Prophylactic immunization of mice with phospholipase A2-loaded gas-filled microbubbles is protective against Th2-mediated honeybee venom allergy.

BACKGROUND: People suffering from honeybee venom allergy can be treated by venom immunotherapy, which consists in the subcutaneous injection of increasing doses of allergen extracts over a period of 3-5 years. Such a procedure is time-consuming, and the risks of severe side reactions are important. Approaches based on the use of novel adjuvants to blunt pro-allergic Th2-type immune responses represent a sound alternative. OBJECTIVES: In this study, we evaluated in a mouse model of honeybee venom allergy the protection induced by the prophylactic use of the major allergen phospholipase A2 (PLA2) associated with microbubbles (MB). METHODS: Antibody (Ab) and T cell responses, as detected by ELISA and CFSE-based proliferation assays, were first examined after prophylactic immunization of CBA/J mice with PLA2-MB, and second after sensitization with native PLA2. Mice were eventually challenged with a lethal dose of PLA2 to assess protection against anaphylaxis. RESULTS: Prophylactic immunization with PLA2-MB induced PLA2-specific IgG and IgA Ab, triggered the production of IFN-γ and IL-10 and the differentiation of PLA2-specific Foxp3(+) Treg. Immunized/sensitized mice displayed the following: (1) increased titres of potent blocking IgG1, IgG2a and IgG3 Ab, (2) both reduced allergen-specific T cell proliferation and Th2-type cytokine production and (3) elevated frequencies of specific Foxp3(+) Treg and increased production of TGF-ß, as compared to naïve/sensitized animals. Immunomodulation correlated with reduced signs of anaphylaxis after allergen challenge. CONCLUSIONS AND CLINICAL RELEVANCE: Our data demonstrate the ability of PLA2-MB to prophylactically protect mice against subsequent sensitization and death-inducing PLA2 challenge for up to 4 months, revealing so far unravelled immunomodulatory properties of MB. These data, combined with the safe use of MB as contrast agents for in situ imaging in humans, render them an immunotherapeutic agent of great interest for further evaluation.

Efficacy of a therapeutic treatment using gas-filled microbubble-associated phospholipase A2 in a mouse model of honeybee venom allergy.

BACKGROUND: Venom immunotherapy is efficient to desensitize people suffering from insect sting allergies. However, the numerous injections required over several years and important risks of severe side reactions complicate the widespread use of immunotherapy. In the search for novel approaches to blunt the overwhelming pro-allergic Th2 response, we evaluated the therapeutic efficacy of a treatment based on a denatured form of the major allergen, phospholipase A2, associated with microbubbles (PLA2denat -MB) in a mouse model of honeybee venom allergy. METHODS: Antibodies measured by ELISA, T-cell responses assessed by CFSE-based proliferation assays and ELISA, and basophil degranulation were examined after PLA2denat -MB-based therapeutic treatment of sensitized mice. Mice were challenged with a lethal dose of PLA2 to evaluate protection against anaphylaxis. RESULTS: Therapeutic subcutaneous administration of two different PLA2denat -MB formulations, in contrast to PLA2denat alone, reduced allergic symptoms and protected all mice from anaphylaxis-mediated death after allergen challenge. At the functional level, the use of PLA2denat decreased IgE-mediated basophil degranulation as compared to the native form of the allergen. In comparison with PLA2denat alone, both PLA2denat -MB formulations decreased allergen-specific Th2 CD4 T-cell reactivity. At the mechanistic level, PLA2denat -MB containing 20% palmitic acid and PEG induced PLA2-specific IgA and increased Foxp3(+) Treg frequencies and TGF-ß production, whereas the formulation bearing 80% palmitic acid triggered the production of IFN-γ, IgG2a, and IgG3. CONCLUSIONS: In contrast to conventional PLA2 subcutaneous immunotherapy, the therapeutic administration of PLA2-MB treatment to mice that already had established allergy to PLA2 protects all subsequently challenged animals.

Limits on Anisotropy in the Nanohertz Stochastic Gravitational Wave Background.

