Efficacy and acceptability of lanreotide Autogel® 120 mg at different dose intervals in patients with acromegaly previously treated with octreotide LAR.

OBJECTIVE: To assess the efficacy of different dosing intervals of lanreotide, Somatuline Autogel® (Lan-ATG) 120 mg in patients with acromegaly, previously treated with octreotide, long-acting release (Oct-LAR). PATIENTS AND STUDY DESIGN: Patients previously on Oct-LAR 10, 20, or 30 mg were switched to 6 repeated deep subcutaneous injections of Lan-ATG 120 mg at intervals of 56, 42, or 28 days, respectively. After the third injection, dose intervals were adjusted on the basis of insulin-like growth factor 1 (IGF-1) levels. RESULTS: The ITT (Intention To Treat) population comprised 35 patients who received at least one dose of study medication and at least one post-baseline efficacy assessment. Overall, 62.9% (n=22) of patients had normalised IGF-1 levels with Lan-ATG at study end (one injection interval after the 6 (th) injection of Lan-ATG), which was similar to the proportion at baseline (60.0% [n=21]). QoL did not change from baseline to study end. Patient preference for Lan-ATG was highest in the 56-day dosing interval group: 71%, 54% and 41% of the patients in the 56, 42 and 28 day groups, respectively, expressed a preference for treatment with Lan-ATG (preference for Oct-LAR: 29%, 9% and 35%, respectively, while the remainder had no preference). CONCLUSION: Lan-ATG 120 mg injected at intervals of 56, 42 and 28 days provided equivalent hormonal control and QoL to Oct-LAR 10, 20 and 30 mg injected every 28 days, respectively. The proportion of patients preferring Lan-ATG treatment was greater in the longer injection interval groups.

Effect of treatment with Ginkgo biloba extract EGb 761 (oral) on unilateral idiopathic sudden hearing loss in a prospective randomized double-blind study of 106 outpatients.

OBJECTIVE: Test of dose-response relationship for Ginkgo biloba extract EGb 761 (oral) in outpatients with acute idiopathic sudden sensorineural hearing loss (ISSHL) of at least 15 dB at one frequency within the speech range occurring less than 10 days before study inclusion. DESIGN: Multicentre, randomized, double-blind phase III study comparing dosages of 120 mg twice daily and 12 mg twice daily over 8 weeks. MAIN ENDPOINT: Recovery (in dB) of the auditory threshold from the initial measurement to the value on the last day of treatment, averaged over those frequencies from 0.25, 0.5, 1, 2, and 3 kHz for which the initial hearing loss amounted to 15 dB or more compared to the level on the opposite side. PATIENTS: 106 patients with an average age of 44+/-16 years and with hearing loss at affected frequencies 26 dB +/- 9 dB included between December 1995 and July 1997. RESULTS: Large majorities of both treatment groups recovered completely. In exploratory analyses of the 96 patients included according to the protocol, patients given the higher dose had less risk of not recovering well (< or =10 dB residual hearing loss) (one-sided Fisher test: P = 0.0061), especially if they had no tinnitus (n = 44, P = 0.00702). CONCLUSION: A higher dosage of EGb 761 (oral) appears to speed up and secure the recovery of ISSHL patients, with a good chance that they will recover completely, even with little treatment. This was already observed after one week of treatment. We find it justified to treat patients who have unilateral ISSHL of less than 75 dB and neither tinnitus nor vertigo with 120 mg oral EGb 761 twice daily.

Ultra-high-dose lanreotide treatment in patients with metastatic neuroendocrine gastroenteropancreatic tumors.

BACKGROUND: Symptomatic control and occasionally even tumor regression of functional neuroendocrine tumors (NET) of the gastroenteropancreatic (GEP) system can be achieved by somatostatin analogues. Assuming a dose-dependent antiproliferative effect of somatostatin analogues, we performed a study with the somatostatin analogue lanreotide in ultra-high dosages in patients with progressive, metastatic GEP NET. PATIENTS AND METHODS: 30 patients with metastatic GEP NET, progressive during treatment with somatostatin analogues (< or =1.5 mg/day) and/or interferon-alpha, underwent ultra-high-dose lanreotide therapy (5 mg lanreotide s.c. three times a day). Tumor growth was evaluated every 3 months. Serum chromogranin A, serum serotonin as well as urinary 5-hydroxyindoleacetic acetic acid levels were also determined at 3-month intervals. In patients with functional tumors, tumor-related symptoms were documented. RESULTS: After a 1-year treatment period with ultra-high-dose lanreotide, 1 complete and 1 partial remission were observed in patients with functional midgut NET. Eleven patients had stable disease and 11 patients showed continuing tumor growth after 3-12 months of treatment. Symptoms decreased significantly during therapy. CONCLUSIONS: Our data show that ultra-high-dose lanreotide treatment in patients with metastatic GEP NET can lead to control of both symptoms and proliferation in at least some patients refractory to conventional therapies.

