Breed does not affect the association between murmur intensity and disease severity in dogs with pulmonic or subaortic stenosis.

OBJECTIVES: To determine whether breed affects the ability of murmur intensity to predict the severity of stenosis in dogs with pulmonic stenosis or subaortic stenosis. MATERIALS AND METHODS: Retrospective multi-investigator study of dogs with pulmonic stenosis or subaortic stenosis. Murmur intensity, assessed by a four-level classification scheme, was compared with echocardiographically-determined pressure gradient across the affected valve. Breeds represented by at least 10 dogs at any murmur intensity were compared to determine the effect, if any, of breed. RESULTS: A total of 1088 dogs (520 with pulmonic stenosis and 568 with subaortic stenosis, representing 106 breeds and the mixed breed group) were included; 208 dogs had soft, 210 had moderate, 283 had loud and 387 had palpable murmurs. Fifteen breeds were represented by at least 10 dogs: five breeds with at least 10 dogs had soft murmurs (132 dogs), nine breeds had moderate murmurs (149 dogs), 10 breeds had loud murmurs (188 dogs), and 11 breeds had palpable murmurs (286 dogs). No breeds differed in stenosis severity from any other breeds within any murmur grade. Post hoc power calculations suggested that we would have been able to detect at least a moderate or large effect size, had one existed. Several dogs with soft murmurs had more-than-mild disease severity. CLINICAL SIGNIFICANCE: Despite anecdotally perceived differences in the detection of heart murmurs between breeds, which have been proposed to potentially affect the interpretation of stenosis severity, we found no obvious breed effect in the ability to predict severity of stenosis.

Redirecting effector T cells through their IL-2 receptors.

Fusion proteins constructed of a tumor-specific Ab joined to IL-2 (Ab-IL-2) have been used in the past to deliver cytokine directly to the site of tumor cells in vivo. These molecules mimic the activity of IL-2 and assist in activating and expanding antitumor effector cells. To enhance the cytolytic activity of CTL specific for peptide epitopes of the Her-2/neu tumor Ag presented by HLA-A*0201 molecules, a fusion protein was constructed consisting of a single chain Ab specific for Her-2/neu, linked to IL-2 (neu-Ab-IL-2). When added to a mixture of tumor cells and Her-2/neu-specific CTL, the protein was found to augment lysis of tumor cells. In addition, the hybrid molecule also promoted lysis of Her-2/neu expressing tumors by non-tumor-specific cloned T cell lines, including Th1 CD4 cells. Analysis of the mechanism of cytotoxicity revealed that the fusion protein mediates the formation of stable conjugates between T cells expressing IL-2R and tumor cells expressing Her-2/neu, resulting in lysis through the Fas-Fas ligand pathway. Lysis induction was independent of specific engagement by the TCR. When tested for its ability to enhance tumor cell eradication by Her-2/neu-specific CD8+ T cells in an adoptive transfer model in SCID mice, neu-Ab-IL-2 facilitated the elimination of tumor cells in vivo. Surprisingly, the combination of non-tumor-specific CD8+ T cells and fusion protein also induced a significant delay of tumor growth. This represents a novel approach for redirecting non-tumor-specific T cells to eliminate tumors.

Latanoprost treatment for glaucoma: effects of treating for 1 year and of switching from timolol. United States Latanoprost Study Group.

