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IL-12 has been shown to enhance cellular immunity in vitro and in vivo. Recent reports have suggested that combining DNA vaccine approach with immune stimulatory molecules delivered as genes may significantly enhance Ag-specific immune responses in vivo. In particular, IL-12 molecules could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of IL-12 cDNA as an adjuvant for a herpes simplex virus-2 (HSV-2) DNA vaccine in a mouse challenge model. Direct i.m. injection of IL-12 cDNA induced activation of resting immune cells in vivo. Furthermore, coinjection with IL-12 cDNA and gD DNA vaccine inhibited both systemic gD-specific Ab and local Ab levels compared with gD plasmid vaccination alone. In contrast, Th cell proliferative responses and secretion of cytokines (IL-2 and IFN-gamma) and chemokines (RANTES and macrophage inflammatory protein-1alpha) were significantly increased by IL-12 coinjection. However, the production of cytokines (IL-4 and IL-10) and chemokine (MCP-1) was inhibited by IL-12 coinjection. IL-12 coinjection with a gD DNA vaccine showed significantly better protection from lethal HSV-2 challenge compared with gD DNA vaccination alone in both inbred and outbred mice. This enhanced protection appears to be mediated by CD4+ T cells, as determined by in vivo CD4+ T cell deletion. Thus, IL-12 cDNA as a DNA vaccine adjuvant drives Ag-specific Th1 type CD4+ T cell responses that result in reduced HSV-2-derived morbidity as well as mortality.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) could in theory attract antigen-presenting cells in muscle following intramuscular DNA immunization, resulting in enhanced antigen-specific immune responses. Thus, such adjuvants could constitute an important addition to a herpes vaccine by amplifying specific immune responses. Here we investigate the utility of GM-CSF cDNA as a vaccine adjuvant for herpes simplex virus (HSV)-2 in a mouse challenge model. GM-CSF cDNA co-injection enhanced levels of specific IgG, IgE and IgA against HSV-2 gD protein significantly higher than gD plasmid vaccination alone. Moreover, GM-CSF co-injection induced a dramatic increase in IgG1 levels, as compared to IgG2a levels, suggesting a Th2 bias in the response. T helper cell proliferation and secretion of cytokines (IL-2 and IFN-gamma) were significantly increased by GM-CSF cDNA co-injection. When challenged with a lethal dose of HSV-2, GM-CSF co-injection increased survival rates to 90%, an improvement as compared to gD vaccination alone (60-63%). Furthermore, GM-CSF cDNA co-injection reduced herpetic lesions and resulted in a faster recovery from lesions. These data indicate that GM-CSF cDNA enhances both humoral and cellular immune responses and enhances vaccine efficacy, resulting in reduced HSV-2-derived morbidity as well as mortality.

Human herpetic infections have been described in ancient Greek and Roman times and are documented in the writings of both Hippocrates and Herodotus (Nahmias and Dowdle 1968). The causative agents of these infections are viruses belonging to a large family of vertebrate pathogens known as the Herpesviridae. Classification of viruses as Herpesviridae is based on virion structure. Viral particles are comprised of an icosohedral capsid surrounded by an amorphous tegument. The core of the virion, which is enclosed by the capsid, contains the viral genome, a linear double-stranded DNA molecule ranging in size from 100 to several hundred kilobase pairs. The viral particle is surrounded by an outer lipid envelope into which the virus encoded glycoproteins are inserted (Fields et al. 1990). Several of the viral glycoproteins, including glycoprotein D (gD) of HSV (as discussed below), are essential for a productive viral infection in humans (Hay and Ruyechan 1992).

Interleukin-4 (IL-4) is a T-cell-derived cytokine that may mediate murine tumor rejection through the activation of host eosinophils. In association with a Phase I clinical trial of IL-4 in cancer patients, we have examined changes in eosinophil counts and characterized systemic eosinophil degranulation. As previously reported, IL-4 administration induced a modest eosinophilia in all 17 evaluated patients. Here, we report that IL-4 therapy induced systemic eosinophil degranulation based on increases in serum major basic protein (MBP) (P = 0.018) and urine MBP (P = 0.031). The increase in serum MBP was IL-4 dose dependent (P = 0.001). Following the highest dose (600 microgram/m2/day) of IL-4 administered, mean serum MBP levels were2000 ng/ml. Skin biopsies of rashes from patients receiving IL-4 revealed MBP deposition. Sera from eight patients receiving IL-4 at 360 and 600 microgram/m2/day exhibited eosinophil survival-enhancing activity (on days 3, 5, 7, and 9) significantly above pretreatment (on day 1) activity (P values 0. 0469, 0.0039, 0.0395, and 0.0313, respectively). This enhanced eosinophil survival could be neutralized by antibodies to IL-5, granulocyte-macrophage-colony-stimulating factor, and IL-3. The eosinophil activation demonstrated in this trial may be relevant to the clinical effects of IL-4 in cancer patients. Furthermore, an association between IL-4 and eosinophil activation should be explored in other disease states.

