Validation of a suite of ERP and QEEG biomarkers in a pre-competitive, industry-led study in subjects with schizophrenia and healthy volunteers.

OBJECTIVE: Complexity and lack of standardization have mostly limited the use of event-related potentials (ERPs) and quantitative EEG (QEEG) biomarkers in drug development to small early phase trials. We present results from a clinical study on healthy volunteers (HV) and patients with schizophrenia (SZ) that assessed test-retest, group differences, variance, and correlation with functional assessments for ERP and QEEG measures collected at clinical and commercial trial sites with standardized instrumentation and methods, and analyzed through an automated data analysis pipeline. METHODS: 81 HV and 80 SZ were tested at one of four study sites. Subjects were administered two ERP/EEG testing sessions on separate visits. Sessions included a mismatch negativity paradigm, a 40 Hz auditory steady-state response paradigm, an eyes-closed resting state EEG, and an active auditory oddball paradigm. SZ subjects were also tested on the Brief Assessment of Cognition (BAC), Positive and Negative Syndrome Scale (PANSS), and Virtual Reality Functional Capacity Assessment Tool (VRFCAT). RESULTS: Standardized ERP/EEG instrumentation and methods ensured few test failures. The automated data analysis pipeline allowed for near real-time analysis with no human intervention. Test-retest reliability was fair-to-excellent for most of the outcome measures. SZ subjects showed significant deficits in ERP and QEEG measures consistent with published academic literature. A subset of ERP and QEEG measures correlated with functional assessments administered to the SZ subjects. CONCLUSIONS: With standardized instrumentation and methods, complex ERP/EEG testing sessions can be reliably performed at clinical and commercial trial sites to produce high-quality data in near real-time.

Three-dimensional chemoarchitecture of the basal forebrain: spatially specific association of cholinergic and calcium binding protein-containing neurons.

The basal forebrain refers to heterogeneous structures located close to the medial and ventral surfaces of the cerebral hemispheres. It contains diverse populations of neurons, including the cholinergic cortically projecting cells that show severe loss in Alzheimer's and related neurodegenerative diseases. The basal forebrain does not display any cytoarchitectural or other structural features that make it easy to demarcate functional boundaries, a problem that allowed different investigators to propose different organizational schemes. The present paper uses novel three-dimensional reconstructions and numerical analyses for studying the spatial organization of four major basal forebrain cell populations, the cholinergic, parvalbumin, calbindin and calretinin containing neurons in the rat. Our analyses suggest that the distribution of these four cell populations is not random but displays a general pattern of association. Within the cholinergic space (i.e. the volume occupied by the cortically projecting cholinergic cell bodies) the three other cell types form twisted bands along the longitudinal axis of a central dense core of cholinergic cells traversing the traditionally defined basal forebrain regions, (i.e. the medial septum, diagonal bands, the substantia innominata, pallidal regions and the bed nucleus of the stria terminalis). At a smaller scale, the different cell types within the cholinergic space occupy overlapping high-density cell clusters that are either chemically uniform or mixed. However, the cell composition of these high-density clusters is regionally specific. The proposed scheme of basal forebrain organization, using cell density or density relations as criteria, offers a new perspective on structure-function relationship, unconstrained by traditional region boundaries.

Developmental emergence of hippocampal fast-field "ripple" oscillations in the behaving rat pups.

Sharp wave and associated fast oscillatory ripples (140-200 Hz) in the cornu ammonis 1 region are the most synchronous hippocampal patterns in the adult rat. Spike sequences associated with sharp waves are believed to play a critical role in transferring transient memories from the hippocampus to the neocortex and the emergence of superfast ripples is pathognostic in temporal lobe epilepsy. Sharp waves in cornu ammonis 1 stratum radiatum are induced by a strong depolarization by the cornu ammonis 3 Schaffer collaterals, due to the synchronous discharge of cornu ammonis 3 pyramidal cells. Although during the first postnatal week, sharp-wave events are associated with hippocampal unit bursts in the pyramidal layer, ripple oscillations are absent. We investigated the emergence of fast-field oscillations in rat pups ranging from postnatal day 12-20 by recording with wire tetrodes in freely behaving pups and with 16-site linear silicon probes in head fixed animals. Cornu ammonis 1 pyramidal cell layer was determined by the presence of multiple unit activity and a reversal of the field potential in the deeper electrode sites. On-line verification of the recording sites was determined via an evoked response to commissural stimulation, showing a clear reversal in the field potential. Sharp wave-associated fast-field oscillations did not begin to emerge until the end of the second postnatal week and showed a gradual increase until day 18. Once ripples emerged, the intra-ripple frequency assumed adult values. The developmental time course of the ripple parallels the switch in the GABA(A) receptor-mediated signaling from excitation to inhibition. The time course may also reflect hitherto unidentified emergence of neuronal gap junctions.

