Thiazole analogues of the NSAID indomethacin as selective COX-2 inhibitors.

The carboxyl group of the NSAID indomethacin was replaced with a variety of substituted thiazoles to obtain a series of potent, selective inhibitors of COX-2. Additional substitutions were made at the 1-position and 5-position of the indole of indomethacin.

High-dose busulfan, melphalan, thiotepa and peripheral blood stem cell infusion for the treatment of metastatic breast cancer.

The purpose of this study was to determine the outcome of patients with metastatic breast cancer treated with high-dose busulfan (Bu), melphalan (Mel) and thiotepa (TT) followed by peripheral blood stem cell (PBSC) infusion. Fifty-one patients with chemotherapy refractory (n = 32) or responsive (n = 19) metastatic breast cancer received Bu (12 mg/kg), Mel (100 mg/m2) and TT (500 mg/m2) followed by PBSC collected after chemotherapy and growth factor (n = 43) or growth factor alone (n = 8). The 100 day treatment-related mortality was 8% including one death from cytomegalovirus pneumonia, one from aspiration pneumonia and two from regimen-related toxicity (RRT). Seven of 28 refractory (25%) and 5/7 (71%) responsive patients with evaluable disease achieved a complete response of all measurable disease or all soft tissue disease with at least improvement in bone lesions (PR*). Fifteen of 51 patients (29%) are alive and progression-free a median of 423 days (range 353-934) after treatment, 5/32 (16%) with refractory disease and 10/19 (53%) with responsive disease. The probabilities of progression-free survival (PFS) at 1.5 years for the patients with refractory (n = 32) and responsive (n = 19) disease were 0.24 and 0.53, respectively. These preliminary data suggest that high-dose Bu/Mel/TT has significant activity in patients with advanced breast cancer and may be superior to some previously published regimens.

Antiphospholipid antibodies and adrenal hemorrhage.

We recently encountered two cases of massive bilateral adrenal hemorrhage in patients with antiphospholipid antibodies. A search of the records of this institution covering the past 15 years revealed two additional patients with massive adrenal hemorrhage associated with evidence of antiphospholipid antibodies. Three of these four patients were receiving anticoagulant drug therapy. The presence of the antiphospholipid antibodies may increase the risk of massive adrenal hemorrhage, particularly in patients who receive anticoagulant drugs.

Acute tumor lysis syndrome and treatment response in patients treated for refractory chronic lymphocytic leukemia with short-course, high-dose cytosine arabinoside, cisplatin, and etoposide.

Acute tumor lysis syndrome resulting from rapid neoplastic cell lysis after chemotherapy is an unusual event, generally seen in histological aggressive lymphatic tumors. The authors saw four patients who developed acute tumor lysis syndrome when treated for advanced-stage, refractory chronic lymphocytic leukemia (CLL) with an initial cycle of cytosine arabinoside (Ara-C) 2 g/m2 every 12 hours x 4, cisplatin 35 mg/m2 every 24 hours x 2, and etoposide 100 mg/m2 every 24 hours x 2 (ACE). With aggressive hydration, urine alkalinization, forced diuresis, and high-dose allopurinol, acute tumor lysis syndrome was not seen in three subsequent cases of CLL treated with ACE. Of a total of eight patients treated, seven patients had marked reductions in lymphocyte counts after the first course of ACE. Of the eight patients, three are alive: one in a complete remission greater than 2 years, one in partial remission after three cycles of ACE, and one in Richter's transformation to large cell lymphoma. The remaining patients died after one cycle of ACE chemotherapy, one as a direct complication of acute tumor lysis and pancytopenia, and four others from complications of severe pancytopenia and general debilitation. Therefore, ACE appears to cause a rapid dissolution of tumor cells in CLL, and with appropriate aggressive management of the tumor lysis and infectious complications may have a favorable impact on survival in advanced CLL.

p-Nitrophenylglycosides as substrates for measurement of amylase in serum and urine.

Pantrak E.K. (endpoint and kinetic) Amylase reagent (Calbiochem-Behring) is the first commercially available alpha-amylase reagent in which p-nitrophenyl-d-glycosides are used as the substrate. We describe the effect of reagent composition on reagent performance. The reagent performance compares well with that of Amylochrome reagent (Hoffmann-La Roche), Du Pont aca, and Beckman D.S. amylase reagents in assays of sera and urines. We detected no interference from increased concentrations of glucose or pyruvate in the sample. The reagent can be used in either a manual fixed-time or an automatable kinetic assay.

Effects of stimulus frequency, level, and duration on auditory temporal ordering.

Auditory temporal ordering was investigated in 5 normal-hearing young adults. Ss made diotic 2IFC judgments for pure tones of 0.5, 1, 2, or 4 kc/s and critical-band noises centered at those frequencies, on duration (standard: 40 msec; variables: 10, 20, or 30 msec), level (standard: 70 db HL; variables: 40, 50 or 60 HL), and frequency (standard: 0.5 kc/s; variables: 1,2, or 4 kc/s). Interstimulus interval (ISI) was 5, 10, 20, 50, 100, or 200 msec. All stimuli were at 70 db HL except of course the variable stimuli in the level judgments. Performance improved with increasing ISI. Mean threshold ISIs (performance at 75%-correct) collapsed across pure tones and noise bands were 12.5, 6.25, and 6.25 msec for duration, level, and frequency, respectively. With ISI constant at 100 msec, ANOVAs revealed statistically significant differences among the variables for duration and for level but not for frequency (performance for frequency was nearly perfect at the shortest ISI). There were statistically significant differences between mean performance, and between mean threshold ISIs, for duration, level, and frequency, indicating that auditory temporal acuity is not independent of the kinds of sound, as has been suggested (Hirsh, J. Acoust. Soc. Am., 1959, 31, p. 759).

