginosa meningitis in a surviving ELGAN is extremely rare.

Interhemispheric Paracallosal Approach for an Arteriovenous Malformation of the Atrium: A Novel Technique.

Background: Intraventricular lesions present a surgical challenge because of the complexity of the ventricular anatomy, various perforating arteries, and eloquent brain areas surrounding the system. The ventricular atrium is particularly challenging because of the cingulate gyrus, corpus callosum, optic pathways, and significant vascular structures. We present the case of a patient for whom we used a new surgical approach to reach a lesion in the ventricular atrium. Case Report: A 26-year-old male presented with an intraventricular hemorrhage, acute hydrocephalus, and a grade III arteriovenous malformation (AVM) in the atrium of the left lateral ventricle. We approached the AVM through a posterior parietooccipital paracallosal interhemispheric approach. Instead of transecting the cingulate cortex as is traditionally done, we gently retracted the cingulate gyrus and made a small paracallosal incision to reach the atrium of the left lateral ventricle. The surgery was uneventful. The patient recovered well and was discharged home on postoperative day 3 without any deficits. Conclusion: This case illustrates a novel variation to an established approach to the ventricular atrium. With this technique, the surgeon minimizes disruption of brain tissue and thereby avoids the associated postoperative deficits associated with traditional approaches (transcortical, transcingulate, and conventional transcallosal). Tractography studies and a large cohort of patients are necessary to ensure the reproduction of good outcomes.

Carotid Web Stenting.

Background: Carotid webs are luminal, shelf-like protrusions at the carotid bulb. Considered to be a variant of fibromuscular dysplasia, carotid webs have been observed principally in African American females. The association between carotid webs and recurrent ischemic strokes continues to be established as patients without traditional stroke risk factors are found to have carotid webs as the only possible cause of symptomatic deficits. The majority of patients undergo endarterectomy; few stent placements are reported. We present the case of an African American female who underwent stent placement for treatment and secondary prevention of stroke attributed to a carotid web. Case Report: A 33-year-old African American female presented with acute onset left hemiparesis and left facial droop. Alteplase was administered; multiphase head and neck computed tomography angiography revealed an occlusion of the right middle cerebral artery with a web at the carotid bulb. Aspiration catheter thrombectomy achieved a Thrombolysis in Cerebral Infarction (TICI) score of 3. She was placed on 2 antiplatelet agents, and 3 weeks later she underwent stent placement. Follow-up digital subtraction angiography at 3 months showed obliteration of the right carotid artery web and satisfactory integration of the stent into the vessel wall. She was reassessed at 1 year and reported no neurologic symptoms. Conclusion: Although carotid webs are most commonly treated with endarterectomy, they may be amenable to stent therapy with favorable clinical outcomes as shown with this patient.

Commentary: The Tulane University-Ochsner Clinic Foundation Neurosurgery Program: 75 Years of History, Including the Program's Rebirth After Katrina.

Neurosurgery training in New Orleans began when Dr Dean Echols became the head of Neurosurgery for the Ochnser Clinic and Charity Hospital in 1944. The oldest in Louisiana, the Tulane-Ochsner program has trained 63 board-certified neurosurgeons since its founding, including 5 chairmen. The program has a colorful history linked to New Orleans. Its residents have enjoyed training at Charity Hospital, Tulane Hospital and Clinics, Veterans Affairs Medical Center, and the Ochsner Clinic Foundation.

Transcirculation Pipeline embolization device deployment: a rescue technique.

The Pipeline embolization device (PED) has become a very important tool in the treatment of nonruptured cerebral aneurysms. However, a patient's difficult anatomy or vascular stenosis may affect the device delivery. The purpose of this article was to describe an alternate technique for PED deployment when ipsilateral anatomy is not amenable for catheter navigation. A 44-year-old woman with a symptomatic 6-mm right superior hypophyseal artery aneurysm and a known history of right internal carotid artery dissection presented for PED treatment of her aneurysm. An angiogram showed persistence of the arterial dissection with luminal stenosis after 6 months of dual antiplatelet treatment. The contralateral internal carotid artery was catheterized and the PED was deployed via a transcirculation approach, using the anterior communicating artery. Transcirculation deployment of a PED is a viable option when ipsilateral anatomy is difficult or contraindicated for this treatment.