Mycobacterium bovis tuberculosis: from animal to man and back.

Rare cases of tuberculosis due to Mycobacterium bovis have been described in humans who have been exposed to cattle or other infected animals. We report a case of tuberculosis in cattle exposed to a patient infected with M. bovis, where the strain isolated in the cattle and the patient were identical. As the patient is reported to have been exposed and contaminated during childhood, this seems to be the first documented case of transmission of M. bovis from animal to man and back to animal.

False-positive Mycobacterium tuberculosis culture revealed by restriction fragment length polymorphism analysis.

BACKGROUND: The microbiological analysis of respiratory specimens is the most reliable approach to diagnose active pulmonary tuberculosis. PATIENT AND METHODS: We report a 60-year-old female patient (index patient) who underwent diagnostic bronchoscopy for chronic cough. No acid-fast bacilli were detected in bronchial washings. Although cough subsided with symptomatic treatment, Mycobacterium tuberculosis grew on egg-based media after 12 weeks. A false-positive culture result was suspected. Chart review and DNA fingerprinting were carried out. RESULTS: The bronchoscope used to examine the index patient was previously used for a 30-year-old patient (source patient) with smear- and culture-positive pulmonary tuberculosis. Restriction fragment length polymorphism (RFLP) analysis based on the IS 6110 element confirmed that the two strains were identical. CONCLUSION: Cross-contamination is a reason for false-positive cultures with M. tuberculosis and should be suspected in patients with a low clinical probability for active tuberculosis.

Hippocampal network patterns of activity in the mouse.

Genetic engineering of the mouse brain allows investigators to address novel hypotheses in vivo. Because of the paucity of information on the network patterns of the mouse hippocampus, we investigated the electrical patterns in the behaving animal using multisite silicon probes and wire tetrodes. Theta (6-9 Hz) and gamma (40-100 Hz) oscillations were present during exploration and rapid eye movement sleep. Gamma power and theta power were comodulated and gamma power varied as a function of the theta cycle. Pyramidal cells and putative interneurons were phase-locked to theta oscillations. During immobility, consummatory behaviors and slow-wave sleep, sharp waves were present in cornu ammonis region CA1 of the hippocampus stratum radiatum associated with 140-200-Hz "ripples" in the pyramidal cell layer and population burst of CA1 neurons. In the hilus, large-amplitude "dentate spikes" occurred in association with increased discharge of hilar neurons. The amplitude of field patterns was larger in the mouse than in the rat, likely reflecting the higher neuron density in a smaller brain. We suggest that the main hippocampal network patterns are mediated by similar pathways and mechanisms in mouse and rat.

[Filaria: a tropical disease as the etiology of acute scrotum]. / Filarien: eine Tropenkrankheit als Ursache für das akute Skrotum.

In the diagnosis and treatment of acute scrotal pain and swelling it is important to differentiate between testicular torsion and epididymo-orchitis. A special case of a thirty-eight-year-old male asylant from Nepal was presented in the urological service with acute scrotal pain. To exclude testicular torsion, a diagnostic exploration of the scrotum was done with the findings of an acute funiculitis with abscess formation. Under surgical drainage of abscess together with medical treatment the acute inflammation disappeared. The diagnosis of filarial funiculitis was made after identifying the microfilariae in a blood vessel and in the peripheral blood smear. A filaricide medication with diethylcarbamacine citran was administered with good symptomatic relief.

Brucellosis: an occupational hazard for medical laboratory personnel. Report of five cases.

