Subjects presented at ASHP Midyear Clinical Meetings, 1967-90

The subject matter and trends of presentations made at ASHP Midyear Clinical Meetings (MCMs) were studied. A computerized database of information from MCM and Annual Meeting (AM) program and abstract books was created. The data were analyzed to determine the distribution of MCM presentations by subject and by author for the period 1967 to 1990, determine if there were differences in subjects covered between MCMs and AMs, explore the proposition that there has been duplication of material in MCM presentations, and evaluate the frequency with which MCM presentations have been published in ASHP journals. The total number of presentations made at MCMs from 1967 through 1990 was 8180, while the total for the AMs was 1547 for the two periods (1962-71 and 1985-90) studied. The most common keywords in titles were "pharmacy," "drug," "patient," "hospital," and "service." All International Pharmaceutical Abstracts subject categories and two other categories were represented; presentations in the institutional pharmacy practice category were the most frequent, while pharmacognosy-related presentations were least frequent. The overwhelming number of authors made only one presentation and were listed as the first author. The subjects of presentations were similar between AMs and MCMs. A tendency toward duplication of material was found. Of the 8180 MCM presentations, at least 1005 were published in an ASHP journal. Between 1967 and 1990, presentations at MCMs covered a wide range of subjects but were sometimes duplicative or not on the cutting edge.     

Nematic polymer liquid-crystal wave plate for high-power lasers at 1054 nm

A nematic polymer liquid crystal is used to construct wave plates for use at 1054 nm. Three methods of wave-plate construction are discussed: double substrate with fiber spacers in homogeneous distribution, double substrate with fiber spacers in annular distribution, and single substrate. The polymer liquid crystal shows high laser-damage resistance, making it particularly useful for high-peak-power laser applications. Alignment techniques and measurement of birefringence for the highly viscous polymer are described.     

Midinfrared modulation through the use of field-induced scattering in ferroelectric liquid crystals

The feasibility of the use of modulation devices based on field-induced transient scattering in ferroelectric liquid crystals (LC) to replace mechanical choppers used in uncooled infrared-imaging systems was investigated. Devices fabricated with ITO-coated ZnSe substrates and a ferroelectric LC path length of 25 μm were able to modulate optical radiation by transient forward scattering at rates approaching 20 kHz. Through the use of a commercial arbitrary waveform generator and associated PC-based software, drive waveforms were developed that produced a variable, square-wave optical-modulation pattern by the extension of the duration of the scattering state to periods ranging from hundreds of microseconds to milliseconds. The ability of these extended-scattering-mode (ESM) devices to modulate radiation in both the visible and midinfrared regions was verified in a simple experiment through the use of a Fourier-transform infrared spectrometer, in which an unoptimized ESM device displayed a 40% modulation dep th for IR radiation in the 8-12-μm region.     

Cytomechanics of axonal development

Mechanical tension is a robust regulator of axonal development of cultured neurons. We review work from our laboratory, using calibrated glass needles to measure or apply tension to chick sensory neurons, chick forebrain neurons, and rat PC12 cells. We survey direct evidence for two different regimes of tension effects on neurons, a fluid-like growth regime, and a nongrowth, elastic regime. Above a minimum tension threshold, we observe growth effects of tension regulating four phases of axonal development: 1. Initiation of process outgrowth from the cell body; 2. Growth cone-mediated elongation of the axon; 3. Elongation of the axon after synaptogenesis, which normally accommodates the skeletal growth of vertebrates; and 4. Axonal elimination by retraction. Significantly, the quantitative relationship between the force and the growth response is surprisingly similar to the simple relationship characteristic of Newtonian fluid mechanical elements: elongation rate is directly proportional to tension (above the threshold), and this robust linear relationship extends from physiological growth rates to far-above-physiological rates. Thus, tension apparently integrates the complex biochemistry of axonal elongation, including cytoskeletal and membrane dynamics, to produce a simple "force input/growth output" relationship. In addition to this fluid-like growth response, peripheral neurons show elastic behaviors at low tensions (below the threshold tension for growth), as do most cell types. Thus, neurites could exert small static forces without diminution for long periods. In addition, axons of peripheral neurons can actively generate modest tensions, presumably similar to muscle contraction, at tensions near zero. The elastic and force-generating capability of neural axons has recently been proposed to play a major role in the morphogenesis of the brain.     

