Oral clonidine pre-treatment and diazepam/meperidine sedation.

Clonidine has recently been used as a pre-operative medication and sedative/anxiolytic drug. Its extended duration of action makes it suitable for longer procedures. In this randomized, crossover, placebo-controlled clinical trial, we characterized the effects of oral clonidine pre-treatment on intravenous diazepam/meperidine sedation using the bi-spectral index (BIS) in 13 participants. Clonidine significantly increased the numbers of BIS-depressed readings and percent memory loss during sedation, while reducing total diazepam and post-operative analgesic dosages by 44% and 55%, respectively. Systolic, diastolic, and mean arterial blood pressures, as well as pulse rates, were reduced. Respiratory rate, oxygen saturation, end-tidal CO(2), and recovery from sedation were unchanged. Participants, surgeons, and sedationists preferred clonidine over the placebo. Clonidine pre-treatment increased and prolonged sedation and amnesia and stabilized vital signs while significantly decreasing diazepam and post-operative analgesic usage. These results suggest that pre-operative clonidine administration could be a useful supplement to intravenous sedation for dental procedures of long duration.

Using the Internet for training.

An indisputable fact of life is that the Internet is changing the way business is done. The number of businesses that have web sites is growing at an incredible rate. Many of these supply training; online training offers numerous advantages over traditional training methods.

A logistic dose-ranging method for phase I clinical investigations trials.

This paper describes an alternative to the continual reassessment method (CRM) for phase I trials. The logistic dose ranging strategy (LDRS) uses logistic regression and a dose allocation scheme similar to the CRM. It can easily be implemented from any logistic regression program. The LDRS can be a stand alone dose allocation scheme or it can be incorporated into standard three on a dose strategies to indicate when escalation can proceed more rapidly. Finally, the effect of covariates such as age or comorbid conditions on the toxicity expected for the dose selected for a phase II trial can be examined.

Effect of methoxychlor on implantation and embryo development in the mouse.

Methoxychlor (MXC) has been shown to have adverse effects on reproductive functions. However, it has not been fully determined whether the effects of MXC on reproduction are due to its estrogenic or antiestrogenic effects. Therefore, to further elucidate the estrogenic action of this pesticide in the mouse, we studied the effect of MXC on implantation and embryo development. MXC was found to initiate implantation in most delayed implanting mice at 400 microg/g body weight. However, at the higher dose of 800 microg/g body weight, MXC initiated implantation in only 50% of animals and the number of embryos implanting was significantly decreased (P < 0.05). It was determined that MXC inhibited implantation in intact pregnant mice only when given on Day 1 or Day 2 at 800 microg/g but not at lower doses or later in the preimplantation period. Embryonic development and transport were delayed on Days 3 and 4 in these animals. Finally, reciprocal embryo transfers with donor embryos recovered from MXC-treated animals (800 microg/g body weight on Day 1) transferred to untreated recipients resulted in no implantation compared to 79% implantation when donor embryos were treated with vehicle. These data indicate that MXC acts as an estrogen agonist at the level of the uterus and oviduct but as an antiestrogen in the ovary. In addition, MXC appears to alter normal preimplantation embryonic development. These results suggest the need for further studies to assess the mechanism of action of MXC in preimplantation embryos.

A comparison of sonically derived and traditional cephalometric values.

The roentgenocephalometric technique is the standard used by orthodontists to assess skeletal, dental, and soft-tissue relationships. However, this technique exposes patients to radiation, preventing orthodontists from taking frequent cephalograms to assess growth and to monitor treatment. Recently, the Dolphin Imaging Company developed the DigiGraph, a nonradiographic cephalometric method that uses sound waves and mathematical algorithms, and consequently does not expose patients to radiation. But the DigiGraph's accuracy as a cephalometric alternative has not been adequately investigated. The purpose of this study was to compare the values obtained by traditional cephalometrics with those obtained by the DigiGraph technique for 30 well-known measurements, and then to assess the repeatability (intraobserver comparison) and reproducibility (interobserver comparison) for both techniques. Eighteen of the 30 measurements had mean differences that were statistically significant (p > .0067). Regression plots generally illustrate low correlations for the measurements, although Ricketts' esthetic line (upper and lower lip) and Steiner's soft-tissue convexity reveal strong linear relationships between the two methods. Additionally, the radiographically generated measurements showed greater repeatability and reproducibility.

Cataract surgery and anticoagulants.

Sixty-nine new cases are reported to reinforce the author's contention that anticoagulants should not be terminated for cataract surgery. All surgeries were performed through clear corneal wounds and 44 utilized topical anesthesia. As no blood vessels are encountered by this technique, bleeding is not possible; the remainder of the procedures were done under regional anesthesia, producing one retrobulbar hemorrhage.

Active human cytomegalovirus protease is a dimer.