Sentence comprehension in elderly listeners: the factor of rate.

The study was designed to test the clinical observation that sentence comprehension in elderly listeners is enhanced when rate is slowed (time-expanded) and that comprehension is affected adversely when rate is speeded (time-compressed). Twenty normally-active elderly persons who ranged in age from 65 through 88 years listened to four matched sets of 10 sentences each that were modified electronically to produce the following four rate-alteration percentages: 100% (normal rate), 60% compression, 140% expansion, and 180% expansion. Sentences were presented binaurally to listeners who responded by selecting pictures that matched the sentences heard. Results indicated that sentence comprehension scores were significantly higher (p less than .01) at both the 60% and 140% alteration rates than at the normal speaking rate. Possible effects of the stimulus upon comprehension performance are discussed.

Is eye color a predictor of noise-induced hearing loss?

This study investigated the hypothesis that eye color is related to permanent threshold shift. Hearing levels and eye color determinations (gray, blue, hazel, and brown) were obtained for 100 industrial employees. Discriminant function analyses were utilized to attempt to establish linear combinations of variables that would identify group membership (i.e., eye color) correctly. Linear combinations of variables were not effective in delineating group membership. Probabililty statistics were then utilized to evaluate the probability of the determined relationships. These results indicated predictive accuracy of 69% for blue-eyed workers and 59% for brown-eyed workers.

Auditory fusion in children.

"Auditory fusion" was defined in terms of a listener's ability to distinguish paired acoustic events from single acoustic events. Children from the ages of 3-12 years listened to 270 pairs of tones controlled for frequency, intensity, and duration. Stimuli consisted of numerous pairs of tone pulses, separated by interpulse intervals that varied systematically from 0 through 40 msec. Results indicate that (a) auditory fusion improves rapidly and in an orderly fashion between 3 and 8 years of age, (b) signal intensity affects the fusion point, and (c) stimulus frequency--253 hertz through 4,000 hertz, at 5-octave intervals--does not affect the fusion point.

Dynamic auditory localization by normal and learning disability children.

Twenty children from regular classrooms and 20 children from self-contained, learning disability classrooms tracked four different acoustic stimuli through three fixed paths in space. An apparatus specifically designed to provide objective data on accuracy of tracking was used. The results showed that learning disability children as a group were inferior in their abilities to follow a moving speech signal and a moving white noise. The position of the target with respect to the listeners' midlines affected accuracy of tracking, but this was not a function of the hand used to control the pointer.

Technical note: an apparatus for exploring dynamic auditory localization.

The purpose was to develop and test an apparatus for objective specification of localization of a moving acoustic target. The system involves computer analysis and graphic display of vectors created from rotational and linear potentiometers that are activated by listeners using a hand-held pointer as they track an acoustic event.

Lipase-triggered kinetic assay of serum triglycerides.

We describe a kinetic method for assay of serum or plasma triglycerides, by use of an enzymatic hydrolysis and reaction sequence already described [Clin. Chem. 19, 476 (1973)]. The reaction is triggered by addition of lipase, at a time when free glycerol, or pyruvate (or both) are no longer present. In this method, therefore, there is no need for a blank glycerol assay. In the procedure, reagents are used that are available commercially in the form of stable, dry powders; the method for the preparation of the reagents has been changed to achieve improved stability and performance. Stability and recovery of added triglycerides are satisfactory.

Polypeptide chain initiation and stepwise elongation with Artemia ribosomes and factors.

The supernatant initiation factor from Artemia salina embryos promotes, besides the AUG-dependent binding of fMet-tRNA(f), the poly(U)-dependent binding of N-acetylPhe-tRNA to 40S ribosomal subunits; the bound N-acylaminoacyl-tRNA reacts directly with puromycin upon addition of 60S subunits. Both the binding reaction and the synthesis of N-acylaminoacyl-puromycin occur in the absence of GTP or other ribonucleoside triphosphates. To a smaller extent, the factor also mediates the 40S ribosomal binding of Met-tRNA(f) and Phe-tRNA; in this case, the bound aminoacyl-tRNA is less reactive with puromycin. After the poly(U)- and supernatant factor-dependent binding of N-acetylPhe-tRNA to 40S subunits at low Mg(2+) concentration, binding of a second aminoacyl-tRNA (Phe-tRNA), with ensuing formation of the first peptide bond, is dependent upon the addition of the 60S subunit, elongation factor EF-1, and GTP. Further growth of the polypeptide chain requires translocation and is, therefore, dependent upon the addition of elongation factor EF-2. As with the Escherichia coli system, once requirements for translation of the third codon have been met, no further additions are necessary for elongation of a peptide chain.