Binaural masking and sensitivity to interaural delay in the inferior colliculus.

The binaural masking level difference (BMLD) is a psychophysical effect whereby signals masked by a noise at one ear become unmasked by sounds reaching the other. BMLD effects are largest at low frequencies where they depend on signal phase, suggesting that part of the physiological mechanism responsible for the BMLD resides in cells that are sensitive to interaural time disparities. We have investigated a physiological basis for unmasking in the responses of delay-sensitive cells in the central nucleus of the inferior colliculus in anaesthetized guinea pigs. The masking effects of a binaurally presented noise, as a function of the masker delay, were quantified by measuring the number of discharges synchronized to the signal, and by measuring the masked threshold. The noise level for masking was lowest at the best delay for the noise. The mean magnitude of the unmasking across our neural population was similar to the human psychophysical BMLD under the same signal and masker conditions.

Binaural masking level difference effects in single units of the guinea pig inferior colliculus.

We have studied the masking effects of a binaurally presented noise on the responses to binaural signals recorded from low-frequency cells in the inferior colliculus of the guinea pig. The spike rates to the masker and signal + masker were compared to quantify masking at different interaural time delays of the noise. The signal was a 50-ms tone burst at best frequency or a 50-ms segment of a synthetic vowel presented at the best interaural delay of the unit tested. At each noise masker delay, the noise level was adjusted to obtain a criterion spike difference. In most cases, the level required was lowest at the best delay for the noise. The mean difference between maximum and minimum masked thresholds across the cell population was very similar to the human psychophysical masking level difference under the same signal and masker conditions. In another series of tests, we measured the effect of the noise masker on the temporal pattern of the discharge to the signal. The signal used was a 500-ms segment of the synthetic vowel. In virtually all cases the addition of a continuous noise masker reduced the discharge rate synchronized to the fundamental frequency of the vowel. The degree of this reduction was dependent on the interaural time delay of the noise masker. For most units, maximum reduction was seen when the vowel and noise had the same interaural time delay. The similarity between the masking which we have shown physiologically and the reported in a variety of human psychophysical experiments suggests that the processing at levels up to and including the inferior colliculus contributes to the psychophysical BMLD.

Functional organization of auditory cortical fields in the Mongolian gerbil (Meriones unguiculatus): binaural 2-deoxyglucose patterns.

Unilaterally deafened (cochlear destruction) gerbils were exposed to white noise after injection of 14-C-2-deoxyglucose. The labelling patterns were compared to those of unstimulated operated animals, noise stimulated control animals and bilaterally ear plugged animals. Serial transverse, horizontal and tangential autoradiographs through the cortex were analysed. In lesioned animals, labelling was strongly reduced on the side contralateral to the lesion in the high frequency regions of A1 and the anterior auditory field (AAF). We assume that these regions correspond to the high frequency EI cell areas. Fine banding could be seen superimposed on this pattern in transverse and tangential sections. We suggest that this may be due to alternating strips of EI and EE cells orthogonal to iso-frequency contours. In the low frequency regions of A1 and AAF, labelling asymmetries were also present, but were less pronounced. We assume that these effects are due to low frequency EE cells. In sub-cortical structures, labelling was reduced in the inferior colliculus and ventral part of the medial geniculate body contralateral to the lesioned ear, but no labelling pattern was visible. We presume that the spatial separation of EE and EI inputs to these structures is not marked enough to allow labelling patterns to be seen. In the superior olivary complex, labelling was reduced on the side contralateral to the lesioned ear in the medial dendritic field of the medial superior olivary nucleus and in the nucleus of the trapezoid body. Ipsilateral to the lesioned ear, labelling was reduced in the lateral dendritic field of the medial superior olive.

Task variables and visual discomfort associated with the use of VDT's.

We investigated task variables that may influence the incidence of visual discomfort amongst subjects who routinely spent a proportion of their day working with visual display terminals (VDT's). A diary was kept by subjects over five consecutive working days, in which they recorded visual symptoms, the visual tasks undertaken, the amount of time spent on workbreaks, work pressure, work interest, and personal moderating factors which may have influenced the symptoms recorded. The symptoms recorded by subjects were then treated as dependent variables in multiple regression analyses with the diary findings (task-related factors) as independent variables. The incidence of some types of symptoms was significantly associated with specific categories of work tasks, personal moderating influences, work pressure, work interest, time of day, and day of week.