The paucity of observed supermassive black hole binaries (SMBHBs) may imply that the gravitational wave background (GWB) from this population is anisotropic, rendering existing analyses suboptimal. We present the first constraints on the angular distribution of a nanohertz stochastic GWB from circular, inspiral-driven SMBHBs using the 2015 European Pulsar Timing Array data. Our analysis of the GWB in the ~2-90 nHz band shows consistency with isotropy, with the strain amplitude in l>0 spherical harmonic multipoles ≲40% of the monopole value. We expect that these more general techniques will become standard tools to probe the angular distribution of source populations.

Grafting of abciximab to a microbubble-based ultrasound contrast agent for targeting to platelets expressing GP IIb/IIIa - characterization and in vitro testing.

Abciximab-grafted ultrasound sensitive microbubbles were developed for the diagnosis of stroke. The antibody fragment abciximab, which binds to the GP IIb/IIIa and alpha v beta 3 receptors expressed by activated platelets, was chosen because most ischemic strokes are due to arterial thrombi that are mainly composed of platelets. The abciximab antibody fragment was activated by reduction of the disulfide bond for grafting on the microbubbles. The suspension was freeze-dried after the grafting was performed directly on the formed microbubbles. Quantification of the amounts of abciximab present on the surface of the microbubbles was assessed semi-quantitatively by flow cytometry, and quantitatively using radio-labeled abciximab. A protocol for human and rat platelets deposition and fixation was implemented and the expression of the GP IIb/IIIa receptor was validated by immunostaining. The abciximab-grafted microbubbles showed high static and dynamic binding to fixed platelets. Detection by ultrasonography of microbubbles bound on white and red clots gave higher signals compared to Sono Vue microbubbles.

Comparison of ciclopirox olamine 1% cream with ciclopirox 1%-hydrocortisone acetate 1% cream in the treatment of inflamed superficial mycoses.

The hydroxypyridone antifungal agent ciclopirox olamine cream 1% has been shown to be as effective in the treatment of inflamed, superficial fungal infections as a formulation in which ciclopirox 1% and hydrocortisone acetate 1% were combined. In a randomized, double-blind, parallel group comparison study, 138 patients with culture-confirmed superficial fungal diseases applied their assigned medication twice daily for 21 days. Clinical assessments were made at the baseline visit; at visits on days 4, 7, 14, and 21 during treatment; and on day 28 (one week posttreatment). Specimens for cultures were taken at baseline and on day 28. There were no differences for the 69 patients in either treatment group at any visit with respect to improvement in the signs/symptoms evaluated; mycological cures in the two treatment groups also were not significantly different.

Immunoglobulin e-mediated severe allergy to human seminal plasma.

Two women with allergy to human seminal plasma are described. Both patients had generalized and local allergic symptoms, i.e., hypotension, asthmatic dyspnea, urticaria, and vaginal swelling, beginning within a few minutes of intercourse. The antigen causing the reaction in these patients was common to all seminal plasmas examined. Most of the antigenic activity was shown to be present in one protein band detected by acrylamide gel electrophoresis. The seminal plasma reaction was mediated through an immunoglobulin E (IgE) antibody. Passive transfer of the hypersensitivity with the serum of both patients was successful, and the radioallergosorbent test showed that the serum of the first patient contained IgE specific to seminal plasma.

Ocular inflammation in Reiter's disease after Salmonella enteritis.

We studied characteristics of ocular inflammation in Reiter's disease after Salmonella enteritis in eight patients. After an acute onset with diarrhea, fever in six patients, and headache in three patients, all patients developed arthritis; six patients had myalgia; six patients, urethritis; and one patient, carditis. Sacroiliitis was found in four patients. All patients had HLA-B28 antigen. Conjunctivitis occurred in seven patients. It was mostly mild with no chemosis, follicles, or keratitis, and resolved in ten days. In one case palpebral edema, chemosis in the conjunctiva, and purulent exudate were seen. One patient had transient episodes of keratitis and corneal erosion for two months and episodes of conjunctivitis for 11 months. Three patients developed unilateral acute anterior uveitis with aqueous flare, cells, fine keratic precipitates, and fibrinous exudation from three to four years after the onset of the illness. One of these patients had vitritis and macular and papillary edema.