Suspected non-Alzheimer's pathology - Is it non-Alzheimer's or non-amyloid?

Neurodegeneration, the progressive loss of neurons, is a major process involved in dementia and age-related cognitive impairment. It can be detected clinically using currently available biomarker tests. Suspected Non-Alzheimer Pathology (SNAP) is a biomarker-based concept that encompasses a group of individuals with neurodegeneration, but no evidence of amyloid deposition (thereby distinguishing it from Alzheimer's disease (AD)). These individuals may often have a clinical diagnosis of AD, but their clinical features, genetic susceptibility and progression can differ significantly, carrying crucial implications for precise diagnostics, clinical management, and efficacy of clinical drug trials. SNAP has caused wide interest in the dementia research community, because it is still unclear whether it represents distinct pathology separate from AD, or whether in some individuals, it could represent the earliest stage of AD. This debate has raised pertinent questions about the pathways to AD, the need for biomarkers, and the sensitivity of current biomarker tests. In this review, we discuss the biomarker and imaging trials that first recognized SNAP. We describe the pathological correlates of SNAP and comment on the different causes of neurodegeneration. Finally, we discuss the debate around the concept of SNAP, and further unanswered questions that are emerging.

Patency of the posterior communicating artery following treatment with the Pipeline Embolization Device.

OBJECTIVE The Pipeline Embolization Device (PED) has become an effective treatment strategy for some cerebral aneurysms. Concerns regarding the patency of branch arteries have been raised. The objective of this study was to assess the patency of the posterior communicating artery (PCoA) following treatment of PCoA aneurysms using the PED. METHODS All patients with PCoA aneurysms treated with the PED who had angiographic follow-up were retrospectively identified. The patency of the PCoA at follow-up was evaluated by 2 authors who were not involved in the intervention. Univariate and multivariate analyses were performed to identify factors associated with the following: 1) PCoA patency versus no or diminished flow, and 2) PCoA patency and diminished flow versus PCoA occlusion. RESULTS Thirty patients with an angiographic follow-up of 6 months were included. Aneurysm obliteration was achieved in 25 patients (83.3%). The PCoA was patent in 7 patients (23.3%), had diminished flow in 7 patients (23.3%), and was occluded in 16 patients (53.3%). In the univariate analysis of outcome, there was a trend for aneurysms with incomplete occlusion, aneurysms not previously treated, those with presence of a fetal PCoA, and those with an artery coming from the aneurysm to have higher odds of the PCoA remaining patent. In univariate and multivariate analyses of factors associated with outcome, fetal PCoA and presence of an artery coming from the aneurysm were associated with the PCoA remaining open with or without diminished flow. No patients had symptoms related to PCoA occlusion. CONCLUSIONS Occlusion and diminished flow through the PCoA is common following PED treatment of PCoA aneurysms. However, it is clinically insignificant in most cases.

Tau imaging in neurodegenerative diseases.

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike ß-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [(18)F]THK523, [(18)F]THK5117, [(18)F]THK5105 and [(18)F]THK5351, [(18)F]AV1451(T807) and [(11)C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with ß - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future.

Permanent-magnet energy spectrometer for electron beams from radiotherapy accelerators.

