Plasma binding variations of amitriptyline and nortriptyline.

The importance of variation in plasma binding in the uncertain correlation between total plasma concentration and the antidepressive effect of amitriptyline (AT) and its active metabolite nortriptyline (NT) was examined. Plasma binding of AT and NT in 131 plasma samples from 87 patients was analyzed by equilibrium dialysis at 37 degrees for 3 hr. There was a twofold variation in percent unbound AT and NT (range 3.5% to 8.6% and 5.4% to 11.3%) and there was no correlation between percent and unbound drug and total drug concentration (range 54 to 6910 nmol/l and 77 to 3420 nmol/l for AT ant NT). The correlation coefficient relating unbound drug concentration of AT and NT to total concentration in plasma was 0.99 for the whole group and 0.16 for the NT therapy control patients, with total plasma concentrations within the therapeutic range. At therapeutic concentration AT was 66.6% and 63.5% bound to purified isolated orosomucoid (alpha 1-acid glycoprotein) and albumin, at physiologic concentrations. The binding to isolated lipoproteins was not examined, but no correlation was found between percent unbound AT and NT and plasma concentration of triglycerides, cholesterol, or orosomucoid.

Significance of lipoproteins in serum binding variations of amitriptyline, nortriptyline, and quinidine.

Using isotope technique, the serum binding of amitriptyline (AT), nortriptyline (NT), and quinidine (Q) was measured by equilibrium dialysis in sera containing varying amounts of lipoproteins. Sera were obtained from 10 fasting subjects with normal to grossly elevated levels of cholesterol, triglycerides, or both. When the lipoproteins were removed from eight of the sera by a standard ultracentrifugation technique, the ratio bound/unbound (B/F) AT decreased an average of 47% (range 30% to 68%), NT an average of 54% (range 39% to 67%), and Q an average of 6% (range 0 to 16%). This decrease in the ratio B/F correlated linearly with the sum of serum concentrations of cholesterol and triglycerides for AT (r = 0.88) and NT (r = 0.82), but not for Q (r = 0.15). In three lipoprotein-depleted sera resuspended with lipoproteins at eight different concentrations ranging from 0 to 100% of the original content, there was a linear correlation between the ratio B/F for AT and NT and the lipoproteins, as evidence by cholesterol or triglycerides concentrations (r = 0.97 to 0.99), but not for Q (r = -0.17 to 0.36). Finally, in the original 10 serum samples, there was a linear correlation between the ratio B/F and the serum lipoproteins (sum of cholesterol and triglycerides) for AT (r = 0.89) and NT (r = 0.68), whereas there was no such relationship for Q (r = -0.15). These data indicate that basic drugs differ in binding characteristics (probably depending on lipophility).

Binding and displacement of basic, acidic and neutral drugs in normal and orosomucoid-deficient plasma.

The binding of the basic drugs quinidine, propranolol and amitriptyline, the neutral drug digitoxin and the acidic drug phenytoin to heparinised normal plasma, to orosomucoid (alpha 1-acid glycoprotein)-deficient plasma and to purified orosomucoid and albumin was studied in both the presence and absence of tris (2-butoxyethyl)-phosphate (TBEP) and de-(2-ethylhexyl)-phthalate (DEHP). The addition of TBEP and DEHP to heparinised plasma in concentrations up to 2.5 mmol/L markedly increased the unbound fractions of quinidine and propranolol, but the increase was less for amitiriptyline, TBEP being the most potent displacer. In orosomucoid-deficient plasma, which was prepared by immunoprecipitation, the free fraction of quinidine was similar to that of normal plasma in which maximal displacement with TBEP was obtained. The addition of the displacers to orosomucoid-deficient plasma caused no further reduction in the binding, nor was the plasma binding of digitoxin and phenytoin significantly affected. When combining purified albumin and orosomucoid in concentrations found in normal plasma, quinidine binding approached that of heparinised normal plasma. This study confirms the dominant role of orosomucoid in the variable plasma binding of basic drugs, and underlines the value of using immunologically prepared orosomucoid-deficient plasma and TBEP or DEHP as model displacers.