PURPOSE: To determine the efficacy and safety of latanoprost treatment for 1 year in glaucoma patients, and to evaluate the effects of switching from timolol to latanoprost therapy. METHODS: Latanoprost 0.005% was topically applied once daily without masking for 6 months in 223 patients with elevated intraocular pressure after previous treatment with latanoprost once daily or 0.5% timolol twice daily for 6 months in a multicenter, randomized, double-masked, parallel group study. RESULTS: Compared with baseline values before treatment, a significant (P < .0001) diurnal reduction in intraocular pressure of 6 to 8 mm Hg was maintained with minimal fluctuation for the duration of treatment. When treatment was switched from timolol to latanoprost, intraocular pressure was reduced by 1.5 +/- 0.3 mm Hg (mean +/- SEM; 8% change in intraocular pressure; 31% of the intraocular pressure reduction produced by timolol; P < .001) compared with the change in intraocular pressure in patients remaining on latanoprost therapy. Of the patients initially enrolled, 95% successfully completed treatment. There was a slight overall increase in conjunctival hyperemia in patients who switched from timolol to latanoprost, but no change in those who continued latanoprost. The timolol-induced reduction of resting heart rate returned to baseline levels after switching to latanoprost. Of the 247 patients treated with latanoprost during the masked and/or open-label studies, 12 (5%) demonstrated a definite (n = 4) or possible (n = 8) increase in iris pigmentation. CONCLUSIONS: Latanoprost is a well-tolerated ocular hypotensive agent that appears to be more effective than timolol in reducing intraocular pressure. The increase in iris pigmentation appears to be harmless but requires further investigation.

Tolerance to p53 by A2.1-restricted cytotoxic T lymphocytes.

Elevated levels of the p53 protein occur in approximately 50% of human malignancies, which makes it an excellent target for a broad-spectrum T cell immunotherapy of cancer. A major barrier to the design of p53-specific immunotherapeutics and vaccines, however, is the possibility that T cells may be tolerant of antigens derived from wild-type p53 due to its low level of expression in normal thymus and lymphohemopoetic cells. The combination of p53 deficient (p53-/-) and p53+/+ HLA-A2.1/Kb transgenic mice was used as a model to explore the possibility that A2.1-restricted cytotoxic T lymphocytes (CTL) are functionally tolerant of self peptides derived from the wild-type p53 tumor suppressor protein. A2.1-restricted CTL specific for a naturally processed p53 self-epitope spanning residues 187-197 were completely aborted in p53+/+ as opposed to p53-/- transgenic mice. In contrast, CTL specific for a second self-epitope spanning residues 261-269 of the murine p53 sequence were detected in both p53-/- and p53+/+ A2.1/Kb transgenic mice. However, the avidity of the CTL effectors obtained from p53+/+ mice was 10-fold lower than that obtained from p53-/- mice, again suggesting elimination of CTL with high avidity for the A2.1-peptide complex. The circumvention of functional tolerance of high avidity CTL may therefore be a necessary prerequisite for optimizing immunotherapy against A2.1-restricted wild-type p53 epitopes in humans.

Identification of Her-2/Neu CTL epitopes using double transgenic mice expressing HLA-A2.1 and human CD.8.

The Her-2/neu protooncogene is associated with malignant transformation and aggressive disease. Because of its overexpression in tumor cells and because it has been shown to be immunogenic, this protein represents an excellent target for T-cell immunotherapy. By identifying potential HLA-A2.1-binding peptides from the Her-2/neu sequence, peptides were selected as candidate T-cell epitopes. The immunogenicity of each peptide was evaluated by priming double transgenic mice expressing both the human (hu) CD8 and HLA-A2.1 molecules with synthetic peptides corresponding to these sequences. Because of the lack of interaction between murine CD8 and HLA-A2.1, expression of huCD8 on murine cells facilitates recognition of HLA molecules on human tumor cell lines. This led to the identification of two peptides that elicit an A2-restricted CTL response, one of which has not been previously identified. Both peptide-specific CTL populations were able to specifically lyse A2.1 and Her-2/neu expressing human tumor cells originating from a variety of tissues, demonstrating the utility of this murine model in identifying peptides presented by human cells. However, several Her-2/neu peptides previously reported to be immunogenic for human CTL were found not to be immunogenic in transgenic mice. The basis for these discrepancies is discussed.

Prolonged inhibition of IgE production in mice following treatment with an IgE-specific immunotoxin.