PURPOSE: The purpose of this work was to adapt a lightweight, permanent magnet electron energy spectrometer for the measurement of energy spectra of therapeutic electron beams. METHODS: An irradiation geometry and measurement technique were developed for an approximately 0.54-T, permanent dipole magnet spectrometer to produce suitable latent images on computed radiography (CR) phosphor strips. Dual-pinhole electron collimators created a 0.318-cm diameter, approximately parallel beam incident on the spectrometer and an appropriate dose rate at the image plane (CR strip location). X-ray background in the latent image, reduced by a 7.62-cm thick lead block between the pinhole collimators, was removed using a fitting technique. Theoretical energy-dependent detector response functions (DRFs) were used in an iterative technique to transform CR strip net mean dose profiles into energy spectra on central axis at the entrance to the spectrometer. These spectra were transformed to spectra at 95-cm source to collimator distance (SCD) by correcting for the energy dependence of electron scatter. The spectrometer was calibrated by comparing peak mean positions in the net mean dose profiles, initially to peak mean energies determined from the practical range of central-axis percent depth-dose (%DD) curves, and then to peak mean energies that accounted for how the collimation modified the energy spectra (recalibration). The utility of the spectrometer was demonstrated by measuring the energy spectra for the seven electron beams (7-20 MeV) of an Elekta Infinity radiotherapy accelerator. RESULTS: Plots of DRF illustrated their dependence on energy and position in the imaging plane. Approximately 15 iterations solved for the energy spectra at the spectrometer entrance from the measured net mean dose profiles. Transforming those spectra into ones at 95-cm SCD increased the low energy tail of the spectra, while correspondingly decreasing the peaks and shifting them to slightly lower energies. Energy calibration plots of peak mean energy versus peak mean position of the net mean dose profiles for each of the seven electron beams followed the shape predicted by the Lorentz force law for a uniform z-component of the magnetic field, validating its being modeled as uniform (0.542 ± 0.027 T). Measured Elekta energy spectra and their peak mean energies correlated with the 0.5-cm (7-13 MeV) and the 1.0-cm (13-20 MeV) R90 spacings of the %DD curves. The full-width-half-maximum of the energy spectra decreased with decreasing peak mean energy with the exception of the 9-MeV beam, which was anomalously wide. Similarly, R80-20 decreased linearly with peak mean energy with the exception of the 9 MeV beam. Both were attributed to suboptimal tuning of the high power phase shifter for the recycled radiofrequency power reentering the traveling wave accelerator. CONCLUSIONS: The apparatus and analysis techniques of the authors demonstrated that an inexpensive, lightweight, permanent magnet electron energy spectrometer can be used for measuring the electron energy distributions of therapeutic electron beams (6-20 MeV). The primary goal of future work is to develop a real-time spectrometer by incorporating a real-time imager, which has potential applications such as beam matching, ongoing beam tune maintenance, and measuring spectra for input into Monte Carlo beam calculations.

Diseases associated with leaky hemichannels.

Hemichannels (HCs) and gap junction channels (GJCs) formed by protein subunits called connexins (Cxs) are major pathways for intercellular communication. While HCs connect the intracellular compartment with the extracellular milieu, GJCs allow the interchange of molecules between cytoplasm of two contacting cells. Under physiological conditions, HCs are mostly closed, but they can open under certain stimuli allowing the release of autocrine and paracrine molecules. Moreover, some pathological conditions, like ischemia or other inflammation conditions, significantly increase HCs activity. In addition, some mutations in Cx genes associated with human diseases, such as deafness or cataracts, lead to the formation of more active HCs or "leaky HCs." In this article we will revise cellular and molecular mechanisms underlying the appearance of leaky HCs, and the consequences of their expression in different cellular systems and animal models, in seeking a common pattern or pathological mechanism of disease.

Sepsis progression to multiple organ dysfunction in carotid chemo/baro-denervated rats treated with lipopolysaccharide.

Sepsis progresses to multiple organ dysfunction (MOD) due to the uncontrolled release of inflammatory mediators. Carotid chemo/baro-receptors could play a protective role during sepsis. In anesthetized male rats, we measured cardiorespiratory variables and plasma TNF-α, glucocorticoids, epinephrine, and MOD marker levels 90min after lipopolysaccharide (LPS) administration in control (SHAM surgery) and bilateral carotid chemo/baro-denervated (BCN) rats. BCN prior to LPS blunted the tachypneic response and enhanced tachycardia and hypotension. BCN-LPS rats also showed blunted plasma glucocorticoid responses, boosted epinephrine and TNF-α responses, and earlier MOD onset with a lower survival time compared with SHAM-LPS rats. Consequently, the complete absence of carotid chemo/baro-sensory function modified the neural, endocrine and inflammatory responses to sepsis. Thus, carotid chemo/baro-receptors play a protective role in sepsis.