Photon correlations of a sub-threshold optical parametric oscillator.

A microscopic multimode theory of collinear type-I spontaneous parametric downconversion in a cavity is presented. Single-mode and multimode correlation functions have been derived using fully quantized atom and electromagnetic field variables. From a first principles calculation the FWHM of the single-mode correlation function and the cavity enhancement factor have been obtained in terms of mirror reflectivities and the first-order crystal dispersion coefficient. The values obtained are in good agreement with recent experimental results [Phys. Rev. A 62 , 033804 (2000)].

Theory of photon statistics and squeezing in quantum interference of a sub-threshold parametric oscillator.

A multimode theory describing quantum interference of a subthreshold optical parametric oscillator (OPO) with a coherent local oscillator (LO) in a homodyne detection scheme is presented. Analytic expressions for the count rates in terms of the correlation time and relative phase difference between the LO and OPO have been derived. The spectrum of squeezing is also derived and the threshold for squeezing obtained in terms of the crystal nonlinearity and LO and OPO beam intensities.

Optimal coupling of entangled photons into single-mode optical fibers.

We present a consistent multimode theory that describes the coupling of single photons generated by collinear Type-I parametric downconversion into single-mode optical fibers. We have calculated an analytic expression for the fiber diameter which maximizes the pair photon count rate. For a given focal length and wavelength, a lower limit of the fiber diameter for satisfactory coupling is obtained.

Inhibition of trypanothione reductase by substrate analogues.

Trypanothione reductase (TR) catalyzes the NAPDH-dependent reduction of the spermidine-glutathione conjugate trypanothione, an antioxidant found in Trypanosomatid parasites. TR plays an essential role in the parasite's defense against oxidative stress and has emerged as a prime target for drug development. Here we report the synthesis of several trypanothione analogues and their inhibitory effects on T. cruzi TR. All are competitive inhibitors with K(i) values ranging from 30 to 91 microM.

Chronic subclinical intake of dietary anticholinesterase agents during the spraying season.

The dietary intake of anticholinesterase (anti-ChE) agents was estimated in 331 schoolteachers during the spraying season. Summer plasma-cholinesterase (ChE) activity was compared with the baseline value obtained during winter. Intraindividual plasma-ChE activity varied independently of factors such as drugs, non-malignant diseases, alcohol and smoking. A depressed mean plasma-ChE, indicating an intake of anti-ChE agents (P = 0.04), was observed in individuals who consumed exclusively agriculturally-grown fruits and vegetables without an additional intake of unsprayed, home-grown products. It remains to be determined whether a subclinical but chronic intake of anti-ChE agents in the diet can be hazardous to humans.

Chondroblastoma of bone: use of fine-needle aspiration biopsy and potential diagnostic pitfalls.

Chondroblastoma of bone is a well-characterized entity. When the radiographic features are classic and the lesion is present in typical locations (i.e., epiphysis of a long bone), the diagnosis is often easily established by fine-needle aspiration biopsy and/or surgical curettage. Tumors in unusual locations, in older patients, or when complicated by aneurysmal bone cysts may pose more diagnostic difficulty. We report four examples (three primary and one-recurrent) of chondroblastoma of bone diagnosed by fine-needle aspiration biopsy. All patients were men, ranging from 18 to 28 yr of age. Sites of involvement included the acromion process of the scapula, left humerus, right ischium, and left distal femur. Three of the tumors were diagnosed as chondroblastoma on fine-needle aspiration cytology; the fourth case, involving the scapula, consisted mostly of a large aneurysmal bone cyst and remained unrecognized until surgical curettage was performed. Typical-appearing chondroblasts were present in three of the cases; osteoclast-type giant cells were observed in all four cases. Matrix material consistent with chondroid was also identified in all cases. We believe that in the absence of inflammatory cells, the presence of classic-appearing chondroblasts, even without chondroid matrix, is sufficient for a diagnosis of chondroblastoma of bone.

Fine-needle aspiration biopsy of gouty tophi: lessons in cost-effective patient management.