Protein phosphatases are intimately involved in a variety of cellular processes, many of which are of interest to the pharmaceutical industry. Phosphatase assays generally employ radioisotopes, making them tedious to perform, costly, and hazardous, while other procedures require antibodies and/or are unsuitable for mass screening efforts. To facilitate screening for inhibitors of the CD45 protein tyrosine phosphatase (PTPase), we have developed a sensitive colorimetric assay, using small volumes in 96-well microtiter plates and read on a standard ELISA plate reader. The assay was sensitive down to 0.5 nmol of released phosphate and can be easily run by robotics to assay thousands of compounds in a day. The assay is sparing of reagents and has been successfully used with all classes of phosphatases. The reagents are nonradioactive, readily obtainable, and minimal in cost. This assay should facilitate the search for specific inhibitors of phosphatases.

A total of 4676 patients and 1759 patients were treated with lisinopril and nifedipine respectively in a post-marketing surveillance study conducted in general practice in the UK. Patients were followed up for 12 months. Most of the lisinopril patients had hypertension, but a small number (180) had heart failure. Most of the nifedipine patients had uncomplicated hypertension, but some (22.57%) had other cardiovascular disease with or without hypertension. Lisinopril and nifedipine were equally effective in reducing blood pressure. During the study, 1.5% of hypertensive patients assigned to lisinopril died compared with 1.8% of patients assigned to nifedipine, and 15.1% of lisinopril patients compared with 19.7% of patients in the nifedipine group withdrew because of adverse events. Cough, malaise and fatigue, nausea and vomiting were more frequent causes of withdrawal from lisinopril than nifedipine. Conversely, headaches, pallor and flushing, oedema and palpitations caused more frequent withdrawals from nifedipine. Anaemia was more often encountered on nifedipine treatment than on lisinopril. In hypertensive patients, the frequency of first-dose hypotension was similar on both treatments. Serious events occurred in 0.8% and 0.5% of patients given lisinopril and nifedipine respectively. Lisinopril was well tolerated by heart failure patients: 16 patients (8.88%) died and an incidence of 4.44% of serious adverse events was reported, a pattern to be anticipated in such patients; dizziness, giddiness, dyspnoea, cough, nausea and vomiting were the most frequent causes of withdrawal; the incidence of first-dose hypotension was low (2.22%).(ABSTRACT TRUNCATED AT 250 WORDS)

Wide variability has been demonstrated in the properties and presumably the genetic constitution of aldehyde oxidases of 30 different strains of inbred mice. Genetic control of aldehyde oxidase (Aox) has been shown to reside in linkage group XIII and to be 9.6±0.4 recombination units from isocitric dehydrogenase (Id-1) and 28.3±3.5 recombination units from dipeptidase-1 (Dip-1). On the basis of these data and a recombination percent of 23.5±3.9 for Id-1 and Dip-1, the following gene order was deduced: Aox-Id-1-Dip-1. Furthermore, aldehyde oxidase activity was shown to be independent of adrenal influence and to have no clear-cut survival value for animals treated with large doses of N1-methylnicotinamide.

In a recent paper (1) Prof. Max Jakob outlined a procedure for calculating the temperature at any point T, the maximum temperature Tm, and the average temperature Ta in an electrical coil maintained at uniform surface temperature. Mr. Jakob derived explicit formulas for certain simple coils, i.e., the circular cylindrical coil, the infinite-plate coil, the spherical coil. The present paper is devoted to effecting formulas for T, Tm, and Ta for the very important case of the toroidal coil of general rectangular cross section. Following Jakob, the procedure is to pose determination of T as a boundary-value problem in the mathematical theory of heat; effect the formal solution for T; and obtain the corresponding formulas for Tm and Ta by use of their known relationship with T. Illustrative of application of the general formulas derived in the present paper, the maximum and average temperatures in a coil of given dimensions are calculated and are found to be in excellent agreement with the known measured values.