The synthesis of IgE antibodies by B cells is the first in a series of steps resulting in an allergic response. To eliminate IgE-bearing B cells and thereby prevent IgE production, we have developed an immunotoxin (ITA) composed of the non-anaphylactic 84.1c anti-mouse IgE mAb and the A chain of ricin (ricin A). This ITA specifically inhibited the induction of IgE synthesis by lipopolysaccharide plus interleukin-4 (LPS + IL-4) in vitro, and antigen-specific IgE production in vivo in adult mice. A single dose of anti-IgE ITA, given within a week (either before or after) of antigen challenge completely abolished antigen-specific primary IgE responses. No IgE production was seen for 2 months after ITA treatment. Following antigenic re-challenge, a suppressed secondary response (over 50% reduction) was still seen in the ITA-treated mice, 100 days after immunization. The results of this study demonstrate the potential use of anti-IgE toxin conjugates for the suppression of periodic (seasonal) allergic outbreaks.

Specific elimination of IgE production using T cell lines expressing chimeric T cell receptor genes.

B cells that are destined to secrete IgE express a membrane-bound form of IgE (mIgE) on their cell surface. Thus, elimination of such mIgE-positive cells should result in the suppression of IgE production, thereby alleviating the symptoms of IgE-mediated allergy. In this study, we examined, in a model system, whether IgE-specific effector T cells can be used specifically to eradicate IgE-producing B cells. To this end, we endowed T cells with anti-IgE specificity using chimeric T cell receptors (cTCR) containing the variable region domain (Fv) of the 84.1c non-anaphylactic anti-mouse IgE monoclonal antibody (mAb). Two configurations of chimeric receptor were used: in the first, we combined the heavy and light variable region chains of 84.1c with the constant (C) regions of the TCR alpha and beta chains. The second construct consisted of a chimeric single-chain receptor (scFvR), composed of a single-chain Fv region of the 84.1c antibody and the C beta domain of the TCR. Following transfection of the cTCR or the scFvR genes into the murine MD.45 cytotoxic T cell hybridoma or the Jurkat human T cell line, functional expression of IgE-specific chimeric receptors was detected on the cell surface. The transfected cells secreted interleukin-2 upon stimulation with immobilized IgE or fixed IgE-producing hybridoma cells. Moreover, cytotoxic T cell hybridomas expressing the chimeric receptor genes specifically eliminated IgE-secreting B cells in vitro, resulting in isotype-specific suppression of IgE production.

Effects of coregistration of MR to CT images on MR stereotactic accuracy.

Coregistration of different modality imaging serves to increase the ease and accuracy of stereotactic procedures. In many cases, magnetic resonance (MR) stereotaxis is supplanting computerized tomography (CT). The advantages of increased anatomical detail and multiplanar imaging afforded by MR, however, are offset by its potential inaccuracy as well as the more cumbersome and less available nature of its hardware. A system has been developed by one of the authors by which MR imaging can be performed separately without a stereotactic fiducial headring. Then, immediately prior to surgery, a stereotactic CT scan is obtained and software is used to coregister CT and MR images anatomically by matching cranial landmarks in the two scans. The authors examined this system in six patients as well as with the use of a lucite phantom. After initially coregistering CT and MR images, six separate anatomical (for the patients) and eight artificial (for the phantom) targets were compared. With coregistration, in comparison to CT fiducial scans, errors in each axis are less than or equal to 1 mm using the Cosman-Roberts-Wells system. In fact, the coregistered images are more accurate than MR fiducial images, in the anteroposterior (p = 0.001), lateral (p < 0.05), and vertical (p < 0.03) planes. Three-dimensional error was significantly less in the coregistered scans than the MR fiducial images (p < 0.005). The coregistration procedure therefore not only increases the case of MR stereotaxis but also increases its accuracy.

The use and clinical importance of a substrate-specific electrode for rapid determination of blood lactate concentrations.