Local treatment of acne. A clinical study and evaluation of the effect of different concentrations of benzoyl peroxide gel.

A total of 50 patients with moderately severe acne was treated with either 3%, 5% or 10% benzoyl peroxide gel for 4 weeks. Forty-eight patients maintained the treatment for the whole trial period while in 2 cases treatment has to be discontinued because of severe irritation of the treated skin areas. In all the remaining cases a definite remission of the acne activity could be observed at the end of the 4-weeks' trial. In some cases the gel had to changed to a stronger or a milder concentration during the trial either because of insufficient effectiveness or irritation.

Clobetasone butyrate and hydrocortisone butyrate in the treatment of eczema: a double-blind comparison.

Forty patients with symmetrical eczematous lesions on their extremities were treated in a double-blind fashion with 0.05% clobetasone butyrate and 0.1% hydrocortisone butyrate in cream bases. After 2 weeks of treatment, a preference for clobetasone butyrate was observed in 7 cases, for hydrocortisone butyrate in 9 cases and in 24 cases both sides responded equally. The lesions on both sides improved steadily throughout the study in all cases. When completing the trial after 2-weeks' treatment, the clobetasone butyrate-treated lesions had healed in 8 cases and the hydrocortisone butyrate-treated lesions in 10 cases. No local side-effects were observed.

Local treatment of psoriasis with desoxymethasone and betamethasone 17,21-dipropionate: a double-blind comparison.

A double-blind comparison of the effectiveness of 0.25% desoxymethasone and 0.05% betamethasone 17,21-dipropionate creams was carried out in 40 patients with symmetrical, chronic psoriatic lesions. The lesions were pre-treated for 1 week with an inactive cream base and then the trial preparations were applied, without occlusion, to one or other side at random twice daily for 21 days. Overall response to treatment and the effect of the two topical steroids on scaling, induration, erythema, and pruritus were assessed at the start of and 4, 7, 14, and 21 days after the start of active treatment. The results indicated a better but not statistically significant response to desoxy-methasone. By the end of the trial period, the desoxymethasone-treated side was better in 22.5% of cases compared with 10% of cases in the betamethasone dipropionate-treated side. No side-effects of treatment were observed.

A comparative pilot study of azapropazone and indomethacin in the treatment of psoriatic arthritis and Reiter's disease.

A double-blind crossover study to compare 1200 mg. azapropazone per day with 100 mg. indomethacin per day was carried out on 34 patients with psoriatic arthritis and 16 patients with Reiter's disease. The same comparison was initiated in 8 additional patients but withdrawn in 3 cases because of side-effects to indomethacin, in 2 cases because of side-effects to azapropazone, and in the 3 remaining cases for other stated reasons. The results of the study showed no overall difference between the treatment results of azapropazone and indomethacin, but azapropazone seemed to be more effective in cases with psoriatic arthritis and indomethacin in cases with Reiter's disease. Indomethacin caused more side-effects than azapropazone. Neither drug seemed to influence the skin manifestations of either disease.

Local treatment of psoriasis of the scalp with clobetasol propionate and betamethasone-17,21-dipropionate: a double-blind comparison.

A double-blind evaluation was carried out in 40 patients with moderate to severe psoriasis of the scalp to assess the effectiveness of a 0.05% alcoholic solution of clobetasol propionate as compared with a 0.05% alcoholic solution of betamethasone-17,21-dipropionate. Patients were treated on a non-selective basis with a twice a day application for 2 weeks. When comparing the effects on the parameters scaling, induration, erythema and itching it was concluded that clobetasol propionate was superior to betamethasone-17,21-dipropionate as an antipsoriatic compound. Clobetasol propionate did not cause any side-effects, while 2 of the patients using betamethasone-17,21-dipropionate developed a forehead folliculitis during the second week of treatment.

Local treatment of psoriasis of the scalp with clobetasol propionate in alcoholic solution: a comparison of once and twice a day application.