“Es gibt nichts Praktischeres als eine gute Theorie (There is nothing more practical than a good theory)” —Boltzmann. The first section of this paper stresses the fact that nonlinear control-system theory is rooted in the theory developed earlier for the solution of other types of nonlinear systems, especially those of nonlinear mechanics and nonlinear electric circuits; whence the control engineer interested in nonlinear systems should gain a thorough knowledge of nonlinear system theory in the large. To facilitate such study this paper advances a concise résumé of the major stages of development of nonlinear system theory to date; a list of papers which encompasses a more detailed account of development; a list of the principal books on general theory; and a list of sources on special aspects of the general theory—each item being characterized as to its particular merit. The principal methods of nonlinear analysis and the phenomena of particular interest in nonlinear systems are noted. Finally, the possible use of these methods and the actual occurrence of these phenomena in nonlinear control-system analysis are emphasized.

Electrical relaxation measurements from 0.04 Hz to 2.5 MHz between 80° and 283°C and mechanical relaxation measurements from 120 to 3600 Hz between -44° and 305°C were conducted for 0.5Na2O·0.5K2O·3SiO2 glass. The average time constant for the electric-field relaxation, which is controlled by the diffusion of the more mobile Na+ ion, was smaller by a factor of ∼30 to 50 than that for the mechanical relaxation associated with the mixed-alkali internal friction peak. This result supports the theory of Day and co-workers that the time constant for mixed-alkali mechanical relaxation is controlled by the less mobile alkali ion (K+). The results indicate that a distinct mixed-alkali electrical relaxation analogous to mixed-alkali mechanical relaxation is not observed because the electric field in the glass decays rapidly to zero via diffusion of the more mobile cation, rather than because the mixed-alkali mechanical-relaxation mechanism is inherently electrically inactive.

THREE-PHASE busses comprised of 120-degree-angle conductors, as shown in Fig. 1, possess certain very desirable electrical-mechanical characteristics. Thus, they can be closely nested to the end that the reactance per unit length of bus, and thus the voltage drop per unit length of bus, are much smaller than on other shaped busses of similar current-carrying capacity. Again, 120-degree-angle conductors have considerable mechanical rigidity with which to withstand short-circuit forces. Finally, their shape enables an open, compact construction which simplifies ventilation and heat-dissipation problems, minimizes the space required for installation, and provides easy tap-off to individual loads.

IN VIEW of the important, numerous, and rapidly increasing uses of servomechanisms, analytic procedures that facilitate rapid design are of obvious technical value. The prime purpose of this paper is to set out the details of such a procedure. It has two major uses: First, in analysis it affords quick ascertainment of the roots of a specified cubic characteristic equation, thus enabling rapid determination of the stability characteristics of the corresponding third-order servo system; conversely, in synthesis it enables selection of the coefficients of a cubic characteristic equation to the end that a third-order servo system can be formulated with a desired degree and kind of stability.

Mechanical relaxation in Na2O·3SiO2 glass was measured. The data are compared with dielectric relaxation results for the same glass. The mechanical and electrical relaxation processes have not only the same activation energy but also (within experimental error) the same average relaxation time and distribution of relaxation times. From this result, it may be concluded that the mechanical loss in single-alkali silicate glass arises from the same ionic process that is associated with long-range ionic diffusion.

Guinea pig peritoneal exudate cells incubated with water soluble glycolipids obtained from macrophages show an enhanced response to migration inhibitory factor. Incorporation of these glycolipids into liposomes greatly facilitates their interaction with indicator cells. Enhancement of peritoneal exudate cell responsiveness to migration inhibitory factor was specific for glycolipids from guinea pig macrophages. Glycolipids extracted from guinea pig brain and polymorphonuclear leukocytes as well as several bovine and porcine glycolipids had no effect. Specificity of enhancement was not due merely to a preferential association of macrophage glycolipids with indicator cells. The possible role of macrophage glycolipids as receptors for MIF is discussed.