Cortical hypermetabolism in MCI subjects: a compensatory mechanism?

PURPOSE: Alzheimer's disease (AD) is associated with amyloid accumulation that takes place decades before symptoms appear. Cognitive impairment in AD is associated with reduced glucose metabolism. However, neuronal plasticity/compensatory mechanisms might come into play before the onset of dementia. The aim of this study was to determine whether there is evidence of cortical hypermetabolism as a compensatory mechanism before amyloid deposition takes place in subjects with amnestic mild cognitive impairment (aMCI). METHODS: Nine AD subjects and ten aMCI subjects had both [(11)C]PIB and [(18)F]FDG PET scans with arterial input in order to quantify the amyloid deposition and glucose metabolism in vivo in comparison with healthy control subjects who underwent either [(11)C]PIB or [(18)F]FDG PET scans. The [(11)C]PIB PET scans were quantified using [(11)C]PIB target region to cerebellum uptake ratio images created by integrating the activity collected from 60 to 90 min, and regional cerebral glucose metabolism was quantified using spectral analysis. RESULTS: In MCI subjects, cortical hypermetabolism was observed in four amyloid-negative subjects and one amyloid-positive subject, while hypometabolism was seen in five other MCI subjects with high amyloid load. Subjects with hypermetabolism and low amyloid did not convert to AD during clinical follow-up for 18 months in contrast to four amyloid-positive hypometabolic subjects who did convert to AD. CONCLUSION: This preliminary study suggests that compensatory hypermetabolism can occur in aMCI subjects, particularly in those who are amyloid-negative. The increase in metabolic rate in different cortical regions with predominance in the occipital cortex may be a compensatory response to the neuronal damage occurring early in the disease process. It may also reflect recruitment of relatively minimally affected cortical regions to compensate for reduced function in the temporoparietal cortical association areas.

Petrosal ganglion: a more complex role than originally imagined.

The petrosal ganglion (PG) is a peripheral sensory ganglion, composed of pseudomonopolar sensory neurons that innervate the posterior third of the tongue and the carotid sinus and body. According to their electrical properties PG neurons can be ascribed to one of two categories: (i) neurons with action potentials presenting an inflection (hump) on its repolarizing phase and (ii) neurons with fast and brisk action potentials. Although there is some correlation between the electrophysiological properties and the sensory modality of the neurons in some species, no general pattern can be easily recognized. On the other hand, petrosal neurons projecting to the carotid body are activated by several transmitters, with acetylcholine and ATP being the most conspicuous in most species. Petrosal neurons are completely surrounded by a multi-cellular sheet of glial (satellite) cells that prevents the formation of chemical or electrical synapses between neurons. Thus, PG neurons are regarded as mere wires that communicate the periphery (i.e., carotid body) and the central nervous system. However, it has been shown that in other sensory ganglia satellite glial cells and their neighboring neurons can interact, partly by the release of chemical neuro-glio transmitters. This intercellular communication can potentially modulate the excitatory status of sensory neurons and thus the afferent discharge. In this mini review, we will briefly summarize the general properties of PG neurons and the current knowledge about the glial-neuron communication in sensory neurons and how this phenomenon could be important in the chemical sensory processing generated in the carotid body.

Evaluation of two quantitative analysis methods of optical coherence tomography for detection of enamel demineralization and comparison with microhardness.