The quaternary state of the human cytomegalovirus (hCMV) protease has been analyzed in relation to its catalysis of peptide hydrolysis. Based on results obtained from steady state kinetics, size exclusion chromatography, and velocity sedimentation, the hCMV protease exists in a monomer-dimer equilibrium. Dimerization of the protease is enhanced by the presence of glycerol and high concentrations of enzyme. Isolation of monomeric and dimeric species eluted from a size exclusion column, followed by immediate assay, identifies the dimer as the active species. Activity measurements conducted with a range of enzyme concentrations are also consistent with a kinetic model in which only the dimeric hCMV protease is active. Using this model, the dissociation constant of the protease is 6.6 microM in 10% glycerol and 0.55 microM in 20% glycerol at 30 degrees C and pH 7.5.

Activation of the herpes simplex virus type 1 protease.

The catalytic efficiency of the mature HSV-1 protease has been examined as a function of solvent composition. With the peptide substrate HTYLQASEKFKMWG-amide, the specificity constant (kcat/Km) at pH 7.5 for cleavage is 5.2 M-1 s-1. This value increases to 38 M-1 s-1 when 25% glycerol is present in the reaction mixture. It was found that glycerol activation is but one case of the general phenomenon of HSV-1 protease activation by kosmotropes, or water structure-forming cosolvents. For example, an 860-fold increase in the protease activity (kcat/Km = 4500 M-1 s-1) occurs in the presence of 0.8 M sodium citrate. Similarly, the presence of 0.8 M sodium phosphate activates the catalytic efficiency by 420-fold (kcat/Km = 2200 M-1 s-1). The extent of HSV-1 protease activation by various anions correlates with the Hofmeister series. Both the susceptibility to proteolysis by trypsin and the protein fluorescence spectra of the HSV-1 protease change in the presence of activating solvents, suggesting a conformational change accompanying activation.

Crystal structure at 1.9-A resolution of human immunodeficiency virus (HIV) II protease complexed with L-735,524, an orally bioavailable inhibitor of the HIV proteases.

L-735,524 is a potent, orally bioavailable inhibitor of human immunodeficiency virus (HIV) protease currently in a Phase II clinical trial. We report here the three-dimensional structure of L-735,524 complexed to HIV-2 protease at 1.9-A resolution, as well as the structure of the native HIV-2 protease at 2.5-A resolution. The structure of HIV-2 protease is found to be essentially identical to that of HIV-1 protease. In the crystal lattice of the HIV-2 protease complexed with L-735,524, the inhibitor is chelated to the active site of the homodimeric enzyme in one orientation. This feature allows an unambiguous assignment of protein-ligand interactions from the electron density map. Both Fourier and difference Fourier maps reveal clearly the closure of the flap domains of the protease upon L-735,524 binding. Specific interactions between the enzyme and the inhibitor include the hydroxy group of the hydroxyaminopentane amide moiety of L-735,524 ligating to the carboxyl groups of the essential Asp-25 and Asp-25' enzymic residues and the amide oxygens of the inhibitor hydrogen bonding to the backbone amide nitrogen of Ile-50 and Ile-50' via an intervening water molecule. A second bridging water molecule is found between the amide nitrogen N2 of L-735,524 and the carboxyl oxygen of Asp-29'. Although other hydrogen bonds also add to binding, an equally significant contribution to affinity arises from hydrophobic interactions between the protease and the inhibitor throughout the pseudo-symmetric S1/S1', S2/S2', and S3/S3' regions of the enzyme. Except for its pyridine ring, all lipophilic moieties (t-butyl, indanyl, benzyl, and piperidyl) of L-735,524 are rigidly defined in the active site.

Shape discriminations of three-dimensional objects depend on the number and location of bends.

In three experiments, subjects made shape discriminations of three-dimensional objects differing in orientation, number of bends, and location of bends (e.g., the central arm vs. a minor subarm). In general of bends, but only after a certain threshold of bends in the objects had been reached (Experiment 1). This effect was not due to the subjects' having to search for matching ends of the objects (Experiment 2). In contrast, rotation rates were influenced by the location of the bends, but not by the number of bends per se (Experiment 3). The results support a representational scheme that is hierarchical, but not necessarily one in which the principal axis of an object is paramount.

Purification of active herpes simplex virus-1 protease expressed in Escherichia coli.

Assembly of viral capsids for replication of herpes simplex virus requires the proteolytic processing of the assembly protein ICP35. The protease responsible for this process is encoded within the 635-amino acid open reading frame of the UL26 gene of the virus. A simple purification scheme is given in this report for the native, mature form of the protease expressed in Escherichia coli. The scheme allows the preparation of milligram quantities of purified enzyme for elucidation of kinetic mechanism as well as for structural studies. Utilizing a 13-residue peptide substrate representing the natural cleavage site that releases the protease, kcat and Km values of the purified native enzyme are 2.0 min-1 and 0.88 mM, respectively. Thus, peptide cleavage is less efficient than reported for other viral proteases. The possibility exists that viral or cellular factors are involved in vivo for activation of the protease for herpes capsid maturation.