A clinical evaluation was carried out in 53 patients with moderate to severe psoriasis of the scalp to assess the effectiveness of a 0.05% alcoholic solution of clobetasol propionate. Patients were treated on a non-selective basis with either a once a day or twice a day application. After a 2-weeks' treatment period, the results showed that there was an excellent or good response in 65% of patients treated once a day and in all of the patients on twice daily application of the topical steroid. It is recommended, therefore, that clobetasol propionate should be applied twice daily for the control of severe cases of psoriasis of the scalp.

Systemic side-effects of three topical steroids in diseased skin.

Two clinical trials were carried out in order to study adrenal suppression in 6 patients with psoriatic erythroderma and in 28 patients with psoriasis treated with topical glucocorticosteroids. Betamethasone-17-valerate (0.1%), betamethasone-17,21-dipropionate (0.05%) and budesonide (0.025%) ointments were studied in erythroderma; betamethasone-17,21-dipropionate and budesonide in psoriasis. The erythroderma study was an open, crossover experiment; the psoriasis study was a double-blind, group-comparative study. Adrenal suppression was measured as plasma cortisol concentrations with and without ACTH stimulation. The depressive activity on the HPA-axis in increasing order was budesonide, betamethasone-17-valerate and betamethasone-17,21-dipropionate. The differences, however, did not reach statistically significant levels.

Clinical experience with 1000 patients treated with cefetamet pivoxil.

Clinical studies have been carried out world-wide on cefetamet pivoxil, a new orally active cephalosporin. This paper reports on the first 1000 patients treated with the antibiotic; another 505 patients received standard antibiotics, mainly cefadroxil and cefaclor, for comparison. The results show that single doses of 1500 and 1200 mg cefetamet pivoxil were fully effective in gonorrhoea. Comparative trials in uncomplicated urinary tract infection indicate a significant superiority of a single dose of 2 g cefetamet pivoxil (n = 158; 90.0% cure) versus 2 g cefadrox (n = 162; 77.0% cure). In complicated urinary tract infections, a comparable outcome was achieved with a single daily dose of 2 g cefetamet pivoxil for 10 days (n = 99; 90% cure) and 1 g cefadroxil twice daily for 10 days (n = 98; 76.5% cure). The clinical response rate in acute exacerbation of chronic bronchitis was 89.4% in the group receiving cefetamet pivoxil (136 patients) and 83% in the cefaclor-treated group (n = 122). Treatment with 1000 or 2000 mg cefetamet pivoxil achieved a (bacteriological) success rate of 96% compared to 95% with cefaclor in acute ear, nose and throat-infections (n = 91). Overall, based on 894 isolated pathogens prior to therapy, the bacteriological response rate was 90% and it would appear that in vivo the spectrum of this cephalosporin covers a wide range of Gram-negative and Gram-positive pathogens, including urinary pathogens, but excluding Enterococci and Pseudomonas. Cefetamet pivoxil proved to be well tolerated. Mild to moderate adverse events were reported in 7.1% of patients but only 2 of the 1000 patients treated with cefetamet pivoxil were withdrawn because of diarrhoea, which subsided rapidly. There were no clinically relevant deviations in laboratory parameters.

Pharmacokinetics of 8-methoxypsoralen in serum and suction blister fluid.

Micronized 8-methoxypsoralen (8-MOP), with a smaller crystal size, produced significantly higher serum level profiles than nonmicronized 8-MOP. Furthermore, the absorption of the micronized drug was more rapid, resulting in peak serum levels within 1 h in 75% of the patients. Our blister fluid studies suggest, however, that reduction of the photosensitizer concentration is slower in skin than in serum. This implies that despite markedly reduced 8-MOP serum level after 2 h the skin remains sufficiently sensitized up to that point of time.

Genivir (DIP-253) 1% cream versus placebo cream in the treatment of recurrent genital herpes: a double-blind study.

