Modern diagnostics strive to be accurate, fast, and inexpensive in addition to properly identifying the presence of a disease, infection, or illness. Early diagnosis is key; catching a disease in its ...early stages can be the difference between fatality and treatment. The challenge with many diseases is that detectability of the disease scales with disease progression. Since single molecule sensors, e.g., nanopores, can sense biomolecules at low concentrations, they have the potential to become clinically relevant in many of today's medical settings. With nanopore-based sensing, lower volumes and concentrations are required for detection, enabling it to be clinically beneficial. Other advantages to using nanopores include that they are tunable to an enormous variety of molecules and boast low costs, and fabrication is scalable for manufacturing. We discuss previous reports and the potential for incorporating nanopores into the medical field for early diagnostics, therapeutic monitoring, and identifying relapse/recurrence.
Nanopores have already established themselves as a robust sequencing tool and, in time, will be utilized in diagnosing the presence of disease. Specifically, samples extracted from patients will be prepped by isolating the nucleic acid, protein, or combination of the two for disease/ailment presence via nanopores. In this review, we describe the promising future and potential challenges for incorporating nanopores into the medical field for health care professionals to quickly and accurately diagnosis and treat patients. Display omitted
Nanopore sensing is nearly synonymous with resistive pulse sensing due to the characteristic occlusion of ions during pore occupancy, particularly at high salt concentrations. Contrarily, conductive ...pulses are observed under low salt conditions wherein electroosmotic flow is significant. Most literature reports counterions as the dominant mechanism of conductive events (a molecule-centric theory). However, the counterion theory does not fit well with conductive events occurring via net neutral-charged protein translocation, prompting further investigation into translocation mechanics. Herein, we demonstrate theory and experiments underpinning the translocation mechanism (i.e., electroosmosis or electrophoresis), pulse direction (i.e., conductive or resistive) and shape (e.g., monophasic or biphasic) through fine control of chemical, physical, and electronic parameters. Results from these studies predict strong electroosmosis plays a role in driving DNA events and generating conductive events due to polarization effects (i.e., a pore-centric theory).
Previous studies have suggested that both the prefrontal cortex (PFC) and inferior temporal cortex (ITC) are involved in high-level visual processing and categorization, but their respective roles ...are not known. To address this, we trained monkeys to categorize a continuous set of visual stimuli into two categories, "cats" and "dogs." The stimuli were parametrically generated using a computer graphics morphing system (Sheltonelton, 2000) that allowed precise control over stimulus shape. After training, we recorded neural activity from the PFC and the ITC of monkeys while they performed a category-matching task. We found that the PFC and the ITC play distinct roles in category-based behaviors: the ITC seems more involved in the analysis of currently viewed shapes, whereas the PFC showed stronger category signals, memory effects, and a greater tendency to encode information in terms of its behavioral meaning.
Aberrant Notch signaling has been implicated in the pathogenesis of many human cancers. MK-0752 is a potent, oral inhibitor of γ-secretase, an enzyme required for Notch pathway activation. Safety, ...maximum-tolerated dose, pharmacokinetics (PKs), pharmacodynamics, and preliminary antitumor efficacy were assessed in a phase I study of MK-0752.
MK-0752 was administered in three different schedules to patients with advanced solid tumors. Hair follicles were collected at higher dose levels to assess a gene signature of Notch inhibition.
Of 103 patients who received MK-0752, 21 patients received a continuous once-daily dosing at 450 and 600 mg; 17 were dosed on an intermittent schedule of 3 of 7 days at 450 and 600 mg; and 65 were dosed once per week at 600, 900, 1,200, 1,500, 1,800, 2,400, 3,200, and 4,200 mg. The most common drug-related toxicities were diarrhea, nausea, vomiting, and fatigue. PKs (area under the concentration-time curve and maximum measured plasma concentration) increased in a less than dose proportional manner, with a half-life of approximately 15 hours. Significant inhibition of Notch signaling was observed with the 1,800- to 4,200-mg weekly dose levels, confirming target engagement at those doses. One objective complete response and an additional 10 patients with stable disease longer than 4 months were observed among patients with high-grade gliomas.
MK-0752 toxicity was schedule dependent. Weekly dosing was generally well tolerated and resulted in strong modulation of a Notch gene signature. Clinical benefit was observed, and rational combination trials are currently ongoing to maximize clinical benefit with this novel agent.
1 Department of Brain and Cognitive Sciences and 2 The McGovern Institute for Brain Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, 3 The Picower Institute for Learning and ...Memory, 4 Department of Neurobiology, The University of Chicago, Chicago, Illinois; and 5 Department of Ophthalmology and Program in Neuroscience, Children's Hospital Boston, Harvard Medical School, Massachusetts
Submitted 8 February 2008;
accepted in final form 14 June 2008
Most electrophysiology studies analyze the activity of each neuron separately. While such studies have given much insight into properties of the visual system, they have also potentially overlooked important aspects of information coded in changing patterns of activity that are distributed over larger populations of neurons. In this work, we apply a population decoding method to better estimate what information is available in neuronal ensembles and how this information is coded in dynamic patterns of neural activity in data recorded from inferior temporal cortex (ITC) and prefrontal cortex (PFC) as macaque monkeys engaged in a delayed match-to-category task. Analyses of activity patterns in ITC and PFC revealed that both areas contain "abstract" category information (i.e., category information that is not directly correlated with properties of the stimuli); however, in general, PFC has more task-relevant information, and ITC has more detailed visual information. Analyses examining how information coded in these areas show that almost all category information is available in a small fraction of the neurons in the population. Most remarkably, our results also show that category information is coded by a nonstationary pattern of activity that changes over the course of a trial with individual neurons containing information on much shorter time scales than the population as a whole.