Dissociation and association of the HIV-1 protease dimer subunits: equilibria and rates.

The kinetics and equilibrium properties were investigated for the interconversion between the active dimer of human immunodeficiency virus 1 (HIV-1) protease and its inactive monomeric subunits. The equilibrium dissociation constant (Kd) of the dimeric protease as well as the monomer association rate were obtained by monitoring the fluorescence change of an active-site-directed fluorescent probe (L-737244) upon its binding to the protease. The Kd of the HIV-1 protease is strongly pH dependent. At pH 5.5 where the enzyme is most active catalytically, the extrapolated values of Kd are 0.75 and 3.4 nM at 30 and 37 degrees C, respectively. The rate constant for HIV-1 monomer association, approximately 4 x 10(5) M-1 s-1, is within the range commonly observed for protein-protein interactions. Dimer dissociation was further scrutinized in the presence of an inactive, point mutant form of the enzyme. As a result of subunit exchange between the native and mutant enzymes and the formation of an inactive heterodimer, there was a time-dependent decrease in the activity of the native protease. Enzyme activity could be reinstated with the addition of an active-site-directed inhibitor (L-365862) which selectively binds active dimers. The rate of dimer dissociation was found to also decrease with pH. At pH 5.5 and 30 degrees C, the half-life for subunit dissociation is about 0.5 h. The slow dissociation, coupled with the high stability for dimer association, attests to the importance of allowing sufficient time for dimer-monomer equilibration in kinetic assays in order to avoid reaching erroneous conclusions in studies of dimer dissociation.

Fluoxetine-induced SIADH: a geriatric occurrence?

After major depression was diagnosed in a 83-year-old woman, fluoxetine was prescribed. Six days later she became delirious and weak, necessitating hospitalization. She was found to have hyponatremia secondary to fluoxetine-induced syndrome of inappropriate antidiuretic hormone secretion (SIADH). Recovery was complete after discontinuation of the medication.

A prospective, randomized, double-masked comparison of a zonal-progressive multifocal intraocular lens and a monofocal intraocular lens.

INTRODUCTION: Multifocal intraocular lenses (IOLs) have been designed to provide improved near visual acuity without spectacles compared with monofocal IOLs. Early studies have reported variables amounts of decreased visual acuity and contrast sensitivity with multifocal IOLs, and some patients have experienced halos and glare. METHODS: The authors performed a prospective, double-masked, multicenter evaluation of 62 patients randomized between a new zonal-progressive optic multifocal IOL and a monofocal IOL. RESULTS: Mean postoperative spherical equivalent, astigmatism, and uncorrected and best-corrected distance visual acuity were similar between the two groups. Patients with a multifocal IOL achieved significantly better uncorrected near visual acuity than patients with monofocal IOLs (J3+ versus J7; P less than 0.0001). With distance correction only, mean near visual acuity was J2 versus J5- (P = 0.0001). Best-corrected near visual acuity was J1 for both groups, with 1.36 diopters (D) for the multifocal group versus 2.37 D for the monofocal group (P less than 0.0001). Regan contrast sensitivity was lower for the multifocal patients at all contrast levels, and achieved statistical significance at very low contrast (11% contrast; P = 0.0024). Fifty-two percent of patients with a multifocal IOL reported that they did not need spectacles at all or used them only for their fellow eye, compared with 25% of the patients with monofocal IOLs. CONCLUSION: Both monofocal and multifocal implant patients were very satisfied with the results of their cataract extraction and IOL implant surgery. A small loss of contrast sensitivity with the multifocal IOL was demonstrated, consistent with theoretical predictions. The functional significance of the loss of contrast sensitivity appears to be small and counterbalanced by the advantage of improved uncorrected near visual acuity.

Silicone intraocular lens implants and circular anterior capsulotomy (capsulorhexis).

Anterior circular capsulorhexis is used to guarantee accurate placement and stability for the flexible silicone intraocular lens. The smaller wound needed for this procedure allows for immediate postoperative bending by the patient. The visual results achieved with this implant are excellent.

Anticoagulants and cataract surgery.

A series of 49 cataract operations in 42 patients is presented in support of our contention that if anticoagulants are necessary for a patient's well being, they should not be discontinued for cataract surgery.

Dentists who practice with spouses or relatives: a pilot study of practitioners in Iowa.

Of 130 practicing dentists in Iowa surveyed, 73, or 6% of the practicing dentists in that state, responded that they worked with a total of 108 relatives. Half of the relatives were the dentists' spouses. One to ten relatives worked in each office. Overall, the dentists were satisfied with the associations and expected them to continue. Most dentists had informally defined associations, and 10% had written contracts. Dentists named "office policy and organization" most often and "finances" least often as motives behind the associations and "personal growth" most often and "recognition" least often as a satisfaction with the association. The respondents suggested 567 ideas for other dentists considering such associations.