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D McFadden

Publications and source records attributed to D McFadden.

At least 37 records · Page 2Linked to original sources
PubMed1998

Changes in otoacoustic emissions in a transsexual male during treatment with estrogen.

Otoacoustic emissions (OAEs) were monitored in two human males undergoing estrogen treatment prior to sex-reversal surgery. In one subject, multiple spontaneous emissions (SOAEs) appeared where none had been evident previously. One reasonable interpretation is that (in this male, at least) androgens normally produced a suppressive effect on the cochlear mechanisms responsible for SOAEs, and that the decline in androgen levels produced by the estrogenic drug led to a reduction in that suppression.

Acoustic Stimulation↗
PubMed1998

Efficacy of MK-991 (L-743,872), a semisynthetic pneumocandin, in murine models of Pneumocystis carinii.

In addition to its potent efficacy in animal models against Candida sp., Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B0. The 90% effective dose (ED90) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED90 was 0.02 mg/kg. MK-991 was also effective orally, with an ED90 for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days). Complete prevention of P. carinii development was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg. As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of P. carinii cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals. In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.

Administration, Oral↗
PubMed1998

TRAF-4 expression in epithelial progenitor cells. Analysis in normal adult, fetal, and tumor tissues.

TRAF-4 was discovered because of its expression in breast cancers and is a member of the tumor necrosis factor (TNF) receptor-associated factor (TRAF) family of putative signal-transducing proteins. In vitro binding assays demonstrated that TRAF-4 interacts with the cytosolic domain of the lymphotoxin-beta receptor (LT beta R) and weakly with the p75 nerve growth factor receptor (NGFR) but not with TNFR1, TNFR2, Fas, or CD40. Immunofluorescence analysis of TRAF-4 in transfected cells demonstrated localization to cytosol but not nucleus. Immunohistochemical assays of normal human adult tissues revealed prominent cytosolic immunostaining in thymic epithelial cells and lymph node dendritic cells but not in lymphocytes or thymocytes, paralleling the reported patterns of LT beta R expression. The basal cell layer of most epithelia in the body was very strongly TRAF-4 immunopositive, including epidermis, nasopharynx, respiratory tract, salivary gland, and esophagus. Similar findings were obtained in 12- to 18-week human fetal tissue, indicating a highly restricted pattern of expression even during development in the mammary gland, epithelial cells of the terminal ducts were strongly TRAF-4 immunopositive whereas myoepithelial cells and most of the mammary epithelial cells lining the extralobular ducts were TRAF-4 immunonegative. Of 84 primary breast cancers evaluated, only 7 expressed TRAF-4. Ductal carcinoma in situ (DCIS) lesions were uniformly TRAF-4 immunonegative (n = 21). In the prostate, the basal cells were strongly immunostained for TRAF-4, whereas the secretory epithelial cells were TRAF-4 negative. Basal cells in prostate hypertrophy (n = 6) and prostatic intraepithelial neoplasia (PIN; n = 6) were strongly TRAF-4 positive, but none of the 32 primary and 16 metastatic prostate cancer specimens examined contained TRAF-4-positive malignant cells. Although also expressed in some types of mesenchymal cells, these findings suggest that TRAF-4 is a marker of normal epithelial stem cells, the expression of which often ceases on differentiation and malignant transformation.

Adult↗
PubMed1998

Gastric cancer: three decades of surgical management.

Hospital records of all 277 patients who underwent surgery for gastric adenocarcinoma at the University of California at Los Angeles Medical Center from 1970 through 1996 were reviewed. Patients were stratified into three groups comprising 1970 to 1979, 1980 to 1989, and 1990 to 1996. The incidence of stage IV disease decreased by 50 per cent over the course of the study (P < 0.001). Lymph node involvement declined by 30 per cent (P < 0.01). Endoscopy displaced contrast radiography as the primary diagnostic modality. Sensitivity of endoscopic biopsy averaged 92 per cent. Twice as many patients were resected for cure in the current decade compared with the 1970s (P < 0.001). Operative mortality was less than 2.5 per cent for the entire period studied and has been nil in the 1990s. Intraoperative blood loss and transfusion requirements also decreased significantly each decade. Hospital stay was shortened by 41 per cent and the length of postoperative stay in the intensive care unit decreased from a median of 4 days to zero. Five-year survival improved significantly during the study period, mirrored by an increase in survival for early cancers. We have found an earlier presentation of gastric adenocarcinoma over the past 3 decades that parallels an increased use of endoscopy and an improved sensitivity of endoscopic biopsy. More patients are now resectable than in previous decades. Survival after surgical treatment of gastric adenocarcinoma improved between 1970 and 1996, partially due to an increase in earlier stage lesions. Improved survival is also demonstrable when only early stage cancers are considered.

