Dense Annotation of Free-Text Critical Care Discharge Summaries from an Indian Hospital and Associated Performance of a Clinical NLP Annotator.

Electronic Health Record (EHR) use in India is generally poor, and structured clinical information is mostly lacking. This work is the first attempt aimed at evaluating unstructured text mining for extracting relevant clinical information from Indian clinical records. We annotated a corpus of 250 discharge summaries from an Intensive Care Unit (ICU) in India, with markups for diseases, procedures, and lab parameters, their attributes, as well as key demographic information and administrative variables such as patient outcomes. In this process, we have constructed guidelines for an annotation scheme useful to clinicians in the Indian context. We evaluated the performance of an NLP engine, Cocoa, on a cohort of these Indian clinical records. We have produced an annotated corpus of roughly 90 thousand words, which to our knowledge is the first tagged clinical corpus from India. Cocoa was evaluated on a test corpus of 50 documents. The overlap F-scores across the major categories, namely disease/symptoms, procedures, laboratory parameters and outcomes, are 0.856, 0.834, 0.961 and 0.872 respectively. These results are competitive with results from recent shared tasks based on US records. The annotated corpus and associated results from the Cocoa engine indicate that unstructured text mining is a viable method for cohort analysis in the Indian clinical context, where structured EHR records are largely absent.

Voltage sensitivity of gap junction currents in rat osteoblast-like cells.

The dependence of macroscopic gap junctional conductance (g(j)) upon transjunctional voltage (Vj) was examined in 39 paired osteoblast-like (OB) cells from primary cultures using the double whole cell patch clamp technique. OB cells were derived from calvarial explants of new-born rats. Instantaneous current-voltage (Ij-Vj) relationships of OB cell pairs (n = 6) were linear in the entire voltage range (-150 < Vj < 150 mV) examined. The steady-state Ij-Vj relationship was non-linear for V > or = +/-60 mV. The curve for the normalised steady-state junctional conductance-voltage relationship (Gss/G0-Vj) was bell-shaped, and was fitted with a two-state Boltzmann equation with a minimum conductance (Gmin) of 0.2-0.3, and a half deactivation voltage (Vo) of +/-83 mV. In two recordings unitary gap junction channel activity was observable. The linear I-V relationships revealed a single channel conductance of approximately 100 pS. Application of parathyroid hormone (10(-8) M) had no effect on the voltage dependence nor the magnitude of macroscopic currents (n = 7).

Cardiovascular disease in the Adventures of Sherlock Holmes.

The Adventures of Sherlock Holmes by Sir Arthur Conan Doyle contains many incidents of medical interest. While disorders of the cardiovascular system do not play an important role in these tales, there are, nevertheless, some illnesses that invite speculation. Eleven such incidents are reviewed and discussed in light of the times in which they occurred and in light of current medical knowledge.

Iatrogenic pancreatitis. A fatal complication in the induction therapy for acute lymphocytic leukemia.

A patient with acute lymphocytic leukemia developed acute pancreatitis during induction therapy with corticosteroids and asparaginase. Postmortem examination showed changes consistent with hemorrhagic pancreatitis and fat necrosis over the pancreas and omentum. Corticosteroids were thought to be responsible for pancreatitis in this patient since "hemorrhagic pancreatitis" has not been previously described with asparaginase. We recommend careful follow-up of serum and urinary amylase values in patients receiving induction therapy with these agents.

Permeability of R6G across Cx43 hemichannels through a novel combination of patch clamp and surface enhanced Raman spectroscopy.

We have measured the permeability of rhodamine-6G across Cx43 hemichannels reconstituted on a pipette tip. Cx43 hemichannels were overexpressed in Sf9 cells, and affinity-purified. The hemichannels were reconstituted in a lipid bilayer on a pipette tip by the tip-dip method. R6G in the pipette permeated across the channels into the bath. The permeability of R6G was quantified by measuring R6G concentration in the bath after several hours by surface enhanced Raman spectroscopy (SERS) with 100 nm silver colloid particles. The ratio of the permeability of dye to salt, as extracted by this combined electrical-SERS technique, is compatible with similar ratios for other dyes across whole gap junction channels. The results for the permeability ratio were further compared to fluorescence measurements. The novel combination of patch and SERS techniques can be extended to quantifying the transport of biologically significant non-fluorescent molecules, such as cAMP and IP3, across 1 nm sized pores, such as the gap junction channel.

The CHEMDNER corpus of chemicals and drugs and its annotation principles.

The automatic extraction of chemical information from text requires the recognition of chemical entity mentions as one of its key steps. When developing supervised named entity recognition (NER) systems, the availability of a large, manually annotated text corpus is desirable. Furthermore, large corpora permit the robust evaluation and comparison of different approaches that detect chemicals in documents. We present the CHEMDNER corpus, a collection of 10,000 PubMed abstracts that contain a total of 84,355 chemical entity mentions labeled manually by expert chemistry literature curators, following annotation guidelines specifically defined for this task. The abstracts of the CHEMDNER corpus were selected to be representative for all major chemical disciplines. Each of the chemical entity mentions was manually labeled according to its structure-associated chemical entity mention (SACEM) class: abbreviation, family, formula, identifier, multiple, systematic and trivial. The difficulty and consistency of tagging chemicals in text was measured using an agreement study between annotators, obtaining a percentage agreement of 91. For a subset of the CHEMDNER corpus (the test set of 3,000 abstracts) we provide not only the Gold Standard manual annotations, but also mentions automatically detected by the 26 teams that participated in the BioCreative IV CHEMDNER chemical mention recognition task. In addition, we release the CHEMDNER silver standard corpus of automatically extracted mentions from 17,000 randomly selected PubMed abstracts. A version of the CHEMDNER corpus in the BioC format has been generated as well. We propose a standard for required minimum information about entity annotations for the construction of domain specific corpora on chemical and drug entities. The CHEMDNER corpus and annotation guidelines are available at: http://www.biocreative.org/resources/biocreative-iv/chemdner-corpus/.