Expression, characterization, and detection of human uridine phosphorylase and identification of variant uridine phosphorolytic activity in selected human tumors

Uridine phosphorylase (UPase) catalyzes the reversible phosphorolysis of uridine to uracil. We purified the enzyme from the murine colon 26 tumor using a two-step procedure through 5-amino-benzylacyclouridine affinity chromatography. Antibodies raised in rabbits against the purified protein revealed single bands in Western blots of normal human tissue and tumor extracts. The polyclonal antibody used to screen a human liver expression library allowed the isolation of a 1.2-kb clone that contained the entire open reading frame of the human UPase. The UPase cDNA has been expressed as a fusion protein in Escherichia coli using the pMal-C2 vector. The kinetic analysis demonstrated that the recombinant UPase preferentially uses uridine, 5-fluorouracil, and uracil as substrates, although lower levels of activity were observed with 2-deoxyuridine and thymidine. Clinical samples of human tumors and adjacent normal tissues were assayed for phosphorolytic activity and sensitivity to 5-benzylacyclouridine (BAU), a potent inhibitor of the enzyme presently in Phase I-II clinical trial. Activity in normal tissues appeared to be low but very sensitive to BAU (approximately 90% inhibition at 10 microM). Tumors had generally 2-3-fold greater activity compared with adjacent normal tissues. In breast cancer specimens and head-neck squamous carcinomas, however, uridine cleavage was only partially inhibited (40-60%) by 10 or 100 microM BAU. The BAU-insensitive activity requires phosphate and pH conditions similar to the normal enzyme, and the new phosphorolytic activity was independent from thymidine phosphorylase. The BAU-insensitive phosphorolytic activity in selected tumors, coupled with the potent inhibitory activity of BAU against the "classical" uridine phosphorylase in normal human tissues, provides the rationale for combining BAU with 5-fluorouracil in the treatment of breast and head-neck tumors.     

Clinicopathologic analysis of microscopically invasive breast carcinoma

Breast biopsy or mastectomy cases having diagnoses of carcinoma in situ with "microinvasion," "minimal invasion," "focal invasion," or "suggestive of invasion" were reviewed and all histologically identified foci of invasive disease from each case were measured using an ocular micrometer. Cases in which any single focus of invasion was greater than 5 mm or the added size of separate invasive foci exceeded 10 mm were excluded, resulting in a study group of 75 patients. Invasive neoplasm was present in the initial biopsy in 69 of 75 cases (92%); however, residual invasive neoplasm was found in the subsequent lumpectomy/mastectomy from 14 of these (20%). In 59% of cases, two or more histologically separate foci of invasion were identified. Invasive foci consisted of isolated cells or cell clusters, each less than 1 mm (microfocal invasion), in 33% of cases. In 12 cases, the sum of individual invasive foci was 5 to 10 mm. Axillary lymph nodes (LN) from 5 of 69 patients (7%) contained metastatic carcinoma (four cases, one LN positive; one case, two LN positive). The cumulative sizes of all invasive foci in the LN-positive group were microfocal invasion (one case), 0.6 mm (one case), 1.1 mm, 2.5 mm, and 5.8 mm. The difference in frequency of axillary node metastasis between tumors with microfocal and measurable invasion (4.3% v 8.6%) was not statistically significant. Follow-up data were available on 55 cases (mean interval, 66.1 months). One (node-negative) patient had duct carcinoma in situ recurrence in the same breast 4 years after initial treatment. Another (with unknown node status) developed an axillary lymph node metastasis 13 months after initial treatment (96% disease-free survival). We conclude that microscopic stromal invasion in breast carcinoma, at least in the setting of significant in situ component, is often initiated from multiple foci. Patients with microscopically invasive breast carcinoma have a small but significant risk of axillary metastases, although a highly favorable survival.     