Academic Medical Centers↗
PubMed1996

Infected internal iliac artery aneurysm: a case report.

Isolated internal iliac aneurysms are rare, and although most are of atherosclerotic origin the cause may also be congenital, traumatic, associated with pregnancy or infectious. A 56-year-old man presented with a swollen, painful left lower limb. Within a few days, weakness of the limb developed with fever and an acute abdomen with free air on x-ray. At emergency laparotomy a small perforation was found in the ascending colon. Examination of the left iliac fossa revealed a ruptured left internal iliac artery aneurysm. Extra-anatomic cross-femoral bypass grafting was done to revascularize the left lower extremity. The patient recovered without complication. At discharge the weakness had improved but knee flexion and extension were weak. Culture of the aneurysm contents grew Staphylococcus aureus and Pseudomonas aeruginosa. The authors discuss the presentation and management of infected internal iliac artery aneurysms.

Aneurysm, Infected↗
PubMed1996

Additional findings on heritability and prenatal masculinization of cochlear mechanisms: click-evoked otoacoustic emissions.

A previous demonstration of a substantial genetic contribution to the expression of spontaneous otoacoustic emissions (SOAEs) is here extended to an aspect of click-evoked otoacoustic emissions (CEOAEs). CEOAEs were measured in the same twins and non-twins used for the SOAE heritability study. The stimuli were 100-microsecond clicks presented a nominal rate of 2/s; the emitted waveforms from 50 clicks were summed, and a 20-ms sample of that averaged waveform (beginning 6 ms after click presentation) was subjected to spectral analysis. The total power in the spectrum from 1 to 5 kHz in this temporal segment of the CEOAE waveform was used as the primary dependent variable. This overall power was significantly greater in female and right ears than in male and left ears, but the difference between dark- and light-eyed subjects was not significant. The overall power in the two left, and two right, ears of monozygotic co-twins was more highly correlated than in dizygotic co-twins, and structural modeling indicated that about 65-85% of the individual variation in the expression of CEOAE power could be attributed to genes-essentially the same heritability estimate as obtained previously from the SOAE data. Within-subject correlations between CEOAE power and number of SOAEs ranged from about 0.3 to 0.7, suggesting that these two forms of otoacoustic emission may depend upon somewhat different aspects of the same underlying mechanism and, thus, that heritability estimates based on one measure are not completely redundant to those from the other. While the average spectral power of the CEOAEs in opposite-sex dizygotic (OSDZ) females was smaller than that in same-sex dizygotic (SSDZ) females- and thus approached the value for males-the difference did not achieve statistical significance. Thus, the evidence for a prenatal masculinizing effect was less definitive in these CEOAE data than in the SOAE data obtained from the same subjects. An interpretation that accounts for both the CEOAE and SOAE results is that the strength of the so-called cochlear amplifiers is under genetic control that is to some extent mediated and/or modified through prenatal exposure to androgens. The indicated direction of effect is that weak cochlear amplifiers result when prenatal androgen levels are high. Under this view, then, androgen level contribute both to the sex differences observed in otoacoustic emissions and the prenatal masculinizing effects observed in opposite-sex twins, and they may be a factor in individual differences in OAE expression as well. Additionally it is shown that, although the powers of the CEOAE waveforms were reasonably highly correlated for the two ears of subjects in all groups, and across MZ co-twins, cross-correlations on the fine structures of those same pairs of CEOAE waveforms were essentially zero-presumably owing largely to the synchronizing of (different) SOAE frequencies in the ears being compared.

Acoustic Stimulation↗
PubMed1995

On the heritability of spontaneous otoacoustic emissions: A twins study.