Gout, a disease resulting from the effects of hyperuricemia and a crystal-induced arthropathy, may produce soft tissue masses (tophi) which mimick neoplasia clinically and radiographically. We have recently diagnosed three cases of gouty tophus, two of which were clinically suspected to represent sarcomas, by fine-needle aspiration biopsy (FNAB) after extensive radiologic and clinical evaluation. There were two women and one man. aged 71, 73, and 50 yr, with palpable soft tissue masses that involved the right forearm, right hand, and right foot, respectively, Biopsies were obtained by using 25-gauge needles without the aid of general anesthesia. Morphologically, aggregates and disassociated slender, needle-shaped crystals were abundant and easily recognized on both Diff-Quik and Papanicolaou stains. By using a polarizing microscope with a first-order red compensator, the crystals showed negative birefringence, characteristic of sodium urate. Benign-appearing histiocytes, foreign-body-type giant cells, neutrophils, and amorphous debris were scattered among the diagnostic crystals. The diagnosis of gouty tophus can be easily established with FNAB in conjunction with compensated polarizing microscopy. Application of FNAB in the initial evaluation of appropriate soft-tissue masses provides a cost-effective diagnostic method, preventing more costly and often unnecessary clinical and radiologic tests.

Test-retest reliability of the participative decision-making scale for student nurses.

The Participative Decision-making Scale for Nurses was administered before and after a six-week interval to 30 nursing students in the final semester of their programme. Reliability coefficients for the four subscales, with the exception of the clinical subscale, were of reasonable magnitude (range .42 to .62).

Measuring expectations for participative decision making among graduating nurses.

This paper reports on the initial stage of a research program that examines decisions nurses expect to participate in and the methods by which they expect to participate. This stage of the research focuses on the development of a scale, the Participative Decision Making Scale for Nurses (PDMSN), to measure expectations for participative decision making (PDM) among graduating nurses. It has four subscales that measure expectations for participation in clinical, unit, hospitalwide, and strategic decisions. The PDMSN was administered to two groups of graduating nursing students. Results indicate that the subscales of the PDMSN have high internal consistency; alpha coefficients in Study 1 and Study 2 ranged from .70 to .85 and from .76 to .90, respectively. Patterns of correlations among the subscales and significant correlations with an alternative scale measuring PDM indicate that it is a valid instrument.

The spreadsheet and physician productivity.

Friction between medical education faculty members and other physicians at St. Vincent Medical Center, Toledo, Ohio, led to a program to assess both the costs and the contribution of the teaching faculty to the overall goals of the institution. Because the existing information system proved to be unequal to the task, a specially designed spreadsheet system was developed to be used for medical education physicians. The computer-based system that was developed permits a detailed analysis of the productivity of these physicians. More important, it allowed the medical education function to provide solid justification of its efforts on behalf of the medical center.

Changes in the bacterial cecal flora of mice infected with Trichuris muris (Schrank, 1788).

Cecal microorganisms of mice were categorized and enumerated weekly during the developmental cycle of infection with the whipworm, Trichuris muris. The cecal bacterial population consisted of Escherichia coli, Proteus spp, Acinetobacter lwoffi (Mima polymorpha), aerobic lactobacilli, staphylococci, enterococci, and anaerobes (bacteroides, streptococci, and lactobacilli) in control and T. muris-infected mice. The aerobic lactobacilli and the anaerobes constituted the greatest number of organisms in both groups. In week three there was a decrease in the number of these organisms, and in week four fewer of these and of all other organisms in the worm-infected mice when compared to controls. The most significantly reduced bacterial counts were observed during the period of T. muris self-cure.

Inverse potential scattering in duct acoustics.

The inverse problem of the noninvasive measurement of the shape of an acoustical duct in which one-dimensional wave propagation can be assumed is examined within the theoretical framework of the governing Klein-Gordon equation. Previous deterministic methods developed over the last 40 years have all required direct measurement of the reflectance or input impedance but now, by application of the methods of inverse quantum scattering to the acoustical system, it is shown that the reflectance can be algorithmically derived from the radiated wave. The potential and area functions of the duct can subsequently be reconstructed. The results are discussed with particular reference to acoustic pulse reflectometry.