A novel human type II cytokeratin, K6hf, specifically expressed in the companion layer of the hair follicle

In an attempt to identify new members of the human type II hair keratin family by means of 3'- and 5'-RACE methods and cDNA from anagen hair follicles, we detected a sequence that encoded a hitherto unknown type II cytokeratin. The novel cytokeratin comprises 251 amino acids and exhibits the highest sequence homology with K5. Comparative one- and two-dimensional western blots of keratins from anagen hair bulbs, containing or not containing the outer and inner root sheaths (ORS/IRS), and from footsole epidermis with an antibody against the new cytokeratin, revealed its comigration with K6 and its expression in the ORS/IRS complex. We have therefore named the new cytokeratin K6hf, to distinguish it from the various K6 isoforms and to indicate its expression in the hair follicle. Both in situ hybridization with a K6hf-specific cRNA probe and indirect immunofluorescence with the K6hf antibody showed that K6hf is exclusively expressed in the so-called "companion layer" of the hair follicle, a single layered band of flat and vertically oriented cells between the cuboidal ORS cells and the IRS that stretches from the lowermost bulb region to the isthmus of the follicle. Concomitant K17 and K16 expression studies showed that besides suprabasal ORS cells, these cytokeratins are sequentially expressed subsequent to K6hf in companion cells above the hair bulb. Our study confirms the view of a vertically oriented companion layer differentiation. The clearly delayed K17 and K16 expression relative to that of K6hf in companion cells most probably excludes these keratins as possible type I partners of K6hf and suggests the existence of a still unknown type I partner of its own. Thus, not only morphologically but also biochemically, the companion layer is different from the ORS and can therefore be regarded as an independent histologic compartment of the hair follicle.     

Proline isomerization-independent accumulation of an early intermediate and heterogeneity of the folding pathways of a mixed alpha/beta protein, Escherichia coli thioredoxin

Oxidized Escherichia coli thioredoxin (Trx) is a small protein of 108 residues with one disulfide bond (C32-C35 essentially involved in the activity) and no prosthetic moieties, which folds into a structural motif containing a central twisted beta-sheet flanked by helices that is found in many larger proteins. The kinetics of refolding of Trx in vitro have been investigated using a newly developed active site titration assay and continuous or stopped-flow (SF) methods in conjunction with circular dichroism (CD) and fluorescence (Fl) spectroscopy. These studies revealed the presence of early folding intermediates with "molten globule or pre-molten globule" characteristics. Measurements of the ellipticity at 222 nm indicated that about 68% of the total change associated with refolding occurred during the dead time (4 ms) of the stopped-flow instrument, suggesting the formation of substantial secondary structure. The reconstruction of the far-UV CD spectrum of the burst intermediate using combined continuous and stopped-flow methods showed the formation of a defined secondary structure that contains more beta-structure than the native state. Kinetic measurements using SF far-UV CD and Fl over a wide range (0.087-6 M) of GuHCl concentrations at two temperatures (6 and 20 degreesC) demonstrated that the population formed during the 4 ms dead time contained multiple species that are stabilized mainly by hydrophobic interactions and undergo further folding along alternative pathways. One of these species leads directly and rapidly to the native state as demonstrated by active site titration, while the two others fold into a fourth intermediate that is slowly converted to the native protein. Double-jump experiments suggest that the heterogeneity in folding behavior results from proline isomerizations occurring in the unfolded state. Conversely, the accumulation of the burst intermediate does not depend on proline isomerizations.     

Structural Induction and Coinduction in a Fibrational Setting

We present a categorical logic formulation of induction and coinduction principles for reasoning about inductively and coinductively defined types. Our main results provide sufficient criteria for the validity of such principles: in the presence of comprehension, the induction principle for initial algebras is admissible, and dually, in the presence of quotient types, the coinduction principle for terminal coalgebras is admissible. After giving an alternative formulation of induction in terms of binary relations, we combine both principles and obtain a mixed induction/coinduction principle which allows us to reason about minimal solutionsX≅σ(X) whereXmay occur both positively and negatively in the type constructor σ. We further strengthen these logical principles to deal with contexts and prove that such strengthening is valid when the (abstract) logic we consider is contextually/functionally complete. All the main results follow from a basic result about adjunctions between “categories of algebras” (inserters).     

Bound-abrasive polishers for optical glass

Polishing abrasives that have been bound in a solid matrix can offer several potential advantages over loose-abrasive processes with pitch or polyurethane laps for finishing of optics. These advantages include polishing efficiency, temperature stability, cost of consumables, and compatibility with computer numerically controlled generating machines. Unfortunately, little has been published on bound-abrasive polishers, and very few commercially available products exist. We have developed several compositions and manufacturing techniques that show promise for polishing a variety of optical glasses. We establish the various criteria for a successful bound-abrasive polisher. The numerous variables to be considered in designing these polishers are identified, and the results of screening experiments are used to find successful compositions. Polishing experiments with bound abrasives in arrays of pellets, as ring tools, and as full-contact laps are described.