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.

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.

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.

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.

Colloidal silicic acid for the treatment of psoriatic skin lesions, arthropathy and onychopathy. A pilot study.

In a randomized, double-blind study, patients with chronic plaque-type psoriasis were either treated with 30 ml colloidal silicic acid gel, orally, daily, and topically with the same gel (n = 15), or were treated identically with placebo gel (n = 15) for 3 months. One stable psoriatic lesion on the knee or elbow was treated topically and followed throughout the study. Five patients in the treated group and seven controls had psoriatic arthropathy and 11 treated patients and 12 controls had psoriatic onychopathy. Three treated patients and six controls withdrew because of skin irritation or lack of efficacy. In the treated group there were clear improvements in scaling, induration and erythema after treatment. The nail changes were cured in five of 10 evaluable patients in the treated group and joint pain was reduced by almost half in the four evaluable patients with arthropathy. There were no such improvements in the placebo group.

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.

The effect of silicol gel compared with placebo on papulopustular acne and sebum production. A double-blind study.

Altogether 30 patients (19 females and 11 males), mean age 19 years, were divided randomly into two groups. All patients had chronic papulopustular acne of the face. A total of 15 patients were treated topically with Silicol gel for 20 min twice daily for 6 weeks and the remaining 15 patients were treated with a placebo gel in a similar fashion. A clinical evaluation was carried out at baseline, and after 2, 4 and 6 weeks of treatment. The clinical variables evaluated were as follows: number of comedones, papules, pustules and cysts on a standard area of the left cheek (area 5 x 5 cm) and measurement of sebum production on the same area by the use of Sebumeter SM 810 PC (Courage and Khazaka, Ltd, Germany). No concomitant treatment was allowed during the study period. One patient using Silicol gel withdrew after 2 weeks of treatment because of severe irritation of the facial skin, leaving 29 patients who could be evaluated. In the active group, the number of comedones decreased from a mean of 48.5 to 15.1 after 6 weeks of treatment. The corresponding figures for papules were 10.7 and 1.0, for pustules 6.8 and 0, and for cysts 0.6 and 0. In the placebo group no improvement could be observed. There was a highly significant difference in efficacy between the two groups (P < 0.001) in favour of the actively treated group. The mean sebum index was 193 at baseline and 88 after 6 weeks. Correspondingly in the placebo group the mean sebum index at baseline was 187 and after 6 weeks 179. This difference between the two groups was also statistically significant (P < 0.001). After a short follow-up period (3 months) no deterioration was observed in the 14 'active' patients, showing either complete cure or improvement.

Colloidal silicic acid for oral and topical treatment of aged skin, fragile hair and brittle nails in females.

In an open study, women with biologically aged skin and fragile or thin hair, or brittle nails were treated orally with 10 ml colloidal silicic acid (Silicol) once daily for 90 days and applied colloidal silicic acid to the face for 10 min twice daily. Of the 50 subjects treated, three withdrew from treatment after 30 days because of excessive drying of the facial skin due to topical application. In the remaining 47 subjects there was statistically significant improvement in the thickness and turgor of the skin, wrinkles and condition of the hair and nails. The number of mottles also declined, but the change was not statistically significant. Ultrasound measurements did not detect any statistically significant change in the thickness of the epidermis or elasticity of the skin, but there was a significant increase in the thickness of the dermis.

A comparative study of a new food supplement, ViviScal, with fish extract for the treatment of hereditary androgenic alopecia in young males.

A controlled, randomized, double-blind, parallel-group study compared the effects of ViviScal (a new food supplement incorporating special marine extracts and a silica compound) with those of a fish extract in the treatment of young males with hereditary androgenic alopecia. The pretreatment histological diagnosis was alopecia with a mild to moderate perifollicular inflammation zone. The study consisted of 20 subjects who received two tablets of ViviScal once daily and 20 who received two tablets of fish extract once daily for 6 months. The mean patient age and mean duration and severity of baldness compared well between the two groups. Most patients had been treated with long-term topical 2% minoxidil for 1 year or more prior to the study. At baseline and after 6 months' treatment, a biopsy was taken for histological examination. A non-vellus hair count was performed at baseline and after 2, 4 and 6 months. In the fish extract treatment group three patients withdrew from the study before the fourth month due to lack of therapeutic effect. After 6 months' treatment, patients receiving ViviScal showed a mean increase in non-vellus hair of 38% compared with a 2% increase in the fish extract treatment group (P < 0.0001). In the ViviScal group, 19 (95%) subjects showed both clinical and histological cure, whereas none treated with fish extract showed any clinical or histological difference after 6 months' treatment (P < 0.0001). In both groups, a minimal decrease in the erythemal index was observed. In conclusion, ViviScal appears to be the first highly active treatment for androgenic alopecia in young males.

Comparison of fleroxacin and penicillin G plus probenecid in the treatment of acute uncomplicated gonococcal infections.

