Drug-induced aseptic meningitis.

Aseptic meningitis is a rare but well-recognized complication of drug therapy. The clinical presentation of drug-induced aseptic meningitis (DIAM) is distinct. Symptoms typically include fever, neck stiffness, headache, confusion, nausea and vomiting. The major categories of causative agents are non-steroidal anti-inflammatory drugs, antimicrobials and also intravenous immunoglobulins, monoclonal antibodies and vaccines. These drugs most commonly implicated as causes of aseptic meningitis act more likely through an immunological mechanisms. However, the exact pathogenetic mechanism of DIAM is still unknown. The diagnosis of drug-induced aseptic meningitis is difficult and infectious etiologies must be excluded. In some cases the diagnosis has been confirmed by rechallenging the patient with the suspected agent. In this case, informed written consent is necessary and rechallenge must be medically supervised both to document the response and to offer medical care and advice, if required. The outcome of DIAM is generally good, usually without long term sequelae.

Beauvericin cytotoxicity to the invertebrate cell line SF-9.

The cyclic hexadepsipeptide beauvericin, initially known as a secondary metabolite produced by the entomopathogenic fungus Beauveria bassiana and toxic to Artemia salina larvae, has been more recently recognized as an important mycotoxin synthesized by a number of Fusarium strains, which parasite maize, wheat and rice. Therefore, this mycotoxin may enter the food chain, causing yet unknown effects to the health of both domestic animals and humans. The cytotoxic effects of beauvericin on mammalian cells have been studied. We investigated the cytotoxicity of this compound in an in vitro invertebrate model, viz. the insect cell line SF-9 (immortalized pupal ovarian cells of the lepidopter Spodoptera frugiperda). Cultures of SF-9 cells in the stationary phase were exposed to beauvericin at concentrations ranging from 100 nM to 300 microM, for different periods of time (from 30' to 120 h). The effects on cell viability were assessed by the trypan blue exclusion method. After 4 h of incubation no significant decrease in cell viability was recorded in SF-9 cell cultures exposed to low concentrations of beauvericin, i.e. 100 nM and 300 nM. However, a slight decrease in viability (3.9%) was seen already in cells exposed to the mycotoxin at the 1 microM concentration. This effect became gradually more evident at higher concentrations (approximately equal to 28% at 30 microM, approximately equal to 50% at 100 microM, approximately equal to 68% at 300 microM). An even more pronounced reduction in cell viability was observed after a 24 h exposure. Under these conditions, 1 microM beauvericin caused an approx. 10% decrease in the number of viable cells, which became more significant at higher concentrations approximately equal to 23% at 3 microM, approximately equal to 47% at 10 microM, approximately equal to 65% at 30 microM, approximately equal to 90% at 100 microM, approximately equal to 99% at 300 microM). Therefore, the 50% cytotoxic concentrations (CC50) at 4 h and 24 h could be estimated as 85 microM and 10 microM, respectively. In time-course experiments, no effect of beauvericin (30 microM) on cell viability could be seen after exposure for periods of time as long as 30', 1 h and 2 h, respectively. In contrast, when SF-9 cells were exposed to the mycotoxin for longer periods of time, from 8 h to 120 h, we recorded a strong cytotoxic effect already in the low micromolar concentration range. Thus, the CC50 after both 72 h and 120 h exposure times was assessed as 2.5 microM. Higher concentrations caused a virtually 100% cell death. The data collected suggest that beauvericin exerts a substantial dose- and time-dependent cytotoxic effect on invertebrate cells, comparable to the effects described in mammalian cells.

Reported latex allergy in dental patients.

OBJECTIVE: The purpose of this study was to alert doctors of dental surgery to the possibility of latex sensitivity in both outpatients and inpatients. STUDY DESIGN: The study involved 2 groups: group A was composed of 21 subjects with a history of immediate reaction in dental environment; group B was composed of 24 healthy individuals. Patients underwent skin prick tests with common inhalant allergens, with latex cross-reacting foods, with a commercial extract of non-ammoniated latex, and the incremental challenge test with local anesthetics. Specific IgE to latex and to latex cross-reacting foods were measured with the fluorescent enzyme immunoassay. RESULTS: All patients in group A and none in group B were latex-allergic. Subjects who were latex-allergic were significantly more likely to be atopic and had positive IgE test to cross-reactive foods. CONCLUSIONS: Dentists and people working in a dental surgery environment must obtain detailed patient history to help identify individuals at risk of latex allergy or those actually allergic to latex. If an allergy exists, equipment used should be made of alternative materials.

