Exposure of human glioblastoma cells to thimerosal inhibits the thioredoxin system and decreases tumor growth-related factors.

Glioblastoma multiforme (GBM) is the most common, aggressive, and fatal primary malignant brain tumor in adults. The therapeutic efficacy of temozolomide (TMZ) is limited owing to frequent treatment resistance. The latter is in part related to the overexpression of redox systems such as the thioredoxin system. This system is fundamental for cell survival and proliferation, regulating hypoxia inducible factor-1alpha (HIF-1α) activity, in turn controlling vascular endothelial growth factor (VEGF), which is indispensable for tumor invasiveness, angiogenesis and microenvironment maintenance. HIF-1α can also be regulated by the signal transducer and activator of transcription 3 (STAT3), an oncogene stimulated by pro-inflammatory cytokines and growth factors. The thioredoxin system has several known inhibitors including mercury compounds such as Thimerosal (TmHg) which readily crosses the blood-brain barrier (BBB) and accumulates in the brain. Though previously used in various applications epidemiological evidence on TmHg's neurotoxicity is lacking. The objective of this study was to verify whether thimerosal is a suitable candidate for hard repurposing to control glioblastoma; therefore, the effects of this molecule were evaluated in human GBM (U87) cells. Our novel results show that TmHg decreased cellular viability (>50%) and migration (up to 90% decrease in wound closure), reduced thioredoxin reductase (TrxR/TXNRD1) and thioredoxin (Trx) activity, and increased reactive oxygen species (ROS) generation. Moreover, TmHg reduced HIF-1α expression (35%) as observed by immunofluorescence. Co-exposure of U87 cells to TmHg and TMZ reduced HIF-1α, VEGF, and phosphorylated STAT3. Consequently, TmHg alone or combined with chemotherapeutic drugs can reduce neoangiogenesis and ameliorate glioblastoma progression and treatment.

[THE CORRECTION OF THE LOCAL IMMUNE RESPONSE AT THE PATIENTS WITH HELICOBACTER PYLORI INFECTION].

INTRODUCTION: Helicobacter pylori infection is due to the high prevalence in population attracts the clinical interest of researchers in the whole World. It is well known that this microorganism not only resides in the mucosa of the gastrointestinal tract, but is also defined in the periodontal pocket of the oral cavity. THE AIM OF INVESTIGATION: to evaluate Helicobacter pylori diagnostics in the mouth and prove a method of relief of the inflammatory process by applying immunomodulator Imudon. RESULTS. On the basis of obtained results it was found that the inclusion of topical immunomodulator Imudon in the complex therapy of Helicobacter pylori-associated diseases leads to reduction of inflammatory potential through the decrease of the TNFα, IL-6 activity in saliva and to increase the protective properties of saliva as a result of increased levels of mucin, significantly reduces the frequency of relapses in the one year after therapy. CONCLUSION: It is practically important to determine the effectiveness of eradication therapy by the study of the contents of the tooth-gingival pocket for the detection of genetic material of Helicobacter pylori, as well as to include in the complex therapy of Helicobacter pylori-associated diseases of the immune modulator Imudon.

The emerging role of α7nAChRs/caspase-3/Nrf-2 signaling pathway in citicoline improved autistic behavior induced by thimerosal in mice.

AIMS: Autism spectrum disorder (ASD) is a global concern,affecting around 75 million individuals.Various factors contribute to ASD,including mercury-containing preservatives like thimerosal (Thim) found in some vaccines.This study explored whether citicoline could be a therapeutic option for Thim-induced neuronal damage in a mouse model of ASD.Additionally,the study investigated the effects of citicoline on the α7nAChRs/Akt/Nrf2/caspase-3 pathway,which may be involved in the development of ASD. MATERIALS AND METHODS: The study separated newborn mice into four groups.The control group received saline injections,while the Thim group received intramuscular injections of 3000 µg Hg/kg Thim on days 7,9,11,and 15 after birth.The two citicoline groups were administered Thim followed by intraperitoneal injections of 250 mg/kg or 500 mg/kg citicoline for three weeks.Afterward,various parameters were assessed, including growth,behavior,brain histopathology,oxidative stress,apoptotic,and inflammatory markers. KEY FINDINGS: Untreated Thim-exposed mice exhibited significant brain damage,which was substantially alleviated by citicoline treatment.This beneficial effect was associated with increased expressions and concentrations of brain α7nAChRs and Akt, increased brain content of Nrf2, and the hippocampus contents of acetylcholine. Citicoline treatment decreased the brain levels of oxidative stress markers (MDA and NO),the apoptotic marker caspase-3,and pro-inflammatory markers (NF-κB,TNF-α,and IL-1ß). The drug also increased the brain GPx activity. SIGNIFICANCE: Based on the results of this study,the α7nAChRs pathway appears to be essential for the therapeutic effectiveness of citicoline in treating Thim-induced ASD in mice.