OBJECTIVE: To investigate the activity of fleroxacin in acute uncomplicated infections with N. gonorrhoeae in comparison with conventional penicillin G plus probenecid treatment. DESIGN: Multicentre open label randomised parallel group study. SUBJECTS: Male patients aged 18 years or over from university departments of urology, epidemiology and dermatology and a clinic for sexually transmitted diseases. INTERVENTIONS: Two hundred and sixty male patients were randomly assigned to treatment with either a single oral dose of fleroxacin 400 mg (130 patients) or a single intramuscular dose of penicillin G (2.4 or 5.0 mega units) plus a single oral dose of probenecid 1 gram (130 patients). Efficacy and safety assessments were undertaken at follow-up (3-14 days after treatment). Efficacy was assessed as bacteriological outcome of treatment. Safety was assessed by evaluation of adverse events, laboratory abnormalities and changes in vital signs. RESULTS: Two hundred and twenty four patients (114 in the fleroxacin group and 110 in the penicillin plus probenecid group) were evaluated for efficacy. Bacteriological cures were achieved in 100% of patients in the fleroxacin group and 97% of patients in the penicillin plus probenecid group. There was no statistically significant difference between the two groups in this respect (Fisher exact test, p = 0.25). Clinical cures were achieved in 100% of patients receiving fleroxacin and 95% of patients receiving penicillin plus probenecid. Safety analyses were undertaken on 255 patients (126 in the fleroxacin group and 129 in the penicillin plus probenecid group). No adverse events were reported for either treatment group, and no clinically relevant laboratory abnormalities were apparent. Thus, there appeared to be no difference in the efficacy or safety of these two treatments when used to treat acute, uncomplicated urethral gonorrhoea in males. CONCLUSIONS: In this study fleroxacin proved to be highly effective therapy for uncomplicated gonococcal urethritis in males and may provide a favourable alternative to standard treatment.

The effect of Vivida cream as compared with placebo cream in the treatment of sun-damaged or age-damaged facial skin.

Vivida when used orally has been previously shown to be effective in treating degenerated skin of women. In the present study, 30 women with moderate to severe sun-damaged facial skin applied Vivida cream twice daily for 120 days on one side of the face and placebo to the other. Vivida was significantly (P < 0.001) more effective than placebo in improving wrinkles. The effects of Vivida cream on mottles and telangiectasis were also significantly (P < 0.01) greater than those of placebo. Scanner measurement showed that epidermal thickness increased from 0.13 mm to 0.29 mm and dermal thickness from 0.91 mm to 1.29 mm on the Vivida-treated side; only minimal changes were observed on the placebo-treated side. The elasticity index increased from about 50% to 69% on the Vivida-treated side and from 49% to 50% on the placebo-treated side.

Imedeen for the treatment of degenerated skin in females.

Imedeen, a new compound for oral administration consisting of special protein fractions and some glucosaminoglycans extracted from marine fish, has been shown in previous pilot studies to have a repairing effect on sun-damaged skin. In an open study, 10 females with sun-damaged skin, aged 39-61 years, were treated with 0.5 g/day Imedeen for 90 days. At baseline and after 30, 60 and 90 days, the following parameters were clinically evaluated: wrinkles; mottles; dryness of skin; and brittleness of hair and nails. After 90 days' treatment all signs of sun-damage had improved and brittleness of hair and nails was normalized in all cases. These clinical observations were confirmed by changes in skin thickness and elasticity. In a second double-blind study, 30 females in the same age range and with similar signs of sun-damage were treated with 0.5 g/day Imedeen or placebo for 90 days. The results in the Imedeen-treated group corresponded to those in the first study whereas no response to treatment was observed in the placebo treatment group.

A double-blind study comparing oleum horwathiensis with placebo in the treatment of psoriasis.

The efficacy and tolerability of topically applied oleum horwathiensis were evaluated in a double-blind, placebo-controlled study of 42 patients with chronic stable psoriasis. Both groups of patients, 19 receiving oleum horwathiensis treatment and 23 receiving placebo treatment for 12 weeks, showed clinically significant effects of treatment. Oleum horwathiensis was more effective than placebo throughout the treatment period but the difference was not statistically significant at any time. No changes in laboratory values attributable to treatment were recorded. The symptoms of the oleum horwathiensis-treated group continued to be less severe than those of the placebo-treated group throughout the 12 weeks of follow-up. The follow-up period, however, occurred partly during the summer and since the clinical status of the patients may have been affected by climate the difference between the treatment groups was not analysed statistically. The tolerability and cosmetic acceptance of oleum horwathiensis were remarkably good, and good clinical efficacy in scalp lesions--which was not the subject of this study--was spontaneously reported by several patients.

Topical idoxuridine for treatment of genital warts in males. A double-blind comparative study of 0.25% and 0.5% cream.