Interaural delay sensitivity to tones and broad band signals in the guinea-pig inferior colliculus.

We have measured the sensitivity of 243 low-frequency cells in the central nucleus of the guinea pig to the interaural time delay of best frequency (BF) tones, wideband noise and synthetic vowels. The highest rate of firing for the majority of cells occurred when the stimulus to the contralateral ear arrived 100-400 microseconds before that to the ipsilateral ear. The best delays for tones and noise measured in the same cell were highly correlated. In contrast to the tone delay functions, the majority of the delay functions obtained in response to wideband signals did not cycle, but were characterized by a single dominant peak or trough. The response frequency calculated from the delay functions to the vowel often did not correspond to the unit's BF, suggesting that the unit was responding to a component close to the first formant frequency (730 Hz) of the vowel. Phase-locked responses, on the other hand, only occurred to the fundamental frequency of the vowel (100 Hz) and not to higher frequency components. The responses to delayed tone and noise signals in the guinea pig are very like those obtained in the cat and other mammals. The similarity of the range of best delays for the guinea-pig with those reported for the cat, despite the difference in head size in these two species, suggests that the sensitivity to interaural delays reflects the properties of the binaural pathways rather than an adaptation to the delays normally experienced by the animal.

Cochlear potentials and auditory evoked potentials in the caiman (Caiman crocodilus (L.)).

Brain-stem auditory evoked potentials (BAEPs) and round window compound action potentials (CAPs) in response to rarefaction and condensation clicks were recorded from anaesthetized and artificially respired caiman. The recorded wave forms were substantially different from the brain-stem and round window potentials recorded in mammals, including man. In particular, wave latencies were much longer than in mammals. Wave amplitudes increased and latencies decreased significantly and reversibly with increases in stimulus intensity and body temperature. The latencies of the first positive wave (P1) in the BAEP and the first negative wave (N1) in the CAP are correlated and co-vary with stimulus level and body temperature. BAEP P1 thus represents the response of the auditory nerve. The cochlear microphonic (CM) latency in caiman is unaffected by stimulus intensity and by cooling of the animal.

Responses of single cells in the cat inferior colliculus to binaural masking level difference signals.

Neurones with low best frequency (less than 2 kHz) and sensitive to interaural phase differences were recorded in the dorsal part of the central nucleus of the cat inferior colliculus. Best frequency tone (S) and noise (N) bursts were delivered binaurally via closed field sound systems either in phase (S0, N0) at both ears or inverted at one ear (SII, NII). The responses to tone + noise bursts in the stimulus configurations S0N0, SIINII and SIIN0 and noise bursts (N0 and NII) were compared. The latter two tone + noise configurations (S0NII and SIIN0) give a binaural masking level difference (BMLD) of up to 15 dB in psychophysical experiments, i.e. an increase in noise level is necessary to mask perception of the tone. Most cells responded better to in phase stimuli (here called 0 cells). A minority of cells responded better to out of phase stimuli (here called II cells). Each cell's response was correlated with the level of acoustic stimulus (tone or masker) in the preferred configuration and not with the BMLD situation: for the 0 cells, the responses were therefore maximal for S0N0 and minimal for SIINII. For II cells, the gradation was reversed: the response to SIINII was maximal and that to S0N0 minimal. For both populations, the responses to S0NII and SIIN0 were intermediate between the S0N0 and SIINII responses. Cells that responded best to S0NII or SIIN0, i.e. cells selectively coding BMLD, were not found. This was also true for the synchronized spike rates of those cells showing phase locked responses to the stimulus frequency. Some cells appeared to be strongly suppressed by the addition of an non-preferred masker (i.e. in the configuration that resulted in less response to a noise-alone burst; e.g. NII for the 0 cells). Other cells were more suppressed by the addition of a preferred masker (N0 for the 0 cells). The difference in the number of spikes evoked by the tone + noise and the noise burst was analyzed according to signal detection theory and neuronal masked threshold determined. Some 0 cells showed lower thresholds in the configuration S0NII whereas others had higher thresholds in this configuration. This correlated with the binaural suppression effects noted above: when the noise in the preferred configuration (N0) gave more suppression, the threshold was lower for S0NII; when NII gave more suppression the threshold was higher for S0NII. Over the whole population, these effects cancelled out and the neuronal threshold was not significantly affected by the BMLD configuration.(ABSTRACT TRUNCATED AT 400 WORDS)

Religiosity and personality: are mystics introverted, neurotic, or psychotic?