[Local immunomodulating agents in complex treatment of oral lichen planus].

The paper presents the results of local immunity status assessment in patients with erosive-ulcerous form of oral lichen planus by etiopatogenetic treatment including imudone and derinate. The positive dynamics of immunological parameters under imudone and derinate is demonstrated.

[Immune reactions of palatine tonsils in the patients with chronic tonsillitis and the possibilities for their immunological rehabilitation with the use of imudon].

The objective of the present study was to develop a rationale for the application of imudon (a bacterial lysate preparation)in the treatment of the patients presenting with chronic tonsillitis based on the elucidation of characteristics of local immunity in the oropharynx (determined from the results of cytograms, immunoenzyme assays for the quantitation of IgG, sIgA, IgA, and IgM antibodies, and calculation of the relative secretion coefficients). A total of 74 patients with chronic tonsillar pathology (24 children and 50 adults) were available for the observation along with 42 subjects having no tonsillar pathology with concomitant chronic bacterial rhinosinusitis. The control group was constituted by 25 practically healthy subjects. It was shown that the local application of imudon in the patients with the preserved function of palatine tonsils (in the absence of symptoms of chronic inflammation) produces the adequate response of the humoral and cellular immunity systems. In the patients with the simple form of chronic tonsillitis imudon therapy ensured statistically significant activation of congenital immunity including the phagocyte function and a tendency toward normalization of antibody formation. It is concluded that alteration of the function of palatine tonsils in the patients presenting with the toxico-allergic form (ТАФ-2) of chronic tonsillitis implies the necessity of surgical treatment (tonsillectomy).

Low-dose Oral Thimerosal for the Treatment of Oral Herpes: Clinical Trial Results and Improved Outcome After Post-hoc Analysis.

BACKGROUND: Thimerosal (TML) is an organomercury antimicrobial. Low doses (1/250th of the amount in a typical vaccine dose) may promote an antiviral immune response. Low-dose TML (BTL-TML) was evaluated for safety and efficacy against herpes labialis in two FDA-approved, randomized, double blind, placebo-controlled clinical trials. METHODS: BTL-TML was evaluated in a Phase IIa trial for its ability to block progression to lesion in subjects with recurrent oral herpes caused by dental trauma. Subjects were administered BTL-TML or a saline control over a 7-day period. In a Phase IIb trial, BTL-TML was evaluated for its ability to block progression to lesion over a 7-day period in subjects with herpes lip infections induced by exposure to ultraviolet (UV) radiation. RESULTS: Progression to lesion post-dental procedure was prevented in 54.5% (12/22) TML subjects versus 22.2% (2/9) control subjects (p = 0.106). Progression to lesion post-UV irradiation was blocked in 47.8% (11/23) BTL-TML treatment subjects and 42.8% (6/14) control subjects. A post-hoc analysis yielded 52.2% (12/23) BTL-TML subjects with no progression to lesion versus 28.6% (6/21) control subjects with no progression (p = 0.099). There were no significant differences in adverse effects between treatment and control groups in either trial. CONCLUSIONS: Neither clinical trial showed a statistically significant effect of BTL-TML on progression to lesion. However, the post-hoc analysis suggested there is a 48-hour period following UV radiation exposure during which the anti-herpes activity of antivirals such as BTL-TML is reduced. Accordingly, BTL-TML may have promise in subsequent, properly designed and powered clinical trials.

[Experience in immunomodulators application for comprehensive dental caries prevention in children and teenagers].