OBJECTIVE: To determine the validity and clinical importance of a newly developed amperometric, enzymatic, substrate-specific electrode for the rapid measurement of circulating lactate concentrations. DESIGN: A prospective multiexperiment study. SETTING: The critical care medicine research laboratory, intensive care unit (ICU), emergency department (ED), and general wards of a university-affiliated hospital. PATIENTS: A total of 1218 patients and control subjects were studied on one or more occasions. INTERVENTIONS: Blood lactate concentrations, descriptive data, physiological parameters, and outcome results were determined in various patient populations. MAIN OUTCOME MEASURES AND RESULTS: Experiment 1: Lactate determinations performed with the new substrate-specific electrode were compared with two laboratory reference methods. Blood samples from 80 ICU patients and 165 ED patients formed the basis of this first experiment. There was excellent agreement between the test instrument and the two reference methods as reflected by bias (with reference method 1, 0.19 mmol/L; reference method 2, 0.09 mmol/L), precision (with reference method 1, +/- 0.47 mmol/L; reference method 2, +/- 0.34 mmol/L), and correlation data (with reference method 1, r = .92; reference method 2, r = .98). Experiment 2: The new test microchemistry instrument was used to analyze blood samples from 927 patients. The mean (SE) blood lactate concentrations in the various patient populations were 1.26 (0.04) mmol/L for control subjects (n = 85), 1.52 (0.03) mmol/L for general ward patients (n = 489; P < .001 vs normal subjects), 2.34 (0.15) mmol/L for ICU patients (n = 180; P < .001 vs normal subjects and general ward patients), and 2.44 (0.15) mmol/L for ED patients (n = 173; P < .001 vs normal subjects and general ward patients). None of the normal subjects and only one (0.2%) of 489 nonhypotensive general ward patients had a blood lactate value greater than 4 mmol/L. Circulating lactate concentrations greater than 4 mmol/L were 98.2% specific in predicting the need for hospital admission in patients presenting to the ED. Furthermore, lactate concentrations greater than 4 mmol/L were 96% specific in predicting mortality in hospitalized nonhypotensive patients. Experiment 3: Blood samples from 46 hypotensive ICU and ED patients and from 353 nonhypotensive ICU and ED patients (the latter samples were derived from experiment 2) were analyzed. A statistically significant difference was noted between the mean (SE) lactate concentration in hypotensive patients in the ICU and ED (4.75 [0.75] mmol/L) when compared with nonhypotensive ICU and ED patients (2.28 [0.10] mmol/L; P < .001). Furthermore, blood lactate values greater than 4 mmol/L were 87.5% specific in predicting mortality in hypotensive patients. CONCLUSIONS: Lactate determinations performed using the new test instrument are precise and accurate. Blood lactate concentrations greater than 4 mmol/L are unusual in normal and noncritically ill hospitalized patients and warrant concern. In hospitalized (non-ICU) nonhypotensive subjects, as well as in critically ill patients, a blood lactate concentration greater than 4 mmol/L may portend a poor prognosis.

Carotid endarterectomy after noninvasive evaluation by duplex ultrasonography and magnetic resonance angiography.

Recent studies documenting the efficacy of carotid endarterectomy (CEA) in selected patients provide further impetus for developing noninvasive techniques to evaluate carotid occlusive disease. Eliminating the morbidity due to preoperative angiography would further refine the treatment of this condition. Recent improvements and greater experience with magnetic resonance angiography (MRA) of extracranial vessels have increased the accuracy of this technique. We present our experience using MRA in combination with duplex ultrasonography as the primary mode of preoperative evaluation for CEA. Fifty-two patients referred for CEA underwent these two studies. In 47 patients (90%), significant stenosis (> 70%) was unambiguously identified on both ultrasound and MRA. Forty-one of these patients underwent CEA on the basis of these studies alone, without conventional angiography. In all of these cases, significant stenosis was identified at the time of surgery (100%), and CEA was performed without difficulty or complications. In five cases (9.6%), the MRA and ultrasound findings did not concur exactly. In three of these cases, the interpretation of the two studies differed with respect to the severity of stenosis; in the others, one of the studies was indeterminate. These patients underwent conventional angiography before surgery. Our experience suggests that the combined use of MRA and ultrasonography affords an accurate noninvasive evaluation of carotid occlusive disease sufficient for surgical planning in most cases.