Five cases of laboratory-acquired infection with Brucella melitensis are reported. This pathogen is highly contagious when handled in the laboratory. Clinicians should alert technologists when brucellosis is suspected so that specimens are handled under the most stringent safety measures. Serological surveys and instructions of laboratory workers regarding the clinical diversity of the disease are helpful for early recognition of secondary cases. On the other hand, clinicians should consider brucellosis in medical laboratory workers with unexplained signs and symptoms.

Tunable diode-laser heterodyne spectrometer for remote observations near 8 microm.

A diode-laser based ultrahigh resolution IR heterodyne spectrometer for laboratory and field use has been developed for operation between 7.5 and 8.5 microm. The local oscillator is a PbSe tunable diode laser kept continuously at operating temperatures of 12-60 K using a closed-cycle cooler. The laser output frequency is controlled and stabilized using a high-precision diode current supply, constant temperature controller, and a shock isolator mounted between the refrigerator cold tip and the diode mount. The system largely employs reflecting optics to minimize losses from internal reflection and absorption and to eliminate chromatic effects. Spectral analysis of the diode-laser output between 0 and 1 GHz reveals excess noise at many diode current settings, which limits the IR spectral regions over which useful heterodyne operation can be achieved. Observations have been made of atmospheric N(2)O, O(3), and CH(4) between 1170 and 1200 cm(-1) using both a single-frequency swept IF channel and a 64-channel rf spectral line receiver with a total IF coverage of 1600 MHz.

Discovery of natural gain amplification in the 10-micrometer carbon dioxide laser bands on Mars: a natural laser.

Fully resolved intensity profiles of various lines in the carbon dioxide band at 10.4 micrometers have been measured on Mars with an infrared heterodyne spectrometer. Analysis of the line shapes shows that the Mars atmosphere exhibits positive gain in these lines. The detection of natural optical gain amplification enables identification of these lines as a definite natural laser.

Submillimeter heterodyne detection of interstellar carbon monoxide at 434 micrometers.

A submillimeter heterodyne radiometer, developed for astronomical applications, uses an optically pumped laser local oscillator and a quasi-optical Schottky diode mixer. The resultant telescope-mounted system, which has a noise temperature less than 4000 K (double sideband) and high frequency and spatial resolution, has been used to detect the J = 6 --> 5 rotational transition of carbon monoxide at 434 micrometers in the Orion molecular cloud. The measurements, when compared with previous millimeter-wave data, indicate that the broad carbon monoxide emission feature is produced by an optically thin gas whose temperature exceeds 180 K.

Precision measurements of NH(3) spectral lines near 11 microm using the infrared heterodyne technique.

Absolute line-center frequencies for eleven lines of ammonia in near coincidence with CO(2)-laser transitions have been determined to accuracies of +/-3 MHz by infrared heterodyne detection. These results were obtained by heterodyning a blackbody with a stable, grating-tuned CO(2) gas laser. A discussion of the apparatus and method of calculation, including error analysis, is presented. With these accurately determined line-center positions, the ammonia molecule will be a useful secondary-frequency standard for diode-laser spectroscopy in the 11-microm wavelength region.

Sensitivity limits of an infrared heterodyne spectrometer for astrophysical applications.

The sensitivity of an ideal heterodyne spectrometer approaches the quantum detection limit provided the local oscillator power is sufficiently large and the shot noise dominates all other sources of noise. The postintegration minimum-detectable-number of photons/sec for an ideal heterodyne system is (B/tau)((1/2)), where B is the IF bandwidth, and tau is the integration time. For astronomical observations, however, a number of factors (Delta(i)) tend to degrade the sensitivity, a fact that becomes significant particularly when the laser power is insufficient. A discussion and an evaluation of the degradation in sensitivity are given for a heterodyne spectrometer employing a HgCdTe photodiode mixer and tunable diode lasers. The minimum detectable source brightness is considered as a function of the mixer parameters, transmission coefficient of the beam splitter, and local oscillator emission powers. The degradation in the minimum detectable line source brightness that results from the bandwidth being a fraction of the line width is evaluated and plotted as a function of the wavelength and bandwidth for various temperature to mass ratios. It is shown that the minimum achievable degradation [pi(i)(Delta(i))] in the sensitivity of a practical astronomical heterodyne spectrometer is ~30. Estimates of SNR's with which ir line emission from astronomical sources of interest may be detected are given.