Spontaneous otoacoustic emissions (SOAEs) were measured in human monozygotic (MZ) and dizygotic (DZ) twins and in a sample of non-twins. The number of SOAEs exhibited was more highly correlated in MZ co-twins than in same-sex DZ co-twins. Model-fitting to the correlations suggested that about three-quarters of the individual variation in the expression of SOAEs is attributable to genes. There was no convincing evidence for the heritability of specific SOAE frequencies. In accord with past surveys, SOAEs were more numerous in right than left ears, and in female than male subjects. Also investigated were the numbers of SOAEs exhibited by dark-versus light-eyed people and by MZ versus DZ twins. Those differences in our data were small and not statistically significant, but they were in a direction consistent with other studies: more SOAEs in dark-eyed individuals and in MZ twins. The view presented here is that SOAEs themselves are unlikely objects for natural selection, and probably are epiphenomena resulting from selection for those cochlear mechanisms that contribute to good hearing sensitivity - which is related to SOAE expression. It is argued that, in addition to genetics, other factors have the potential to affect the specific numbers of SOAEs that are expressed. For example, some aspects of the complex prenatal process of producing a male fetus are presumed to be responsible for the smaller number of SOAEs seen in males than females.

Auditory Cortex↗
PubMed1995

Curative treatment for pancreatic neoplasms. Radical resection.

The available data suggest that lymph node involvement is an important prognostic factor in patients with carcinoma of the head of the pancreas. Lymph node metastases occur in as many as 50% of the cases of even the smallest pancreatic cancers now being diagnosed and resected (i.e., those < 2 cm in diameter). There is some evidence, especially from clinical experience in Japan, that wider lymphatic dissections (i.e., wider than those commonly done with the standard Whipple resection) may prolong survival. Unfortunately, many of the available data around the world are retrospective and are not randomized between the standard and the radical operation. Moreover, the pathologic material has not been staged uniformly according to accepted criteria. Thus the various series are not comparable. Comparisons between series require standardization with respect to stage of disease, pathologic classification, and treatment protocols. Before any modification of the standard pancreaticoduodenectomy is adopted, an appropriately designed study should be performed to test its efficacy. This study would also require a more comprehensive analysis of the pathologic material than is commonly performed today in the United States and Europe.

Humans↗
PubMed1995

New semisynthetic pneumocandins with improved efficacies against Pneumocystis carinii in the rat.

A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B0 (L-688,786) (R. E. Schwartz et al., J. Antibiot. 45:1853-1866, 1992), and > 100 times more potent than cilofungin. One compound in particular, L-733,560, had a 90% effective dose against P. carinii cysts of 0.01 mg/kg of body weight when delivered parenterally (subcutaneously, twice daily for 4 days). This compound was also effective when given orally for the treatment and prevention of P. carinii pneumonia. For treating acute P. carinii pneumonia, oral doses of 2.2 mg/kg twice daily for 4 days were required to eliminate 90% of the cysts. A once-daily oral prophylactic dose of 2.2 mg/kg prevented cyst development, and a dose of 6.2 mg/kg prevented any development of P. carinii organisms (cysts and trophozoites), as determined through the use of a P. carinii-specific DNA probe (P. A. Liberator et al., J. Clin. Microbiol. 30:2968-2974, 1992). These results demonstrate that the antipneumocystis activities of the pneumocandins can be significantly improved through synthetic modification. Several of these compounds are also extremely effective against candidiasis (K. Bartizal et al., Antimicrob. Agents Chemother. 39:1070-1076, 1995) and aspergillosis (G. K. Abruzzo et al., Antimicrob. Agents Chemother. 39:860-894, 1995) in murine models, making them attractive as broad-spectrum antifungal agents.

Animals↗
PubMed1994

Otoacoustic emissions and quinine sulfate.