Control of microwave heating of peritoneal dialysis solutions.

OBJECTIVE: To determine if microwave heating of dialysis solutions to 37 degrees C produced focal overheating (hot spots) and caramelization of dextrose. DESIGN: In vitro determination of conditions for controlling time, temperature, and procedures. Bags had been stored at ambient room temperature. MAIN OUTCOME MEASURES: Solution and external bag surface temperature determinations. Dextrose degradation products determined spectrophotometrically. Microscopy for potential caramel precipitates. RESULTS: A microwave oven with no rotation tray produced uneven heating of bags of two commercially available concentrations of dialysis solutions. The greatest hot spots were evident in spike ports. External bag surface temperatures were within 0.20 degrees C of reservoir temperatures. Initial solution temperatures correlated with temperatures of the solutions after microwave heating (r = 0.895). No statistically significant differences were found between dextrose degradation product concentrations of unheated and heated solutions, including hot spots. No precipitates were observed microscopically. CONCLUSIONS: Despite the presence of solution hot spots in bag infusion ports, 37 degrees C temperatures were achievable in the bag reservoirs with no evidence of increased glucose degradation. This outcome is assured if the initial temperature and the microwave conditions (procedure, time, mixing of solution) are held constant, and the external bag temperatures are measured after heating.

Segmental analysis of computerized optic nerve head imaging.

We evaluated a new method of segmental analysis of the array of numbers representing the depths at points on the optic nerve as generated by a computerized retinal topographic imaging system (the Humphrey Retinal Analyzer). We divided the observed optic nerve head into five rectangular areas, determined the mean depth of each of these areas, and compared them statistically. Intraobserver, interimage, and interobserver variability were calculated. The range of intraobserver variability (+/-SEM) was +/-1.2 to +/-12.0 mum, median 4.6 mum. Interimage variability ranged from +/-3.0 to +/-30.8 mum, median 14.7 mum. Interobserver variability, assessed by intraclass correlation coefficient and two-way analysis of variance, showed observer-to-observer variability was not significant as compared to subject variance and subject-observer interaction variance. Clinical studies further evaluating this segmental analysis of computerized data from the Heidelberg Retinal Tomograph are in progress.

Influence of treatment protocol on the long-term efficacy of argon laser trabeculoplasty.

Forty-five phakic eyes of 36 patients with open-angle glaucoma and uncontrolled intraocular pressure despite maximally tolerated medication underwent initial argon laser trabeculoplasty (ALT) in 1981 and 1982 as part of a prospective, randomized study to evaluate the effectiveness of different treatment standards. Each eye had been randomly assigned to receive either 100 laser applications over 360 degrees of trabecular meshwork, 50 applications over 180 degrees , or 50 applications over 360 degrees in a single session. Further treatment in each group was based on clinical standards prevailing at the time. The long-term results were analyzed using Kaplan-Meier survival analyses. By 4 years after initial ALT, six of the 15 remaining eyes in group 1 (40%), one of 14 eyes in group 2 (7%), and two of 13 eyes in group 3 (15%) had undergone filtration surgery, and one eye in group 1 (7%), three eyes in group 2 (21%), and three eyes in group 3 (23%) had received further ALT. By 7 years after initial ALT, seven of the nine remaining eyes in group 1 (78%), one of 12 eyes in group 2 (8%), and four of 12 eyes in group 3 (33%) received filtration surgery, and two eyes in group 1 (22%), three eyes in group 2 (25%), and four eyes in group 3 (33%) had received further ALT. Kaplan-Meier survival curves predict the following probabilities of avoiding either repeat ALT or filtration surgery at 4 years after an initial ALT: group 1, 54 +/- 12%; group 2, 76 +/- 12%; and group 3, 62 +/- 11%. Our results suggest that performing 50 rather than 100 burns at initial ALT may significantly delay the need for additional surgical or repeat laser intervention.