One hundred and fifteen subjects completed Hood's M scale, a measure of reported mystical experience, and the Eysenck Personality Questionnaire, which measures introversion/extraversion, neuroticism, psychoticism, and a lie score. No significant correlations were found between mysticism and the scales of the EPQ, nor could mysticism be predicted by multiple regression, either by the EPQ scales with sex and age, or by the EPQ scales controlling for sex and age.

The effect of inferior colliculus lesions on auditory evoked potentials.

The brain-stem auditory evoked potential (BAEP) was recorded in Nembutal anaesthetized cats before and after aspiration of the inferior colliculus on each side. The fast P1-P4 waves and the binaural interactions of P4 were unaffected by inferior colliculus removal. P5 and the following slow negative wave were reduced by inferior colliculus lesion. When only one inferior colliculus was ablated, this reduction was greater when the ear contralateral to the lesion side was stimulated.

Processing of interaural time and intensity differences in the cat inferior colliculus.

1. Binaural neurones were recorded in the central nucleus of the cat inferior colliculus and were stimulated with tone and noise bursts. Closed field sound systems were used to produce independent interaural time (ITD) and intensity (IID) differences. Particular attention was paid to high frequency (above 2 kHz) cells. 2. Three main types of binaural neurone were found: High frequency excitatory-inhibitory neurones (EI cells), excited by input from the contralateral ear and inhibited by ipsilateral input, high frequency excitatory-excitatory cells (EE cells), excited by inputs from either ear and low frequency cells sensitive to interaural phase differences (IPD cells). 3. The EI cells had characteristics similar to those of IE cells in the contralateral lateral superior olive. They were sensitive to envelope ITDs (most cells) and IIDs (all cells) favouring the contralateral ear. The response of these cells increased with increasing contra lead ITDs or contra loud IIDs up to values well outside the physiological range. 4. Low frequency binaural cells were sensitive to interaural phase differences (IPDs). The peak response was often in the contralateral physiological range and the response was unaffected by IIDs. 5. Many high frequency EE cells were sensitive to envelope ITDs. These units were relatively unaffected by IID. Although the ITD sensitivity of these cells was generally less than that of the IPD cells, the peak response of the ITD curve was also often in the contralateral physiological range. 6. Some of the high frequency EI and EE cells were sensitive to ongoing time differences (OTDs) in white noise signals, i.e. they showed ITD response curves to carrier only shifted noise bursts. 7. The EI cells often showed recovery from inhibition at large ipsilateral lead. This tendency was increased as the sound pressure level on the inhibitory side was lowered and by the use of click stimuli. Similarly, cycles of suppression could be seen to follow excitation in some EE cells. The time course of these effects was in the order of hundreds of microseconds. 8. Binaural characteristics (degree of ITD, IID or OTD sensitivity) showed considerable interunit variation within each cell type. These variations were also affected by signal type (tone or noise bursts) and did not appear to be correlated with best frequency, nature of the tuning curve or PSTH type. We suggest that the time course of the inhibitory and excitatory effects at each unit (and its interaction with the signal type) determines the type of ITD response and that this time course varies from cell to cell.

Intra- and extracranially recorded auditory evoked potentials in the cat. II. Effects of interaural time and intensity differences.

The effects of interaural time differences and interaural intensity differences on binaural interactions in the brain-stem evoked response (BSER) and auditory field potentials (AFPs) in superior olive and inferior colliculus were studied. Interaural time differences of up to +/- 2048 microseconds and interaural intensity differences of up to +/- 30 dB were used. Binaural interactions were studied for waves P4 and P5 of the BSER and the corresponding AFP components. When binaural interactions were present (wave P4 and subsequent waves), the dichotic potential was less than the sum of left and right evoked potentials. At zero interaural intensity difference the maximum binaural interaction was seen at zero interaural time difference. When an interaural intensity difference was present, maximum interaction was shifted away from zero interaural time difference such that left louder gave maximal interaction at right lead and vice versa. The time intensity trading values for this shift were between 9 and 20 microseconds/dB. The trading ratios for the superior olive wave P4 component and BSER P4/P5 were in the same range, i.e., no extra effects could be seen in the BSER postsynaptic to the superior olive. These time intensity trading ratios correspond to those of medial superior olive cells but not to those of lateral superior olive cells (Caird and Klinke 1983). We suggest that these binaural effects are produced by binaural mechanisms in the medial superior olive and that the lateral superior olive does not significantly contribute to the BSER. The inferior colliculus AFP slow wave binaural interactions do not correspond to those of the BSER.

Intra- and extracranially recorded auditory evoked potentials in the cat. I. Source location and binaural interaction.