Prophylaxis and treatment procedures in children with different dental status was done during 9 years. Children and teenagers of 6-12 and 15-years were given teeth treatment and professional hygiene. One group of patients was additionally treated by immunomodulators imudon. It was demonstrated that improving of oral cavity hygiene and local immunity factor balance was achieved. Positive result was better in the group with imudon.

Can Unconventional Immunomodulatory Agents Help Alleviate COVID-19 Symptoms and Severity?

Severe acute respiratory syndrome coronavirus 2 (SARS coronavirus 2, or SARS-CoV-2) is the cause of the respiratory infection known as COVID-19. From an immunopathological standpoint, coronaviruses such as SARS-CoV-2 induce increased levels of a variety of T-helper 1 (Th1) and inflammatory cytokines and chemokines, including interleukin-1 (IL-1), IL-6, CCL2 protein, and CXCL10 protein. In the absence of proven antiviral agents or an effective vaccine, substances with immunomodulatory activity may be able to inhibit inflammatory and Th1 cytokines and/or yield an anti-inflammatory and/or Th2 immune response to counteract COVID-19 symptoms and severity. This report briefly describes the following four unconventional but commercially accessible immunomodulatory agents that can be employed in clinical trials to evaluate their effectiveness at alleviating disease symptoms and severity: low-dose oral interferon alpha, microdose DNA, low-dose thimerosal, and phytocannabinoids.

Safety of influenza vaccination during pregnancy.

The Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommends routine influenza vaccination for all women who are or will be pregnant during the influenza season. During seasonal influenza epidemics, during previous pandemics, and with the current influenza A (H1N1) pandemic, pregnancy places otherwise healthy women at increased risk for serious complications from influenza, including death. Inactivated influenza vaccine can be safely and effectively administered during any trimester of pregnancy. No study to date has demonstrated an increased risk of either maternal complications or adverse fetal outcomes associated with inactivated influenza vaccination. Moreover, no scientific evidence exists that thimerosal-containing vaccines are a cause of adverse events among children born to women who received influenza vaccine during pregnancy. In this article, we review the evidentiary basis for the recommendation of vaccination of all women who will be pregnant during the influenza season and safety data of influenza vaccination during pregnancy.

[Principles of the immune modulation therapy against papilloma virus infections].

The aim of the study was to investigate the effect of Immudone on local immune responses of cervical mucous in patients with papilloma virus cervicitis. 80 women of reproductive age with chronic cervicitis, 60 women with no signs of infection and 70 bioptates obtained from the base of vaginal section of the cervix. Colposcopic, bacterioscopic, patho-histological and immunohistochemical investigations have been performed. After using of Immudone healing of ectopia was observed in the most of cases. As a result of local application of Immudone in patients with PVI in the tissue of cervix the rate of CD4+ cells was increased, expression of receptors of interleukin-2 was increased, CD4/CD8 ratio also increased, quantity of macrophages and natural killers was increased. Local sIgA synthesis was restored.

A longitudinal cohort study of the relationship between Thimerosal-containing hepatitis B vaccination and specific delays in development in the United States: Assessment of attributable risk and lifetime care costs.

Epidemiological evidence suggests a link between mercury (Hg) exposure from Thimerosal-containing vaccines and specific delays in development. A hypothesis-testing longitudinal cohort study (n=49,835) using medical records in the Vaccine Safety Datalink (VSD) was undertaken to evaluate the relationship between exposure to Hg from Thimerosal-containing hepatitis B vaccines (T-HBVs) administered at specific intervals in the first 6months of life and specific delays in development [International Classification of Disease, 9th revision (ICD-9): 315.xx] among children born between 1991 and 1994 and continuously enrolled from birth for at least 5.81years. Infants receiving increased Hg doses from T-HBVs administered within the first month, the first 2months, and the first 6months of life were significantly more likely to be diagnosed with specific delays in development than infants receiving no Hg doses from T-HBVs. During the decade in which T-HBVs were routinely recommended and administered to US infants (1991-2001), an estimated 0.5-1million additional US children were diagnosed with specific delays in development as a consequence of 25µg or 37.5µg organic Hg from T-HBVs administered within the first 6months of life. The resulting lifetime costs to the United States may exceed $1 trillion.

Soluble artifical tear inserts.

