Studies of twins with systemic lupus erythematosus. A review of the literature and presentation of 12 additional sets.

To assess the role of genetic factors in systemic lupus erythematosus (SLE), 12 twon pairs (seven definitely monozygotic, three definitely dizygotic) of which one or both twins had SLE, were studied and compared to 17 twin pairs (12 definitely monozygotic) previously described. In the present series, four of seven (57 per cent) definitely monozygotic pairs were clinically concordant for SLE, satisfying the preliminary criteria of the American Rheumatism Association (ARA). Concordance for the presence of antinuclear factor (ANF) and hypergammaglobulinemia was 71 and tinuclear factor (ANF) and hypergammaglobulinemia was 71 and 87 per cent, respiectively. These data closely agree with those on the 12 definitely monozygotic sets previously described. All three of the dizygotic sets in the present series were discordant for clinical SLE, although one clinically well twin had marked serologic abnormalities. Comparison of these data with thos from other first degree relatives of out twins clearly suggests a strong genetic component in the pathogenesis of SLE. The relative contribution of nongenetic and environmental factors to the expression of the disease is discussed.

Prognostic importance of cardiac arrhythmias in systemic sclerosis.

Ambulatory electrocardiography was performed in 183 patients with systemic sclerosis recruited from five centers who were selected to reflect a balanced population with respect to disease extent and duration. Ventricular ectopy occurred in 67 percent of patients and was strongly correlated by both univariate and multivariate analyses with total mortality and with sudden death. By multivariate analysis, ventricular ectopy was strongly associated with increasing patient age and with other evidence of cardiac and pulmonary involvement but not with clinical and laboratory measures of duration and extent of systemic sclerosis. Evidence of myocardial fibrosis thought to be secondary to microvascular alteration is common in systemic sclerosis, but the clinical implications of myocardial involvement are less well appreciated. The present data suggest the need for ambulatory electrocardiography in the clinical assessment of selected patients with systemic sclerosis, especially those with cardiac or pulmonary involvement, as well as for studies of the effects of antiarrhythmic therapy.

Scleroderma heart disease with slow flow velocity in coronary arteries.

A young woman with scleroderma heart disease is presented. Complete work-up including hemodynamic studies revealed biventricular dysfunction, left ventricular hypokinesia and normal coronary arteries with slow flow velocity in coronary arteries. This finding, though not diagnostic, is consistent with small vessels disease secondary to scleroderma. Favorable prognosis in our patient on medical management is encouraging. No conclusions can be drawn on the basis of one patient. Further work is warranted in scleroderma patients with cardiomegaly to define the status of the myocardial microcirculation and its possible role in their prognosis.

Purkinje cell degeneration and control mice: responses of single units in the dorsal cochlear nucleus and the acoustic startle response.

The cartwheel cell is the most numerous inhibitory interneuron of the dorsal cochlear nucleus (DCN). It is expected to be an important determinant of DCN function. To assess the contribution of the cartwheel cell, we examined the discharge characteristics of DCN neurons and behavioral measures in the Purkinje cell degeneration (pcd) mice, which lack cartwheel cells, and compared them to those of the control mice. Distortion product otoacoustic emissions and auditory brainstem-evoked response thresholds were similar between the two groups. Extracellularly recorded DCN single units in ketamine/xylazine-anesthetized mice were classified according to post-stimulus time histogram (PSTH) and excitatory-inhibitory response area (EI-area) schemes. PSTHs recorded in mouse DCN included chopper, pauser/buildup, onset, inhibited and nondescript types. EI-areas recorded included Types I, II, III, I/III, IV and V. There were no significant differences in the proportions of various unit types between the pcd and control mice. The pcd units had slightly lower thresholds to characteristic frequency tones; however, they had spontaneous rates, thresholds to noise, and maximum driven rates to noise that were similar to those of the control units. Pcd mice had smaller startle amplitudes, but startle latency, prepulse inhibition/augmentation and facilitation by a background tone were comparable between the two groups. From these results, we conclude that DCN function in response to relatively simple acoustic stimuli is minimally affected by the absence of the cartwheel cells. Future studies employing more complex and/or multimodal stimuli should help assess the role of the cartwheel cells.

Primary biliary cirrhosis and scleroderma. The possibility of a common pathogenetic mechanism.

A woman with clinical manifestations of progressive systemic sclerosis had liver disease with histologic and immunologic features of primary biliary cirrhosis. Biopsy specimens of salivary gland showed necrosis and lymphocytic infiltrates in and around ducts similar to those observed in hepatic ducts, whereas neither of these tissues exhibited immunoglobulin or complement deposition. The ultrastructural and immunohistochemical studies suggest a common cell-mediated immunologic mechanism for the two disorders.

Effects of CIC hearing aids on auditory localization by listeners with normal hearing.