Short-term and long-term tolerability of rofecoxib in patients with prior reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Rofecoxib is a selective cyclooxygenase 2 (COX-2) inhibitor and is well tolerated as an alternative to nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with a previous adverse reaction to other classes of NSAIDs. Until now, there has not been information in the literature about its long-term tolerability. OBJECTIVE: To provide follow-up data on patients with a history of adverse cutaneous reactions to NSAIDs who underwent and tolerated a challenge test with rofecoxib. METHODS: Study patients had historically experienced cutaneous adverse reactions to aspirin and NSAIDs and had undergone single-blind challenges with rofecoxib, 25 mg. A questionnaire was distributed to all participants. In particular, they were asked to clarify any reactive symptoms they had developed after ingestion of the drug. All patients were reexamined 1 to 3 years after testing. At reexamination, they were carefully and personally interviewed using the previously distributed questionnaire. RESULTS: Of the 182 patients who participated in the study, none reacted to rofecoxib during single-blind challenges. Fifty-one (28%) never received rofecoxib again, whereas 131 (72%) were exposed to rofecoxib, often on multiple occasions. Only 7 (5%) of the 131 patients reported cutaneous reactions to rofecoxib during the 3 years of follow-up. CONCLUSIONS: Rofecoxib appears to be a safe alternative drug among atopic individuals, antibiotic-hypersensitive individuals, and individuals who experienced adverse cutaneous reactions to more than 1 class of NSAIDs, but it is less safe among chronic urticaria patients. Further investigations that include a larger sample are required to confirm our results especially among chronic urticaria patients.

Short-term tolerability of etoricoxib in patients with cutaneous hypersensitivity reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Etoricoxib is a novel cyclooxygenase 2 selective inhibitor. Until now, there has not been information in the literature about its tolerability in patients with a history of hypersensitivity reactions to nonsteroidal anti-inflammatory drugs (NSAIDs). OBJECTIVE: To determine the short-term tolerability of etoricoxib in patients with a history of cutaneous adverse reactions to NSAIDs. METHODS: Single-blind challenge testing was performed on 2 different days using placebo (talc) and etoricoxib. On the first day, 2 placebo capsules were administered 1 hour apart; 7 days later, each patient received divided doses of the total therapeutic dose of 90 mg of etoricoxib: 22.5 mg initially and 67.5 mg 1 hour later if no reactive symptoms were noted. RESULTS: Of 141 patients who underwent challenge testing with etoricoxib, only 2 (1.4%) had positive test results; both developed wheals on the extremities. These 2 patients were treated with chlorpheniramine maleate (10 mg intravenously), and the symptoms completely resolved within 2 hours. None of the patients experienced adverse reactions to the placebo challenge. CONCLUSION: The low rate of adverse reactions to etoricoxib, tested by oral challenge, suggests that patients with previous cutaneous hypersensitivity reactions to NSAIDs (primarily urticaria and angioedema) may tolerate this drug.

Cytokine/Chemokine HLDA8 Workshop panel report: analysis of receptors on lymphocytes from cord blood, normal and asthmatic subjects, and HIV positive patients.