Fifty heterosexual male patients with histologically verified genital warts of short duration (less than 3 months) were randomly allocated to treatment with either 0.25% or 0.5% idoxuridine cream. The application of the cream to the warts was performed twice daily for an initial period of 14 days, whereafter patients with partial improvement or no response were retreated in the same way for another period of 14 days. Patients not completely healed after 28 days were regarded as treatment failures and withdrawn from the study. After the initial treatment period of 14 days, 19 of 25 patients (76%) treated with 0.5% idoxuridine cream, and 9 of 25 patients (36%) treated with 0.25% idoxuridine cream were completely healed. This difference is significant (p less than 0.01). The corresponding figures at the second follow-up examination (28 days after start of the study) were 19 of 25 (76%) and 13 of 25 (52%), respectively. At the last follow-up examination three months after start of treatment, four patients treated with 0.5% idoxuridine cream and five patients treated with 0.25% idoxuridine cream had a relapse. Thus, the overall rate of complete healing was 15 of 25 (60%) for the patients treated with 0.5% idoxuridine cream and 8 of 25 (32%) for those treated with 0.25% idoxuridine cream. The difference is significant (p less than 0.01). No adverse reactions were observed or reported by the patients.

A comparative study of topical analgesia with a lidocaine/prilocaine cream (EMLA) and infiltration anesthesia for laser surgery of genital warts in men.

Treatment of genital warts by laser surgery was performed in 100 male patients under local infiltration (2-6 ml 1% Xylocaine) or topical anesthesia with 2.5-7.5 ml EMLA cream. EMLA cream was applied to the warts ten minutes before the operation. Pain was significantly less during application of EMLA than during infiltration of Xylocaine. Infiltration anesthesia resulted in better surgical analgesia than EMLA, although the difference was small. The combined pain scores of application and surgery were significantly smaller in the EMLA group. The result suggests that EMLA applied for ten minutes constitutes a less painful treatment and is thus the anesthetic of choice for the laser surgery of genital warts.

Combination of laser-therapy with 0.5% idoxuridine cream in the treatment of therapy-resistant genital warts in male patients: an open study.

Forty heterosexual male patients with therapy resistant penile warts of long duration (mean 12.9 months) were treated with carbon dioxide laser, immediately followed by topical application of 0.5% idoxuridine cream twice daily for 14 days. In case of incomplete or no response to the initial treatment, the treatment procedure was repeated once. All patients had previously been repeatedly treated with podophyllotoxin 0.5% solution and/or carbon dioxide laser surgery. After two weeks of treatment, 32 patients (80%) were completely healed. The remaining eight patients were retreated and four weeks after the start of the study 35 patients (87.5%) showed complete response. Three months after the study had been initiated 34 patients (85%) were still completely healed. No adverse reactions were observed. It was concluded that laser surgery followed by topical application of 0.5% idoxuridine cream for two to four weeks seems to be highly effective in the treatment of longstanding, therapy-resistant genital warts in men. Because of the uncontrolled nature of the present study and the relatively small number of patients treated, it would be important to carry out controlled studies in larger study populations and to carry out a follow-up examination of at least six months after treatment.

Pivampicillin versus doxycycline in the treatment of chlamydial urethritis in men.

Pivampicillin and doxycycline were compared in the treatment of chlamydial urethritis in 80 heterosexual men. The trial was carried out in a double-blind, comparative parallel group fashion. Forty patients were treated with 700 mg of pivampicillin twice daily and another 40 with 200 mg of doxycycline on the first day and thereafter with 100 mg of doxycycline and one placebo tablet daily. Both treatments lasted for 9 days. Follow-up examinations were carried out 2 weeks (14-16 days) and 4 weeks (26-30 days) after the start of treatment. Altogether five (12.5%) of the forty pivampicillin-treated patients were clinical failures and three (7.5%) still harbored Chlamydia trachomatis after treatment. The corresponding figures for the doxycycline-treated patients were two (5.1%) and one (2.6%). The difference between the treatment results of the two groups did not reach statistical significance.

Comparative studies of azithromycin in skin and soft-tissue infections and sexually transmitted infections by Neisseria and Chlamydia species.

Two open, randomized, single centre studies have investigated the efficacy and safety of azithromycin (CP-62,993) in the treatment of infections by azithromycin-sensitive pathogens: (A) acute bacterial infections of skin or soft tissue (compared with erythromycin; n = 82); and (B) urethritis and/or cervicitis caused by Neisseria gonorrhoeae and/or Chlamydia trachomatis (compared with doxycycline; n = 108). In study A, azithromycin was administered to 42 patients for five days at a dosage of 250 mg bd on day 1 and 250 mg once daily on days 2-5; erythromycin was given to 40 patients for seven days at a dosage of 500 mg every 6 h. In study B, azithromycin was administered either as a single 1 g dose or as a single 500 mg dose on day 1 and 250 mg once daily on days 2 and 3; doxycycline was given at a dose of 100 mg every 12 h for seven days. In study A, 68 patients were clinically assessed: clinical cure or improvement in patients receiving azithromycin or erythromycin was achieved in 86% and 82%, respectively. The principal causative pathogen was Staphylococcus aureus; there was eradication of 15/25 pathogens (60%) with azithromycin and 13/23 (57%) with erythromycin. In study B, 94 and 93 patients were clinically assessed at weeks 1 and 2, respectively: clinical cure was achieved with all treatment regimens at week 1; at week 2 there was reappearance of symptoms in one patient with a mixed infection who had received 3-day azithromycin.(ABSTRACT TRUNCATED AT 250 WORDS)

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.