Auditory field potentials (AFPs) were recorded stereotactically from the superior olivary complex and from the exposed inferior colliculus in the Nembutal anaesthetized cat. The brain-stem evoked response (BSER) was recorded simultaneously between an electrode on the dura mater at the vertex and an electrode on one bulla or in the neck musculature. A closed condenser microphone sound system was used to deliver monaural and binaural clicks. The binaural difference potential (BDP) was calculated by subtracting the sum of both monaurally evoked potentials from the binaurally evoked potential. The first binaural interaction was a reduction of BSER wave P4, arising in the superior olivary complex. The large extracellular AFPs generated in both inferior colliculus and superior olivary complex do not correspond to BSER waves, whereas the small volleys preceding the main waves do. These small waves show a much smaller change with recording distance than do the main AFP waves, i.e., the sources and sinks generating these waves appear to be more widely separated. We suggest that, in contrast to extracellular field potentials, the BSER is generated by action potentials in fibre tracts rather than postsynaptic potentials in nuclei. The implications for stimulation and recording laterality of late BSER waves are discussed.

Processing of binaural stimuli by cat superior olivary complex neurons.

A method was developed to record sterotactically from the cat Superior Olivary Complex (SOC) using glass micropipettes. Sound stimulation was given through a closed system that permitted independent variation of interaural time (delta time) and intensity (delta int) differences. The most common binaural units found (n = 34) were ipsilateral excitatory, contralateral inhibitory (EI1), cells of the Lateral Superior Olive (LSO). Some Medial Superior Olive (MSO) cells and presumed MSO ascending afferents were found but, as noted by other authors, we found it difficult to obtain single unit recordings from this nucleus. The LSO EI cells were mostly sensitive to higher frequencies and showed Peristimulus Time Histograms (PSTHs) consisting of a sharp "On" response followed by a plateau when stimulated with Best Frequency (BF) tone bursts or noise bursts. This "On" response was sensitive to delta time and delta int such that ipsilateral time lead or intensity increase resulted in a stronger response. The response reached a minimum around zero delta time or delta int. No sharp peaks or dips were seen in the physiological range needed for localization, instead the response increased with increasing ipsilateral lead or intensity to the maximum values tested (2048 microseconds delta time, 30 dB delta int). In the physiological range the delta time and delta int response were complementary (both increasing response as ipsilaterality was increased). Provided enough sound energy in the unit's sensitive region was present, the same delta time curves were produced when BF tone bursts, masked tone bursts, "sharp onset" tone bursts or noise bursts were used. Changing the delta time of the carrier of the tone burst alone had no effect (except for one cell with a BF of 560 Hz), only the relative time of arrival of the stimulus envelope seemed to be important. In contrast to these LSO EI cells MSO-type units showed EI or EE predominantly low frequency phase-locked responses. When stimulated with interaurally phase shifted (delta pha) BF tones the unit response was a cyclic function of delta pha. Some cells (all that were tested, n = 6 including the 560 Hz LSO EI cell) showed these cyclic responses when stimulated with noise bursts or non-BF tones. However, these "characteristic delays" were not necessarily in the physiological range, i.e. we could find no evidence that these units were responding to delta time/delta pha values corresponding to a particular sound source direction.(ABSTRACT TRUNCATED AT 400 WORDS)

Experience with arthrography of the first metacarpophalangeal joint.

Arthrography of the first metacarpophalangeal joint at various times after trauma involving suspected rupture of the joint capsule or collateral ligaments has been performed since 1975 and the first four and a half years experience is reviewed. More variations in arthrogram appearance were found than previously reported and the appearance recorded elsewhere as being typical of a Stener lesion was not seen in the forty-one arthrograms examined. The selection of patients for surgery produced satisfactory results subjectively and objectively and the arthrographic appearance agreed with the operative findings up to twenty-one days after injury. Some patients were saved from unnecessary surgery by arthrography.

Interaural attenuation in the cat, measured with single fibre data.

Acoustic crosstalk was measured in the pentobarbital anesthetized cat using the responses of single units in the auditory nerve to ipsilateral and contralateral sound stimuli. The mean interaural attenuation (IATT) was found to be 76 dB between 350 and 18,000 Hz. No systematic variation of IATT with frequency was found although a large variation between different units with similar characteristic frequencies could be seen. We suggest that this scatter is due to the complex fine structure of the bone conduction pathways (Tonndorf (1966) Bone conduction. Acta Otolaryngol. Suppl. 213, 1-132). There are large discrepancies between these data and values obtained using cochlear microphonic potentials as an indicator. We suggest that cochlear microphonic crosstalk data in the literature should be treated with caution as it is extremely difficult to exclude the effect or direct electrical crosstalk on these analog signals.