Address for reprint requests and other correspondence: E. Meyers, Dept. of Brain and Cognitive Sciences, MIT, Bldg. 46-5155, 43 Vassar St., Cambridge, MA, 02139 (E-mail: emeyers{at}mit.edu )
Visual categorization is an essential perceptual and cognitive process for assigning behavioral significance to incoming stimuli. Categorization depends on sensory processing of stimulus features as ...well as flexible cognitive processing for classifying stimuli according to the current behavioral context. Neurophysiological studies suggest that the prefrontal cortex (PFC) and the inferior temporal cortex (ITC) are involved in visual shape categorization. However, their precise roles in the perceptual and cognitive aspects of the categorization process are unclear, as the two areas have not been directly compared during changing task contexts. To address this, we examined the impact of task relevance on categorization-related activity in PFC and ITC by recording from both areas as monkeys alternated between a shape categorization and passive viewing tasks. As monkeys viewed the same stimuli in both tasks, the impact of task relevance on encoding in each area could be compared. While both areas showed task-dependent modulations of neuronal activity, the patterns of results differed markedly. PFC, but not ITC, neurons showed a modest increase in firing rates when stimuli were task relevant. PFC also showed significantly stronger category selectivity during the task compared with passive viewing, while task-dependent modulations of category selectivity in ITC were weak and occurred with a long latency. Finally, both areas showed an enhancement of stimulus selectivity during the task compared with passive viewing. Together, this suggests that the ITC and PFC show differing degrees of task-dependent flexibility and are preferentially involved in the perceptual and cognitive aspects of the categorization process, respectively.
OBJECTIVES
This study presents clinical data from the first large registry of aortic counterpulsation, a computerized database that incorporates prospectively gathered data on indications for ...intra-aortic balloon counterpulsation (IABP) use, patient demographics, concomitant medication and in-hospital outcomes and complications.
BACKGROUND
The intra-aortic balloon pump (IABP) is widely used to provide circulatory support for patients experiencing hemodynamic instability due to myocardial infarction, cardiogenic shock, or in very high risk patients undergoing angioplasty or coronary artery bypass grafting.
METHODS
Between June 1996 and August 2000, 203 hospitals worldwide (90% U.S., 10% non-U.S.) collected 16,909 patient case records (68.8% men, 31.2% women; mean age 65.9 ± 11.7 years).
RESULTS
The most frequent indications for use of IABP were as follows: to provide hemodynamic support during or after cardiac catheterization (20.6%), cardiogenic shock (18.8%), weaning from cardiopulmonary bypass (16.1%), preoperative use in high risk patients (13.0%) and refractory unstable angina (12.3%). Major IABP complications (major limb ischemia, severe bleeding, balloon leak, death directly due to IABP insertion or failure) occurred in 2.6% of cases; in-hospital mortality was 21.2% (11.6% with the balloon in place). Female gender, high age and peripheral vascular disease were independent predictors of a serious complication.
CONCLUSIONS
This registry provides a useful tool for monitoring the evolving practice of IABP. In the modern-day practice of IABP, complication rates are generally low, although in-hospital mortality remains high. There is an increased risk of major complications in women, older patients and patients with peripheral vascular disease.
On 6 December 2013, two laboratory-confirmed cases of chikungunya without a travel history were reported on the French part of the Caribbean island of Saint Martin, indicating the start of the first ...documented outbreak of chikungunya in the Americas. Since this report, the virus spread to several Caribbean islands and French Guiana, and between 6 December 2013 and 27 March 2014 more than 17,000 suspected and confirmed cases have been reported. Further spread and establishment of the disease in the Americas is likely, given the high number of people travelling between the affected and non-affected areas and the widespread occurrence of efficient vectors. Also, the likelihood of the introduction of the virus into Europe from the Americas and subsequent transmission should be considered especially in the context of the next mosquito season in Europe. Clinicians should be aware that, besides dengue, chikungunya should be carefully considered among travellers currently returning from the Caribbean region.
The ability to categorize stimuli into discrete behaviourally relevant groups is an essential cognitive function. To elucidate the neural mechanisms underlying categorization, we constructed a ...cortical circuit model that is capable of learning a motion categorization task through reward-dependent plasticity. Here we show that stable category representations develop in neurons intermediate to sensory and decision layers if they exhibit choice-correlated activity fluctuations (choice probability). In the model, choice probability and task-specific interneuronal correlations emerge from plasticity of top-down projections from decision neurons. Specific model predictions are confirmed by analysis of single-neuron activity from the monkey parietal cortex, which reveals a mixture of directional and categorical tuning, and a positive correlation between category selectivity and choice probability. Beyond demonstrating a circuit mechanism for categorization, the present work suggests a key role of plastic top-down feedback in simultaneously shaping both neural tuning and correlated neural variability.
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