BACKGROUND AND OBJECTIVE: We aimed to evaluate in the same study two quantitative methods for quantification of incipient caries in human dental enamel by using optical coherence tomography (OCT): the optical attenuation coefficient and the area under the A-scan signal, and to compare their results with those obtained from microhardness analysis. STUDY DESIGN/MATERIALS AND METHODS: One hundred and sixty samples were obtained from 40 sound human third molars, which had their crowns sectioned. Simulated caries were created by a pH cycling method. OCT measurements were performed on the samples, before and after the induced demineralization. We determined the total optical attenuation coefficient from the OCT signal in each site and evaluated the sensitivity and specificity of this approach to the detection of the demineralization. Also, the areas under the OCT curves (AUC-OCT) and those from sectional microhardness tests (AUC-MH) were compared. RESULTS: Both the analysis of the optical attenuation coefficient and the AUC-OCT were adequate to efficiently distinguish sound and demineralized samples with sensitivity of 0.93 and specificity of 0.96. The AUC-MH and the AUC-OCT data presented linear relationship and correlation of 0.99. CONCLUSION: Both methods for signal analysis from OCT allowed detection of demineralization with good performance. The AUC-OCT approach enables obtaining a linear relation with the microhardness results, for a quantitative assessment of mineral loss in human teeth.

Synthetic organotelluride compounds induce the reversal of Pdr5p mediated fluconazole resistance in Saccharomyces cerevisiae.

BACKGROUND: Resistance to fluconazole, a commonly used azole antifungal, is a challenge for the treatment of fungal infections. Resistance can be mediated by overexpression of ABC transporters, which promote drug efflux that requires ATP hydrolysis. The Pdr5p ABC transporter of Saccharomyces cerevisiae is a well-known model used to study this mechanism of antifungal resistance. The present study investigated the effects of 13 synthetic compounds on Pdr5p. RESULTS: Among the tested compounds, four contained a tellurium-butane group and shared structural similarities that were absent in the other tested compounds: a lateral hydrocarbon chain and an amide group. These four compounds were capable of inhibiting Pdr5p ATPase activity by more than 90%, they demonstrated IC50 values less than 2 µM and had an uncompetitive pattern of Pdr5p ATPase activity inhibition. These organotellurides did not demonstrate cytotoxicity against human erythrocytes or S. cerevisiae mutant strains (a strain that overexpress Pdr5p and a null mutant strain) even in concentrations above 100 µM. When tested at 100 µM, they could reverse the fluconazole resistance expressed by both the S. cerevisiae mutant strain that overexpress Pdr5p and a clinical isolate of Candida albicans. CONCLUSIONS: We have identified four organotellurides that are promising candidates for the reversal of drug resistance mediated by drug efflux pumps. These molecules will act as scaffolds for the development of more efficient and effective efflux pump inhibitors that can be used in combination therapy with available antifungals.

Midline minimally invasive placement of spinal cord stimulators: a technical note.

BACKGROUND: Spinal cord stimulators (SCSs) have conventionally been implanted through open approaches requiring extensive muscle dissection to perform laminectomies and permanently place the paddle lead. This approach could contribute to worsening the pain syndrome in patients who experience chronic pain. In an attempt to reduce operative times, minimize blood loss and postoperative pain, and ease the technical challenges of placing the paddle lead in the midline via a paramedian and off-midline incision, we designed a new minimally invasive surgery (MIS) technique to place the paddle lead using a tubular retractor system through a true midline approach. METHODS: We performed a retrospective review of all MIS paddle lead placements performed by the senior author between October 2010 and June 2013. Patient demographics; clinical indications for placement of paddle lead; location of paddle lead; and perioperative data including blood loss, length of surgery, and surgical and perioperative morbidity were recorded. RESULTS: Between October 2010 and June 2013, 78 patients had MIS placement of paddle lead SCSs. Patient ages ranged from 27 to 87 years old, with a mean age of 59. The most common levels for paddle lead placement were T8 and T9. No minor or major neurologic complications occurred in our patient population. No patient was readmitted after being discharged from the hospital and all surgeries were outpatient procedures. We had a migration rate comparable to open techniques and minimal blood loss. CONCLUSION: Our technique is safe and effective and carries minimal surgical morbidity compared to standard open techniques for placement of SCSs.