A moderate dose of quinine sulfate, administered to three young adult males, reduced or eliminated various forms of otoacoustic emission (OAE). The individual differences in response to the drug were substantial, but a number of generalizations did emerge. The time courses of onset and recovery were considerably more rapid than for the parallel effects produced by aspirin. Most spontaneous otoacoustic emissions (SOAEs) were eliminated within 7 h of the first 325-mg dose (about 3 h after the second dose). Most SOAEs showed partial or complete recovery about 24 h after the last dose, although considerable instability often remained. The functions relating the magnitude of a distortion-product OAE (DPOAE) to the sound-pressure level (SPL) of the primary tones producing it were displaced toward higher primary levels and became lower sloped following quinine administration. The magnitudes of SOAEs, DPOAEs, and nonlinear peaks in the click-evoked spectra declined and recovered with grossly similar time courses, but there were some partial dissociations. The ability of a DPOAE to suppress an SOAE lying about 50 Hz below it either increased slightly or remained about constant through the drug episode, even though the magnitudes of both DPOAE and SOAE were changing. On several occasions, increases in SOAE magnitude of as much as 10-20 dB were observed during the first 15-30 min of an SOAE measurement period (an initializing effect). Psychophysical measures revealed hearing losses of as much as 20 dB at some frequencies in some subjects. Several short-lived "enhancements" of OAEs are discussed relative to similar quinine-induced effects reported in an animal model.

Acoustic Stimulation↗
PubMed1993

A masculinizing effect on the auditory systems of human females having male co-twins.

Spontaneous otoacoustic emissions (SOAEs) are continuous, essentially tonal sounds that are produced by many normal-hearing cochleas. In humans, females generally exhibit more SOAEs than males, a sex difference that exists from birth. However, it is shown here that females having male co-twins [opposite-sex dizygotic (OSDZ) females] exhibit about half the average number of SOAEs per ear observed in same-sex female twins or female non-twins. Indeed, the average in OSDZ females is about the same as that seen in males--twins or non-twins. The explanation offered here is that prenatal exposure to high levels of androgens has produced a masculinizing effect on the auditory systems of these OSDZ females. Prenatal masculinizing effects have long been recognized in certain litter-bearing mammals, but their existence in humans is not well-studied.

Acoustic Stimulation↗
PubMed1993

On the relation between hearing sensitivity and otoacoustic emissions.

The auditory literature suggests that ears having spontaneous otoacoustic emissions (SOAEs) should also evidence overall better hearing in the quiet than ears with no SOAEs, but no direct tests of this presumed relationship have been made. Accordingly, hearing sensitivity was measured in both males and females having either no SOAEs or at least four SOAEs in the right ear. Averaged across frequencies, the hearing of the subjects with SOAEs was about 3 dB better, in both ears, than the hearing of the subjects with no SOAEs. In accord with past findings, sensitivity was also significantly better in right ears than left. However, the common finding of better hearing in females than males did not emerge, suggesting that this difference may exist only when the sex difference in SOAE prevalence is not taken into account. The existence of a direct relationship between hearing sensitivity in the quiet and the presence of SOAEs suggests that a common mechanism may be responsible for both.

Acoustic Stimulation↗
PubMed1993

A speculation about the parallel ear asymmetries and sex differences in hearing sensitivity and otoacoustic emissions.

Hearing sensitivity and the prevalence of spontaneous otoacoustic emissions show parallel ear and sex differences in humans. Here it is proposed that these lateral asymmetries and sex differences may all result from differences in the 'strength' of the efferent inhibition delivered to individual cochleas. Specifically, it is proposed that the amount of efferent inhibition is relatively less in right ears and in females than in left ears and males. While it is unclear why or how ear asymmetries or sex differences would develop in the efferent system, by assuming that they do, one can begin to explain a number of basic facts of hearing. It is even possible that the lateral asymmetry in the efferent system may be related to the well-known cortical asymmetries that are believed to underlie speech perception, speech production, and other human abilities.

Acoustic Stimulation↗
PubMed1993

Adaptation of suppression as an explanation of enhancement effects.

Delaying the onset of a signal relative to the onset of a simultaneous notched masker often improves the ability of subjects to "hear out" the signal at both threshold and suprathreshold levels. Viemeister and Bacon [J. Acoust. Soc. Am. 71, 1502-1507 (1982)] suggested that such signal-enhancement effects might be attributable to adaptation of the suppression directed from the masker to the signal, thereby releasing the signal from suppression. In support of their hypothesis, Viemeister and Bacon reported that a masker, preceded by an enhancer having no component at the signal frequency, produced more forward masking than did the masker by itself. Here the masker enhancement described by Viemeister and Bacon, signal enhancement, and two-tone suppression were measured in the same six subjects. Parametric manipulations of the masker-enhancement stimulus produced results similar to those previously reported for parallel investigations of signal enhancement, indicating that the two types of enhancement are closely related effects. Although the present data reveal an inverse relationship between the amounts of suppression and enhancement, suggesting that the two processes may be interrelated, no support was obtained for the hypothesis that adaptation of suppression can account for enhancement.