This article reports a new concept in the treatment of tear film abnormalities. Solubilization of an artifical tear insert provides a continuous flow of polymer into the tear film in place of intermittent drop therapy. The physiochemical properties of succinylated collagen were studied in vitro and compared favorably with presently available tear substitutes. The use of this polymer as a solid solubilizable insert was evaluated in normal patients. It was found to be comfortable, resulted in no blurring of vision, and prolonged the tear film breakup time.

Cianidanol ( [+]-cyanidanol-3) prevents the development of abdominal adhesions in rats.

Abdominal adhesions were experimentally induced in rats by gentle scraping. Severe adhesions developed in 38.7% of the control animals. The flavonoid cianidanol ( [+]-cyanidanol-3), an in vitro inhibitor of procollagen production, was administered intragastrically or intraperitoneally in doses of 9 to 72 mg per rat. Administered intraperitoneally at a dose of 36 or 72 mg per rat, cianidanol substantially inhibited adhesion formulation, when given immediately, three days, or five days after surgery. Oral administration of the drug was less effective in preventing the formation of adhesions. Thimerosal, another connective-tissue inhibitor, was found to be toxic at doses of 2.5 or 5 mg per rat, and its effect on the prevention of adhesion formation was poor. The ability of cianidanol to inhibit the development of abdominal adhesions in rats suggests that a possible approach to treatment is to inhibit the production of procollagen and thus prevent the formation of the collagenous fibers that are the cause of adhesions.

ADAPT-treated porcine valve tissue (cusp and wall) versus Medtronic Freestyle and Prima Plus: crosslink stability and calcification behavior in the subcutaneous rat model.

BACKGROUND AND AIM OF THE STUDY: The study aim was to compare the crosslink stability and calcification behavior of porcine tissue (cusp and wall), treated with a new antimineralization process (ADAPT) with that of commercially prepared Freestyle and Prima Plus bioprosthetic tissues. METHODS: Porcine aortic roots were divided into two groups: (i) tissue zero pressure-fixed with 0.625% glutaraldehyde (GA) for seven days and stored in 0.25% GA (as control); and (ii) tissue exposed to the ADAPT process for four days and stored in 0.25% buffered GA. These groups were compared with Freestyle and Prima Plus tissues (cusp and wall). Crosslink stability was assessed by shrinkage temperature and resistance to pronase degradation. Calcification behavior was assessed histologically (Von Kossa staining) and by atomic absorption spectrophotometry of explanted tissue after eight weeks. in a subcutaneous rat model. RESULTS: Crosslink stability and calcification potential of ADAPT-treated porcine valve cusps were comparable to those of Freestyle and Prima Plus cusps (p = NS). ADAPT-treated porcine wall tissue showed improved crosslink stability (p <0.05) and significantly (p <0.001) reduced calcification (-95.95%) compared to control (-0.00%), Freestyle (-47.87%) and Prima Plus (-51.95%) tissues. CONCLUSION: The ADAPT process is effective in reducing calcification in both porcine cusp and wall tissues in a subcutaneous rat model, and further suggest that enhanced crosslinking plays an important role in minimizing aortic wall calcification.

Effect of thimerosal concentration on the efficacy of inactivated Newcastle disease oil-emulsion vaccines.

Different quantities of the preservative thimerosal in inactivated Newcastle disease oil-emulsion vaccines were tested to determine the influence on the hemagglutination-inhibition (HI) response of broilers. The effect of thimerosal was measured in vaccines that had been stored for 1, 21, and 52 weeks; HI serology was conducted at 2, 4, and 6 weeks after vaccination. Mean HI titers 4 weeks after vaccination decreased at a significant rate (P less than or equal to 0.001) with increasing concentrations of thimerosal. HI titers 4 weeks after vaccination with 1-week-old vaccine were significantly (P less than or equal to 0.05) higher than those after vaccination with 52-week-old vaccine at all thimerosal concentrations tested. Titers were also significantly higher (P less than or equal to 0.05) after vaccination with 1-week-old vaccine than after vaccination with 21-week-old vaccine at all thimerosal concentrations below about 8.25 mg/ml of antigen. Thimerosal at the levels recommended in commercial vaccines does not significantly decrease vaccine efficacy.

Myringostomy for middle ear effusions. Results of a two-year study.