An experiment was conducted to determine the effects of completely-in-the-canal (CIC) hearing aids on auditory localization performance. Six normal-hearing listeners localized a 750-ms broadband noise from loudspeakers ranging in azimuth from -180 degrees to +180 degrees and in elevation from -75 degrees to +90 degrees. Independent variables included the presence or absence of the hearing aid and the elevation of the source. Dependent measures included azimuth error, elevation error, and the percentage of trials resulting in a front-back confusion. The findings indicate a statistically significant decrement in localization acuity, both in azimuth and elevation, occasioned by the wearing of CIC hearing aids. However, the magnitude of this decrement was small compared to those typically caused by other ear-canal occlusions, such as earplugs, and would probably not engender mislocalization of real-world sounds.

3-dimensional auditory displays: development, applications, and performance.

Virtual or 3-D audio display technology has become a reality. This type of system has the capability of synthesizing signals presented over headphones that give the user the illusion that the sound is emanating from some external location. The development of this technology, its applications, and its performance in both laboratory and flight test situations are presented. Potential fighter aircraft applications include threat location warning, wingman location indication, spatially separated multi-channel communications, and audio target location indications. The laboratory performance data show an average localization error in azimuth of approximately 5 degrees, a minimum audible angle of approximately 5 degrees, and a speech intelligibility improvement of up to 28%. Flight test results demonstrated successful audio cued target acquisition, a subjective decrease in target acquisition times, a subjective improvement in speech intelligibility, a subjective increase in situational awareness, and a subjective decrease in pilot workload. A summary of both laboratory and flight test results is presented in addition to recommendations for future research.

Role of GABAergic inhibition in the coding of interaural time differences of low-frequency sounds in the inferior colliculus.

A major cue for the localization of sound in space is the interaural time difference (ITD). We examined the role of inhibition in the shaping of ITD responses in the inferior colliculus (IC) by iontophoretically ejecting gamma-aminobutyric acid (GABA) antagonists and GABA itself using a multibarrel pipette. The GABA antagonists block inhibition, whereas the applied GABA provides a constant level of inhibition. The effects on ITD responses were evaluated before, during and after the application of the drugs. If GABA-mediated inhibition is involved in shaping ITD tuning in IC neurons, then applying additional amounts of this inhibitory transmitter should alter ITD tuning. Indeed, for almost all neurons tested, applying GABA reduced the firing rate and consequently sharpened ITD tuning. Conversely, blocking GABA-mediated inhibition increased the activity of IC neurons, often reduced the signal-to-noise ratio and often broadened ITD tuning. Blocking GABA could also alter the shape of the ITD function and shift its peak suggesting that the role of inhibition is multifaceted. These effects indicate that GABAergic inhibition at the level of the IC is important for ITD coding.

Aurally aided visual search in three-dimensional space.

We conducted an experiment to evaluate the effectiveness of spatial audio displays on target acquisition performance. Participants performed a visual search task with and without the aid of a spatial audio display. Potential target locations ranged between plus and minus 180 degrees in azimuth and from -70 degrees to +90 degrees in elevation. Independent variables included the number of visual distractors present (1, 5, 10, 25, 50) and the spatial audio condition (no spatial audio, free-field spatial audio, virtual spatial audio). Results indicated that both free-field and virtual audio cues engendered a significant decrease in search times. Potential applications of this research include the design of spatial audio displays for aircraft cockpits and ground combat vehicles.

Effects of amplitude modulation on the coding of interaural time differences of low-frequency sounds in the inferior colliculus. I. Response properties.

Most sounds in the natural environment are amplitude-modulated (AM). To determine if AM alters the neuronal sensitivity to interaural time differences (ITDs) in low-frequency sounds, we tested neuronal responses to a binaural beat stimulus with and without modulation. We recorded from single units in the inferior colliculus of the unanesthetized rabbit. We primarily used low frequency ( approximately 25 Hz) modulation that was identical at both ears. We found that modulation could enhance, suppress, or not affect the discharge rate. In extreme cases, a neuron that showed no response to the unmodulated binaural beat did so when modulation was added to both ears. At the other extreme, a neuron that showed sensitivity to the unmodulated binaural beat ceased firing with modulation. Modulation could also affect the frequency range of ITD sensitivity, best ITD, and ITD tuning width. Despite these changes in individual neurons, averaging across all neurons, the peak and width of the population ITD function remained unchanged. Because ITD-sensitive neurons also time-locked to the modulation frequency, the location and sound attributes are processed simultaneously by these neurons.

Effects of amplitude modulation on the coding of interaural time differences of low-frequency sounds in the inferior colliculus. II. Neural mechanisms.

