Treating epilepsy via adaptive neurostimulation: a reinforcement learning approach.

This paper presents a new methodology for automatically learning an optimal neurostimulation strategy for the treatment of epilepsy. The technical challenge is to automatically modulate neurostimulation parameters, as a function of the observed EEG signal, so as to minimize the frequency and duration of seizures. The methodology leverages recent techniques from the machine learning literature, in particular the reinforcement learning paradigm, to formalize this optimization problem. We present an algorithm which is able to automatically learn an adaptive neurostimulation strategy directly from labeled training data acquired from animal brain tissues. Our results suggest that this methodology can be used to automatically find a stimulation strategy which effectively reduces the incidence of seizures, while also minimizing the amount of stimulation applied. This work highlights the crucial role that modern machine learning techniques can play in the optimization of treatment strategies for patients with chronic disorders such as epilepsy.

Reduced serum concentration is permissive for increased in vitro endocrine differentiation from murine embryonic stem cells.

Embryonic stem cells (ESCs) have been shown to be capable of differentiating into pancreatic progenitors and insulin-producing cells in vitro. However, before ESC derivatives can be used in clinical settings, efficient selective differentiation needs to be achieved. Essential to improving ESC differentiation to islet endocrine cells is an understanding of the influences of extrinsic signals and transcription factors on cell specification. Herein, we investigate the influence of serum-supplemented growth conditions on the differentiation of murine ESCs to endocrine lineages in the context of over-expression of two pancreatic transcription factors, Pdx1 and Ngn3. To study the effect of different serum formulations and concentrations on the ability of murine ESCs to differentiate into endocrine cells in vitro, cells were grown into embryoid bodies and then differentiated in various serum replacement (SR), fetal calf serum (FCS) and serum-free conditions. Using immunohistochemistry and quantitative real-time RT-PCR (QPCR), we found that, of the conditions tested, 1% SR differentiation medium resulted in the highest levels of insulin-1 mRNA and significantly increased the total number of insulin-expressing cells. Applying this knowledge to cell lines in which Pdx1 or Ngn3 transgene expression could be induced by exposure to doxycycline we differentiated TetPDX1 and TetNgn3 ESCs under conditions of either 10% FCS or 1% SR medium. In the presence of 10% serum, induced expression of either Pdx1 or Ngn3 in differentiating ESCs resulted in modest increases in hormone transcripts and cell counts. However, changing the serum formulation from 10% FCS to 1% SR significantly enhanced the number of insulin+/C-peptide+ cells in parallel with increased insulin-1 transcript levels in both inducible cell lines. In summary, these data demonstrate that induced expression of key pancreatic transcription factors in combination with low serum/SR concentrations increases endocrine cell differentiation from murine ESCs.

Mapping the total phosphorus concentration of biosolid amended surface soils using LANDSAT TM data.

Conventional methods for soil sampling and analysis for soil variability in chemical characteristics are too time-consuming and expensive for multi-seasonal monitoring over large-scale areas. Hence, the objectives of this study are: 1) to determine changes in chemical concentrations of soils that are amended with treated sewage sludge; and 2) to determine if LANDSAT TM data can be used to map surface chemical characteristics of such amended soils. For this study, we selected two fields in NW Ohio, designated as F34 and F11, that had been applied with 34 and 11 ton acre(-1) of biosolids, respectively. Soil samples from a total of 70 sampling locations across the two fields were collected one day prior to LANDSAT 5 overpass and were analyzed for several elemental concentrations. The accumulation of Ba, Cd, Cu, S and P were found to be significantly higher in the surface soils of field F34, compared to field F11. Regression equations were established to search for algorithms that could map these five elemental concentrations in the surface soils using six, dark-object-subtracted (DOS) LANDSAT TM bands and the 15 non-reciprocal spectral ratios derived from these six bands for the May 20, 2005, LANDSAT 5 TM image. Phosphorus (P) had the highest R(2) adjusted value (67.9%) among all five elements considered, and the resulting algorithm employed only spectral ratios. This model was successfully tested for robustness by applying it to another LANDSAT TM image obtained on June 5, 2005. Our results enabled us to conclude that LANDSAT TM imagery of bare-soil fields can be used to quantify and map the spatial variation of total phosphorous concentration in surface soils. This research has significant implications for identification and mapping of areas with high P, which is important for implementing and monitoring the best phosphorous management practices across the region.

Generation and characterization of novel tetracycline-inducible pancreatic transcription factor-expressing murine embryonic stem cell lines.

Pancreatic development in mammals is controlled in part by the expression and function of numerous genes encoding transcription factors. Yet, how these regulate each other and their target genes is incompletely understood. Embryonic stem (ES) cells have recently been shown to be capable of differentiating into pancreatic progenitor cells and insulin-producing cells, representing a useful in vitro model system for studying pancreatic and islet development. To generate tools to study the relationships of transcription factors in pancreatic development we have established seven unique mouse ES cell lines with tetracycline-inducible expression of either Hnf4alpha, Hnf6, Nkx2.2, Nkx6.1, Pax4, Pdx1, and Ptf1a cDNAs. Each of the cell lines was characterized for induction of transgene expression after exposure to doxycycline (DOX) by quantitative real-time PCR and immunofluorescence microscopy. Transgene expression in the presence of DOX was at least 97-fold that seen in untreated cells. Immunofluorescent staining of DOX-treated cultures showed efficient (>95% of cells) transgene protein expression while showing <5% positive staining in uninduced cells. Each of the ES cell lines maintained their pluripotency as measured by teratoma formation. Furthermore, transgene expression can be efficiently achieved in vivo through DOX administration to mice. The establishment of ES cell lines with temporally controllable induction of critical pancreatic transcription factor genes provides a new set of tools that could be used to interrogate gene regulatory networks in pancreatic development and potentially generate greater numbers of beta cells from ES cells.

Posttetanic count revisited: are measurements more reliable using the TOF-Watch accelerographic peripheral nerve stimulator?

OBJECTIVE: Measurement of profound neuromuscular block using posttetanic count is among the most subjective measurements made in clinical anesthesia. The TOF-Watch accelerographic peripheral nerve stimulator provides objective measurements of neuromuscular block that may improve our ability to quantitate intense blockade. METHODS: The TOF-Watch and Digi Stim III peripheral nerve stimulators were used to monitor onset and early recovery of neuromuscular response induced by rocuronium 0.6 mg/kg i.v. in 30 patients anesthetized with general anesthesia. After induction, train-of-four count (when present) was measured at one-min intervals. Subsequently, posttetanic count was measured at three-min intervals until the first response to train-of-four stimulation reappeared. RESULTS: Posttetanic count and train-of-four count measurements were determined to be consistently unreliable throughout the study in seven (23%) patients with the TOF-Watch stimulator and three (10%) patients with the Digi Stim III stimulator (p = NS). Among stimulators yielding reliable measurements, decreases in train-of-four count to 0/4 were noted earlier with the Digi Stim III monitor (median = 2 min) as compared with the TOF-Watch device (median = 4 min) (p < 0.05). Also, posttetanic count decreased to zero in only 35% of patients with the TOF-Watch stimulator versus 67% of patients with the Digi Stim III stimulator (p < 0.05). CONCLUSIONS: Both monitors were similar in their ability to predict return to TOFC = 1 as a function of PTC measurements. The TOF-Watch monitor is easy to apply even in inexperienced hands. However, the device yielded erroneous data in 23% of patients.