Intraocular pressure reduction with PhXA34, a new prostaglandin analogue, in patients with ocular hypertension.

In a randomized, double-masked, parallel study, one drop of 0.003% (1 microgram; n = 9) or 0.01% (3 micrograms; n = 10) PhXA34, a new phenyl-substituted prostaglandin F2 alpha analogue (13,14-dihydro-15[R,S]-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-1-isopropyl ester), or its vehicle (n = 10) was applied topically twice daily for 6 days to one eye in each of 29 patients with ocular hypertension. Compared with either baseline, contralateral, or vehicle control values, PhXA34 caused a significant (P < .001) dose-dependent reduction of intraocular pressure. The reduction lasted at least 12 hours after each drop and 24 to 48 hours after the last drop, with a significant (P < .0001) mean +/- SEM reduction of as much as 10 +/- 1 mm Hg (40%). Conjunctival hyperemia was not produced by 0.003% PhXA34, but was noted in some eyes treated with 0.01% PhXA34, and after repeated tonometry with either concentration. The prostaglandin analogue did not produce clinically obvious miosis, anterior chamber flare or cellular response, or any subjective adverse effects. PhXA34 is a potent, effective, and well-tolerated ocular hypotensive agent based on our results in this small, short-term study. Its potential as a new drug for glaucoma therapy warrants further investigation in long-term, larger studies.

Functional assembly of chimeric T-cell receptor chains.

We have generated cytotoxic T-cell hybridomas expressing chimeric T-cell receptors (cTCR) with an antibody-type specificity for the TNP hapten. Transfectants expressing the cTCR genes could mediate specific lysis of haptenated tumor cell lines of various types and secrete IL-2 upon stimulation with TNP modified cells. In a previous report, we showed that double-gene transfectants expressing either VHC alpha and VLC beta or VHC beta and VLC alpha could be activated by TNP-modified stimulator cells or TNP proteins immobilized on plastic. Single-chain transfectants (expressing VHC alpha or VHC beta alone) could be mainly activated by TNP-cells. We now report that transfection of chimeric VHC alpha gene into an alpha-chain-defective mutant restores the surface expression of the TCR/CD3 complex. In parallel, such transfectants regained the ability to respond to mitogen and anti-CD3 antibodies and responded weakly to TNP cells. Double gene transfectants, bearing 2 complementary chimeric chains, expressed high amounts of cTCR on their surface, sufficient to acquire sound anti-TNP reactivity. Cells expressing the VHC beta gene only were not functional and had no detectable surface TCR chains. Taken together, our results suggest that chimeric VHC alpha chains can pair with endogenous V beta C beta chains, but that there is preferential association between complementary chimeric chains, resulting in higher functional expression of the chimeric TCR.

Six week safety study of 2% MK-927 administered twice daily to ocular hypertensive volunteers.

Ocular hypertensive patients were enrolled in a 6-week double-masked safety study of 2% MK-927 (27 patients), a topically active carbonic anhydrase inhibitor, administered bilaterally b.i.d.; 9 additional patients received 0.5% timolol as the control agent. Intraocular pressure (IOP) was measured weekly prior to a.m. drug administration; twelve hour diurnal curves were performed prestudy and at 3 and 6 weeks. The mean reduction of IOP prior to a.m. drug administration ranged from 1.2 +/- 4.4 mm Hg (SD) to 3.0 +/- 4.2 mm Hg with MK-927 and from 4.7 +/- 3.9 mm Hg to 8.8 +/- 0.6 mm Hg with timolol. Mean outflow facility measured tonographically prestudy and on days 33 to 42 four hours after a.m. drug administration was unchanged in both groups. Corneal sensitivity (Cochet-Bonnet), corneal thickness (ultrasound pachymetry), Schirmer tear testing, and extensive ophthalmologic and medical examinations, and hematologic studies were not substantially altered throughout the study. In this longest chronic administration study to date, MK-927 did not cause adverse ocular or systemic side effects.