Adaptation, Physiological↗
PubMed1992

Evidence that adaptation of suppression cannot account for auditory enhancement or enhanced forward masking.

Delaying the onset of a signal relative to the onset of a simultaneous notched masker often improves the ability of listeners to 'hear out' the signal at both threshold and suprathreshold levels. Viemeister & Bacon (J. acoust. Soc. Am., 71, 1502-1507 (1982)) suggested that such auditory enhancement effects could be accounted for if the suppression produced by the masker on the signal frequency adapted, thereby releasing the signal from suppression. In support of their hypothesis, Viemeister & Bacon reported that a masker preceded by an enhancer having no component at the signal frequency produced more forward masking than did the masker by itself. Here evidence is provided from five new experiments showing that adaptation of psychophysical two-tone suppression is inadequate to account either for auditory enhancement effects or for the enhanced forward masking demonstrated by Viemeister & Bacon.

Acoustic Stimulation↗
PubMed1992

Temporal decline of masking and comodulation masking release.

Masking sounds can be continuously present, gated simultaneously with the signal, or gated somewhat prior to the signal. This continuum of relative onset times was explored using waveforms of the sort commonly employed in studies of comodulation masking release (CMR). There was a 50-Hz masker band centered on the 1250-Hz tonal signal, and four 50-Hz flanker bands centered at 850, 1050, 1450, and 1650 Hz. In some conditions, all four flanker bands had the same temporal envelope, and the masker band either had that same envelope (correlated presentations) or a different envelope (uncorrelated presentations). In other conditions, all five bands had different temporal envelopes (all-uncorrelated presentations). The masker band and/or the four flanker bands were either gated nearly simultaneously with the signal (burst conditions) or were gated prior to the signal by a duration that was systematically varied (fringed conditions). The eight listeners could be partitioned into three groups on the basis of their response to these fringing manipulations. Two listeners (the large fringers) showed a gradual improvement in detectability with increasing fringe duration (called a temporal decline of masking), while three others (the small fringers) showed little improvement in detectability. For the remaining three subjects, there was evidence of a "learning" effect that changed them from large fringers to small fringers over a 10-week period of listening. When present, the temporal decline of masking was greater for the correlated than for the uncorrelated comodulation condition; as a consequence, the difference in detectability between them (the comodulation masking release or CMR) increased with fringe duration. By fringing the masker and flanker bands separately and in combination, it was revealed that the temporal declines of masking were primarily attributable to the fringing of the flanker bands. In contrast, large CMRs required long fringes on both the masker and flanker bands. The above results were obtained with 50-ms signals, but generally similar data were obtained with a signal duration of 240 ms. The difficulties raised for experimentalists and theorists by such long-term practice effects are discussed.

Adult↗
PubMed1990

Reductions in overshoot during aspirin use.

The overshoot effect was measured before, during, and after the administration of a moderate dose of aspirin. Prior to the drug, detectability of the 6-ms, 3550-Hz signal was 5-11 dB worse when presented 2 ms after the onset of the 200-ms wideband masking noise than when presented 190 ms after masker onset. Following 4 days of aspirin use, detectability in the long-delay condition was unchanged from the predrug value, but (for four of the five subjects) detectability in the short-delay condition was improved by about 4-8 dB. Thus the overshoot effect was markedly reduced by aspirin because the drug partially counteracted the normally poor detectability for signals presented soon after masker onset. This paradoxical improvement in detectability was accompanied by an aspirin-induced loss in detectability of 5-16 dB for a 200-ms sample of that same signal presented in the quiet. Similar paradoxical effects have previously been obtained by inducing a temporary hearing loss with exposure to intense sound. It is presumed that the same basic mechanisms underlie the parallel outcomes. The so-called cochlear amplifier is discussed in this regard, and also the possibility that the known differences in those primary auditory fibers having high and low spontaneous rates may be involved. A supplementary experiment demonstrated that shifting audibility with either a wideband or a narrow-band background noise does not affect the overshoot effect in the same way as does aspirin or exposure to intense sound, further suggesting that the cochlear amplifier must be altered in order for overshoot to be diminished.

Acoustic Stimulation↗