From 1972 to 1974, 736 children had tympanostomy tubes inserted for chronic serous otitis media resistant to medical therapy. The total number of ears involved was 2,237. The cleft palate patients constituted 8.8% of the total and had 15.4% of all procedures. Patients with allergy comprised 19% of the total population and had a higher incidence of otitis media following tube insertion. Adenoidectomy was performed in 44% of all patients and 35% of these required further tube insertions, suggesting that adenoidectomy in combination with tube insertion is not necessarily the primary treatment of choice. Children under six made up 78.5% of the total. The most common complication, a draining ear with an incidence of 15.1% was treated successfully with aqueous Merthiolate irrigations. There were 14 tympanic membrane perforations.

A comparison of two different formulations of diclofenac sodium 0.1% in the treatment of inflammation following cataract-intraocular lens surgery.

OBJECTIVE: To compare the efficacy, tolerability and local tolerance of diclofenac sodium 0.1% containing hydroxypropylgamma cyclodextrin preserved with benzalkonium chloride 0.005% (Voltaren Ophtha CD), with that of diclofenac sodium 0.1% preserved with thiomersal 0.004% (Voltaren Ophtha) in the treatment of inflammation after cataract-intraocular lens surgery. DESIGN AND SETTING: Randomised 2:1, double-masked, parallel-group study in six centres in Germany. STUDY PARTICIPANTS: 299 patients scheduled to undergo phacoemulsification with posterior chamber intraocular lens implantation. INTERVENTIONS: Study medications were instilled four times in the 30 minutes before surgery and four times daily from the first postoperative day. MAIN OUTCOME MEASURES: The key efficacy variable was the reduction in anterior chamber flare (photons/millisecond) from day 1 to day 6 to 8. Patients underwent comprehensive ocular examinations, including laser flaremetry (KOWA), preoperatively and postoperatively at days 1, 6 to 8 and 24 to 32. RESULTS: 268 patients (Voltaren Ophtha CD 177, Voltaren Ophtha 91) completed the day 6 to 8 visit without any protocol violations. Reduction in the degree of intraocular inflammation with Voltaren Ophtha CD was equivalent to that achieved with Voltaren Ophtha at the day 6 to 8 [95% confidence interval (CI) -3.07 to +0.54] and day 24 to 32 (95% CI -1.44 to +1.40) visits. Although there was no significant (p = 0.464) difference between the two study groups in patients' global assessment of local tolerance at day 24 to 32, ocular discomfort was significantly (p = 0.023) less with Voltaren Ophtha CD compared with Voltaren Ophtha. CONCLUSIONS: Voltaren Ophtha CD was as effective and well tolerated but had less ocular discomfort compared with Voltaren Ophtha in the treatment of ocular inflammation after phacoemulsification with intraocular lens implantation. This new formulation of diclofenac sodium 0.1% may be used as an alternative to the existing formulations of ophthalmic diclofenac sodium 0.1%.

Avian pox in birds of prey (order Falconiformes) in Bahrain.

Avian pox is an important disease in birds of prey in Bahrain. A live pigeon pox vaccine was administered to hunting falcons (Falco species) together with other therapeutic methods to arrest the development of primary stage pox lesions and for the treatment of well established secondary stage pox lesions. Quarantine and general hygiene procedures were also used as an integral part of the management and control of the disease.

[Otomycosis and topical application of thimerosal: study of 152 cases]. / Otomicosis y aplicación tópica de timerosal. Estudio de 152 casos.

PURPOSE: To evaluate the effectiveness of the topical application of Timerosal (merthilate tintura) in mycosis involving the external auditory canal. PATIENTS AND METHODS: The study includes 152 patients with the clinical, otoscopic and microscopic diagnosis of otomycosis. Results were assessed 72 hours and 10 days after the application. RESULTS: Bacteriological study was performed in 83 patients, finding Aspergilly niger in 54.0% of the cases, Candida albicans in 25.4%, Aspergillus fumigatus in 15.8% and Penicillium in 4.8%. Improvement at 72 h. was found in 66.4% and at 10 days in 93.4% of the patients. Bacteriological contamination was found in 6.6% of the total. COMMENTS: In most of the patients, the otomycosis healed after cleaning of the external auditory canal and topical application of timerosal. This method is easy to apply, fast, effective, of low cost and few side effects.