The safety and tolerability of lisinopril (1.25-160 mg daily) were assessed in 3,270 patients (2,688 hypertensives and 582 patients with congestive heart failure (CHF] and 280 healthy subjects. The duration of therapy ranged from a single dose to 43 months; 438 patients received lisinopril for at least 12 months (mean 20 months). In the hypertensive population, the most frequent adverse events reported were headache, dizziness, cough, nausea, diarrhoea and fatigue, although not all of these events were thought to be related to lisinopril; 6.1% discontinued lisinopril due to adverse clinical events, most commonly cough and nausea. Twelve hypertensive patients died (0.45%), but most of these were not receiving lisinopril at the time of death and none was considered to be drug-related. In CHF patients, the most frequently reported adverse events were dizziness, dyspnoea, diarrhoea, hypotension and fatigue. Again, not all of these reports were considered to be drug-related. Therapy was withdrawn in 9.6% of patients--hypotension, dizziness, diarrhoea and rash being the most frequent reasons. Fifty-three CHF patients died (9.1%) and in three cases death was considered to be related to lisinopril therapy. Hypotension, orthostatic effects or dizziness following the initial dose of lisinopril occurred infrequently (in 1.3% of the hypertensive group, including those receiving hydrochlorothiazide, and in 4.8% of CHF patients). Changes in laboratory parameters were generally minor and seldom resulted in discontinuation of therapy. Long-term treatment of hypertension and CHF with lisinopril for at least 3 years confirms that the drug is well tolerated. Overall, the side-effect profile is very similar to that of other ACE inhibitors with regard to class-specific effects. However, taste disturbance was rarely observed.

A postal survey of 600 dental practitioners in New South Wales was conducted in 1986 to establish a data base on current infection control protocols as they apply to everyday dental practice. Three hundred and sixty-three replies (60 per cent) were returned, representing approximately 16 per cent of Australian Dental Association members in New South Wales (1987).

Nine hundred and thirty nine moderate to severe hypertensive patients were treated with a combination of atenolol, a beta 1 selective receptor blocker, diuretics and where required, additional vasodilator therapy to achieve adequate blood pressure (BP) control. Patients were followed up for a period of 10.2 years (mean 6.1 years). Amassed clinical exposure amounted to 5465 patient years. Mean BP fell from 183.0 +/- 1.0/109.2 +/- 0.5 mmHg to 145.1 +/- 0.6/89.3 +/- 0.3 mmHg and treatment resulted in a significant regression of the electrocardiographic signs of left ventricular hypertrophy (LVH). Side effects of treatment were consistent with those expected from a regime comprising a combination of a beta 1 selective hydrophilic beta-blocker, diuretics and vasodilators. Reported side effects appeared to diminish with time; were more common in the elderly than in the young and increased in frequency as the dose of atenolol increased. Biochemical disturbance was minimal. Total mortality (n = 91) and mortality from myocardial infarction (n = 40) were positively related to treated systolic blood pressure (SBP). A J-shaped curvilinear relationship between treated diastolic blood pressure (DBP) and death rate from myocardial infarction has been shown. Although the number of deaths from stroke was small (n = 21), there appeared to be a positive relationship with treated DBP: by contrast the data suggest that in the elderly, lowering SBP to below about 140 mmHg might be associated with an increased incidence of death from stroke.

A lymphocyte mediator of cellular immunity, the migration inhibition factor (MIF), alters the behaviour of macrophages (David 1966; Bloom & Bennett 1966). Studies so far indicate that MIF is biochemically indistinguishable from the macrophage activating factor (MAF), a lymphocyte mediator that modulates the morphology, biochemistry, and function of macrophages, enhancing their microbicidal and tumoricidal capabilities (Nathan et al. 1973; David & Remold 1976). Thus, one important mechanism for the activation of macrophage function is through lymphocyte mediators (MIF/MAF).

Electrical relaxation measurements from 0.04 Hz to 2.5 MHz between 80° and 283°C and mechanical relaxation measurements from 120 to 3600 Hz between -44° and 305°C were conducted for 0.5Na2O·0.5K2O·3SiO2 glass. The average time constant for the electric-field relaxation, which is controlled by the diffusion of the more mobile Na+ ion, was smaller by a factor of ∼30 to 50 than that for the mechanical relaxation associated with the mixed-alkali internal friction peak. This result supports the theory of Day and co-workers that the time constant for mixed-alkali mechanical relaxation is controlled by the less mobile alkali ion (K+). The results indicate that a distinct mixed-alkali electrical relaxation analogous to mixed-alkali mechanical relaxation is not observed because the electric field in the glass decays rapidly to zero via diffusion of the more mobile cation, rather than because the mixed-alkali mechanical-relaxation mechanism is inherently electrically inactive.

A well-known theorem in functional analysis is modified to provide a simple test for controllability of stable linear systems and a method for finding the subspace of reachable states in systems which are not controllable. The simplicity of application of the results presented is illustrated by an example.