Model invariant method for extracting single-channel mean open and closed times from heterogeneous multichannel records.

We present a proof that the mean open (and closed) times of the individual channels in a multichannel record can be found in a model-independent fashion. As the results are model independent, they can be derived by assuming the simplest model for all the channels, namely that they all have the basic CLOSED in equilibrium with OPEN scheme. In particular, the method can be applied to patches where the channel population is heterogenous with respect to open probability. Multichannel simulations are performed to test the limits of applicability of this method to restricted amounts of data. One conclusion is that increasing the number of channels does not substantially reduce the errors in estimating the mean times, in spite of the 'increased information' present. We also prove the general applicability of the algorithm of Fenwick et al. (1982) in estimating the mean times without knowledge of the number of channels present, and discuss its limitations. An illustration using experimental data is also given.

James Bryan Herrick: a man of intellectual muscle.

James Bryan Herrick was an American physician who made several contributions to clinical medicine. Three of his most important observations are described.

A steady-state electrochemical model of vascular smooth muscle cells.

A model of the steady-state electrochemical response of vascular smooth muscle cells to external stimuli is presented, which accounts for K, Na, and Ca fluxes. The results of the model are broadly in accordance with experimental data 1), at various transmural pressures; 2), with channel and pump blockade; and 3), under manipulation of external ionic concentrations. The model exhibits dual stable states which sometimes coexist, and abrupt transitions between these states may account for nongraded responses in arteries as external potassium or pressure is varied. The simulations suggest that changes in the intracellular sodium concentration ([Na]i) often accompany smooth muscle responses. For example, [Na]i values vary threefold over the range of pressures from 10 to 100 mmHg.

Non-stationary fluctuation analysis of macroscopic gap junction channel records.

Non-stationary fluctuation analysis was applied to macroscopic records of junctional currents arising from homotypic Cx37 and Cx43 gap junction channels expressed in RIN cells. The data were analyzed by a modification of existing analytical methods that takes endemic uncoupling into account. The results are consistent with both channels having open probabilities ranging from 0.7 to near unity for low transjunctional voltages. The analysis also yielded estimates of single-channel conductances for the two channel types similar to those seen in single-channel recordings. The results presented here show that fluctuation analysis can be used to extract single-channel gap junctional conductances from macroscopic double whole-cell recordings. These results also constitute empirically determined estimates of the open probability that are not model-dependent.

Exact solution of a model of diffusion in an infinite chain or monolayer of cells coupled by gap junctions.

Analytic solutions are found for an infinite chain of cells coupled by gap junctions under two initial conditions: (a) One inner cell initially filled uniformly to a fixed concentration and (b) inner cell maintained indefinitely at constant concentration. The solution can be extended by the product method (Carslaw and Jaeger. 1959. Conduction of Heat in Solids. Oxford University Press.) to monolayers. We can also incorporate leakage through the plasma membrane by the product method. We demonstrate the utility of these results by fitting diffusion data from the septate axon of earthworm and by plots of theoretical profiles from monolayers of cells. Use of these analytic solutions enables one to overcome the limitations of methods that lump the effects of cytoplasmic diffusion and junctional permeability into an effective diffusion coefficient.

Multichannel recordings from membranes which contain gap junctions. II. Substates and conductance shifts.

Substates which can last up to several seconds are found in the 100-pS channel of the earthworm septum, a putative gap junction channel. The conductance of these substates is highly variable from preparation to preparation, and they are found at almost every fraction of the whole channel conductance. Another phenomenon seen in multichannel recordings is the "conductance shift": here the current passed by several open channels differs from an integral multiple of the current when only one channel is open. These shifts can be modelled by 1) a resistance in series with the channel or 2) long-lived substates. Each of these models fails in particular cases to explain either the magnitude or direction of the shifts. It is possible that both effects are simultaneously present.

A model for the diffusion of fluorescent probes in the septate giant axon of earthworm. Axoplasmic diffusion and junctional membrane permeability.

The diffusion of the three fluorescent probes dichlorofluorescein, carboxyfluorescein, and Lucifer Yellow within the septate median giant axon of the earthworm was monitored using fluorometric methods. A diffusion model was derived that allowed computation of the apparent axoplasmic diffusion coefficient, junctional membrane permeability (septal membranes), and plasma membrane permeability for each probe. Dichlorofluorescein and carboxyfluorescein have similar apparent axoplasmic diffusion coefficients, which were reduced by a factor of eight relative to that predicted from the Einstein-Stokes equation. Nonspecific reversible binding appears to be the major cause of the retarded diffusion coefficients. Junctional membrane permeability for dichlorofluorescein was 4.7 to 73-fold greater than that for carboxyfluorescein. This difference could not be explained on the basis of molecular size but can be explained by the difference in charge between the two molecules. Diffusion coefficients and junctional membrane permeabilities remained constant with time for both dyes. The diffusion of Lucifer Yellow within the axoplasm and permeability through the junctional membranes did not remain constant with time but declined. From this it was inferred that Lucifer Yellow experienced a slow, irreversible binding to axoplasmic elements. All three probes had finite plasma membrane permeabilities.