CD4 and CD8 accessory molecules function through interactions with major histocompatibility complex molecules which are not directly associated with the T cell receptor-antigen complex.

Both the subset-specific, CD4 and CD8 T cell accessory molecules and the antigen-specific T cell receptor (TcR) interact with major histocompatibility complex (MHC) class I and class II molecules on the surface of antigen-presenting cells. We analyzed whether the CD4/CD8 molecules exert their accessory function through binding with the same MHC molecules which participate in the TcR-antigen-MHC complex. We utilized a CD4-, CD8-, class I-allospecific T cell hybridoma which functionally manifests both cytotoxic T lymphocyte (CTL) and T helper1 (Th1) phenotypes, and rendered it bispecific by transfecting it with genes encoding either a class II-restricted, 2,4,6-trinitrophenyl (TNP)-I-Ad-specific TcR or a non-MHC-restricted chimeric TcR, composed of a variable part of an anti-TNP antibody. Expression of either CD4 or CD8 transgenes in these hybridomas enhanced and augmented their reactivity towards the appropriate target cells regardless of the type of TcR-MHC interaction. Thus, class I-specific responses could be enhanced through CD4-class II interactions, and class II-restricted responses could be augmented through CD8-class I interactions. Furthermore, these accessory molecules also potentiated TNP-specific responses by the chimeric TcR which is MHC unrestricted. The accessory molecules facilitated both interleukin 2 (IL2) production and cytolytic activity by shortening the activation time and rendering the cells responsive to lower antigenic stimuli. The degree of activity of the T cell hybridomas correlated with the level of accessory molecule expression and was not related to the effector function mediated by the cells. Anti-CD4 or -CD8 antibodies completely inhibited the activity of transfectants expressing the corresponding accessory molecule, regardless of the MHC type of the TcR interaction. Such antibodies blocked direct TcR stimulation provided by either anti-T3/Ti antibodies or lectins, but could not inhibit the activation through agents that bypass the TcR such as phorbol 12-myristate 13-acetate plus ionophore. Taken together, these studies demonstrate that the CD8/CD4 molecules can exert their accessory function through interactions with MHC molecules which are not directly associated with the TcR-Ag-MHC complex, and that this accessory effect is associated with TcR-mediated triggering at an early stage of the signaling process and is not related to the effector mechanism assigned to the CD4 and CD8 T cell subsets.

A clinical trial of metipranolol, a noncardioselective beta-adrenergic antagonist, in ocular hypertension.

In randomized, double-masked fashion, 24 volunteers with ocular hypertension received 0.3% or 0.6% metipranolol, a noncardioselective beta blocker; or placebo twice daily to both eyes for six weeks. Intraocular pressure (mean +/- SEM) was reduced (P = .01) in the metipranolol-treated patients (baseline measurement, 25.9 +/- 0.5 mm Hg to 18.1 +/- 1.2 mm Hg at six weeks, 0.6% concentration; baseline measurement, 27.1 +/- 0.4 mm Hg to 21.6 +/- 1.5 mm Hg at six weeks, 0.3% concentration). Intraocular pressure was not markedly changed in placebo-treated patients. Outflow facility was unaltered two hours after instillation of metipranolol at study week 2 compared to baseline measurement. Aqueous humor flow rates were reduced (P = .02) 20% after 0.6% or 0.3% metipranolol instillation and were unchanged after placebo administration compared to baseline measurement. Mean systolic blood pressure, diastolic blood pressure, and pulse rate were not markedly altered. Metipranolol reduces intraocular pressure by suppressing aqueous humor flow rates.