In our companion paper, we reported on interaural time difference (ITD)-sensitive neurons that enhanced, suppressed, or did not change their response when identical AM was added to both ears. Here, we first examined physical factors such as the difference in the interaural correlation, spectrum, or energy between the modulated and unmodulated signals. These were insufficient to explain the observed enhancement and suppression. We then examined neural mechanisms by selectively modulating the signal to each ear, varying modulation depth, and adding background noise to the unmodulated signal. These experiments implicated excitatory and inhibitory monaural inputs to the inferior colliculus (IC). These monaural inputs are postulated to adapt to an unmodulated signal and adapt less to a modulated signal. Thus enhancement or suppression is created by the convergence of these excitatory or inhibitory inputs with the inputs from the binaural comparators. Under modulation, the role of the monaural input is to shift the threshold of the IC neuron. Consistent with this role, background noise mimicked the effect of modulation. Functionally, enhancement and suppression may serve in detecting the degree of modulation in a sound source while preserving ITD information.

Effects of hearing protectors on auditory localization in azimuth and elevation.

An experiment was conducted to determine the effects of two types of hearing protectors on auditory localization performance. Six listeners localized a 750-ms broadband noise from loudspeakers ranging in azimuth from -180 degrees to +180 degrees and in elevation from -75 degrees to +90 degrees. Independent variables included the type of hearing protector and the elevation of the source. Dependent measures included azimuth error, elevation error, and the percentage of trials resulting in a front-back confusion. Performance on each of the dependent measures was found to be mediated by one or more of the independent variables. Actual or potential applications include the generation of improved design guidelines for hearing protectors and workplace alarms.

Aurally aided visual search under virtual and free-field listening conditions.

We examined the minimum latency required to locate and identify a visual target (visual search) in a two-alternative forced-choice paradigm in which the visual target could appear from any azimuth (0 degree to 360 degrees) and from a broad range of elevations (from 90 degrees above to 70 degrees below the horizon) relative to a person's initial line of gaze. Seven people were tested in six conditions: unaided search, three aurally aided search conditions, and two visually aided search conditions. Aurally aided search with both actual and virtual sound localization cues proved to be superior to unaided and visually guided search. Application of synthesized three-dimensional and two-dimensional sound cues in the workstations are discussed.

Allopurinol hepatotoxicity. Case report and literature review.

Significant hepatotoxicity due to allopurinol seems to be rare. Only 6 such cases have been recorded in the literature. The clinical and histopathologic findings of allopurinol-induced liver injury are variable in the previously reported cases. Described herein is another patient with allopurinol hepatotoxicity. Of interest is the similar histopathology between the present case and the two previously reported cases of allopurinol-induced granulomatous hepatitis; thus this is the third such recorded case. Allopurinol should be suspected when liver abnormalities occur following use of this drug.

Diagnostic potential of in vivo capillary microscopy in scleroderma and related disorders.

The prevalence of scleroderma-type capillary abnormalities, as observed by in vivo microscopy, was determined in 173 patients from three rheumatic disease centers. The patients had a variety of connective tissue diseases: scleroderma (systemic sclerosis) 50; systemic lupus erythematosus 60; mixed connective disease 26; Raynaud's disease 11; other rheumatic disorders 26. Enlarged and deformed capillary loops surrounded by relatively avascular areas, most prominently in the nail-folds, were found in 82% of patients with scleroderma and in 54% with mixed connective tissue disease. The rarity of these abnormalities in systemic lupus erythematosus (2%) despite the presence of Raynaud's phenomenon suggests that they are not an expression of the Raynaud's phenomenon frequently associated with scleroderma and mixed connective tissue disease. The single patient with Raynaud's disease and sclerodermatype capillary changes subsequently developed scleroderma.

The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis.

OBJECTIVE: To test the ability of the modified Rodnan skin score to reflect skin thickness in skin biopsies from 141 patients with systemic sclerosis (SSc) obtained at entry during a prospective, double blind study of ketanserin versus placebo in SSc. METHODS: Punch skin biopsies (4 mm) were obtained from the dorsal surface of the distal forearm of 141 patients. Biopsy specimens were trimmed and weighed (wet weight) and then desiccated and reweighed (dry weight). Skin score was recorded for 17 areas, graded 0-4+, while edema was graded 0-4+ in 10 of the same sites using finger pressure. RESULTS: Total skin score correlated with wet weight (r = 0.553) and dry weight (r = 0.517) of the skin biopsies. Local skin score from the biopsied forearm also correlated with wet and dry weight (r = 0.536 and 0.530, respectively). Dry weight as a percentage of wet weight was the same for diffuse cutaneous SSc (dSSc) and limited cutaneous SSc (lSSc) (30.7% for both, NS), despite increased wet weight in patients with dSSc versus lSSc (17.75 vs 13.03 g; p < 0.001). Edema scores correlated poorly both with wet weight (r = 0.069) and dry weight (r = 0.169). CONCLUSION: Total and forearm skin score correlates well with both wet and dry forearm skin biopsy weight from forearm biopsies, indicating that skin score reflects the underlying pathology of SSc. Further, the percentage of dry to wet weight is similar for lSSc and dSSc, supporting the usefulness of skin score in differentiating SSc disease subtypes.