A total of 100 heterosexual adults of either sex with frequent episodes of recurrent genital herpes were allocated to treatment with either Genivir (DIP-253) 1% cream or placebo cream. All patients had genital herpes previously verified by a positive viral culture. The study was carried out as a double-blind parallel group trial. Fifty patients were allocated to each of the two treatment groups. The treatment was initiated within 24 hours after the first sign of a recurrence, and at the pretreatment examination all patients had developed typical lesions with blisters and/or sores. At baseline a sample for herpes virus culture and typing was obtained. The creams were applied four times daily for five days. Follow-up examinations were carried out on days 1, 2, 4 and if needed on days 7, 10 and 14. The major factor used for assessment of efficacy was the time to complete healing of all lesions. Duration of pruritus and pain were also recorded. In the group of patients treated with Genivir cream the time to complete healing was 3.3 days and in the placebo group 6.1 days. The difference was statistically significant (P less than 0.001). The mean duration of pain was 1.3 days in the Genivir group and 2.5 days in the placebo group: this difference also reached significance (P less than 0.01). The duration of pruritus was about the same in both groups. The active agent in Genivir, DIP-253, is a heterocyclic aromatic complex with confirmed anti-herpetic activity and with evidence of a local immunomodulatory effect. It was concluded that the efficacy of topical application of DIP-253 may be due to combined antiviral and immunomodulatory activities.

Topical treatment of venereal warts: a comparative open study of podophyllotoxin cream versus solution.

Podophyllotoxin solution (0.5%) is licensed for use in the treatment of condylomata acuminata (genital warts) in men in a number of European countries. In some countries, approval also extends to treatment of genital warts in women. This controlled randomized prospective study evaluated the efficacy and safety of a cream formulation of podophyllotoxin at 2 concentrations (0.15% and 0.3%), using 0.5% podophyllotoxin solution as a reference treatment. Two separate studies were initiated, to assess the 3 treatment groups in (a) male patients, and (b) female patients. Statistical evaluation was based on a "response rate' calculated at each clinic visit. The mean "response rates' in the male patient study at 4 weeks were 75.1%, 79.0% and 85.6% in the 0.15% cream, 0.3% cream and 0.5% solution groups, respectively. The corresponding "response rates' for the female patient study were 86.2%, 92.6%, and 93.1%, respectively. The relapse rates for both male and female patients were 6.0% in the 0.15% cream group, 8.6% in the 0.3% cream group and 8.6% in the 0.5% solution group. The results show that there were no statistically significant differences between the 3 treatments with regard to both efficacy and safety. This was true for both the male and female patient groups.

Sexually transmitted infections in Estonia--syndromic management of urethritis in a European country?

Sexually transmitted infections (STIs) are considered a major public health problem, globally. In particular, increasing STI rates have been documented throughout eastern Europe and central Asia. The Russian Federation and adjacent countries have, traditionally, managed STIs on an aetiological basis. This approach is expensive in terms of laboratory costs and it may lead to delayed diagnosis and treatment. To overcome the limitations of the aetiological management of STIs, the World Health Organization (WHO) has placed an increased emphasis on integrated care using syndromic management at the primary care level, especially in developing countries. This article reviews the current aetiology of STIs in Estonia, an eastern European country bordering the Baltic Sea and formerly a part of the Soviet Union, with the aim of defining whether infection with Trichomonas vaginalis is common enough to include its management in a syndromic management protocol. The use of syndromic management, in general, is also discussed.

An epidemiological survey of psoriasis in the greater Helsinki area.

A questionnaire survey of all members of the Psoriasis Society of the Greater Helsinki area was carried out during March and April 1984 in order to determine the course of psoriasis. 1517 (85.4%) of the members responded; 1050 of them had psoriasis with skin symptoms only (psoriasis; P) and 400 had also joint symptoms (psoriatic arthritis; PA). In two thirds, the psoriasis had started before the age of 30 years. Skin lesions were more frequent in the PA-group than in the P-group, and more severe in men than in women in both groups. Of the 400 with PA, about 70% had moderate to very severe discomfort in their joints. Most of the patients had experienced their first joint symptoms at the age of 20 to 49 years. In the majority of the patients with PA the skin symptoms begun before the joint symptoms; in 7% the joint symptoms had preceded the skin symptoms; and in 10% both symptoms had begun simultaneously.