Chemokines and cytokines are involved in many processes, both physiological and pathological, particularly the recruitment, differentiation, activation, and proliferation of immune cells taking part in ontogenesis, inflammation, and cancer. It was assumed that chemokines and cytokines receptors are expressed in a regulated manner by human lymphocytes during ontogeny and later on, under the environmental stimulation of antigens they contribute to organogenesis, angiogenesis, and tissue remodeling, as well as modulating leukocyte effector functions. Using monoclonal antibodies classified by the Cytokine/Chemokine section of the 8th International Workshop on Human Leukocyte Differentiation Antigens, we analyzed human lymphocytes in blood samples drawn from the umbilical cord, normal adults, allergic and non-allergic asthma patients, HIV infected, and AIDS positive subjects. The main differences noted between adult and cord blood lymphocytes were related to CCR7 and CXCR4 receptors, which were more strongly expressed on cord blood lymphocytes, confirming the important role of these chemokines during development of the immune system. As with the HIV, CXCR4, and CCR5 co-receptors, we found no differences in CXCR4 expression between HIV and AIDS patients. However CCR5 was more strongly expressed in AIDS patients, which is likely to be associated with the evolution of disease. Further studies are needed to gain a better understanding of the functions of these molecules in the underlying pathogenesis of many diseases and to probe the use of the chemokine receptors as targets for therapeutic intervention.

Systemic reactions to allergen immunotherapy: a review of the literature.

Since its introduction the safety of specific immunotherapy (SIT) was assessed by many well-designed studies. SIT is accepted as an effective treatment of allergic diseases despite the occurrence of side-effects, among which systemic reactions (SRs) are the most dangerous. The reported frequency of SRs after SIT varies among the studies and several factors influence it. Asthma is a particular risk factor for systemic side-effects. Furthermore, SRs occur more often in patients with high allergen sensitivity as determined by skin testing or RAST. Making dosage errors is also considered to be a high risk. It is reported that reactions are more common during rush and clustered induction treatment, whereas a significantly lower incidence of SRs occurred with the use of standardized modified allergen vaccines than with aqueous extracts. On the basis of valuable guidelines, precautions to minimize the risk of SRs from SIT were recommended. Injections should be given or supervised by doctors well-trained in this form of treatment in a clinic where there is the immediate availability of a resuscitative equipment. Consideration should be given to evaluate the patient's conditions and to monitor subjects for a minimum of 30 minutes after the injections. Therefore, if appropriately done, the risk of SIT is negligible.

Tolerability of rofecoxib in patients with cutaneous adverse reactions to nonsteroidal anti-inflammatory drugs.

BACKGROUND: Adverse reactions to nonsteroidal anti-inflammatory drugs (NSAIDs) are very common problems in clinical practice. Rofecoxib is a novel NSAID which selectively inhibits prostaglandin endoperoxide H synthase-2 and has no effect on prostaglandin endoperoxide H synthase-1. OBJECTIVE: To evaluate the tolerability of rofecoxib in NSAID-sensitive patients with cutaneous adverse reactions. PATIENTS AND METHODS: One hundred thirty-nine patients with NSAID-induced adverse reactions [60 urticaria alone (43.1%), 34 angioedema (24.5%), 34 angioedema plus urticaria (24.5%), 5 urticaria plus difficulty in breathing (3.6%), 4 maculopapular rush (2.9%), and 2 Stevens-Johnson syndrome (1.4%)] were submitted to a single-blind, placebo-controlled peroral challenge with increasing doses of rofecoxib. RESULTS: One hundred thirty-eight of 139 (99.3%) patients tolerated rofecoxib without adverse reactions; only one (0.7%) experienced weak urticaria localized at arms. CONCLUSIONS: Rofecoxib is a well tolerated drug in patients with NSAID cutaneous adverse reactions and it may represent a valid alternative drug in NSAID-sensitive patients.

Fig and mulberry cross-allergy.

BACKGROUND: Hypersensitivity reactions to ingestion of figs (Ficus carica) and mulberries (Morus nigra and Morus alba) are considered uncommon and have never been reported as occurring in the same patient. OBJECTIVE: To determine whether hypersensitivity to figs and mulberries can induce cross-allergy. METHODS: We describe 3 cases of associated fig and mulberry allergy in 3 patients with multiple sensitizations to food allergens (mostly fruit) and airborne allergens. The presence of specific IgE was investigated by skin prick tests and radioallergosorbent tests. RESULTS: The 3 patients had a convincing clinical history of food allergy caused by eating fresh figs, and in all 3 cases clinical and/or laboratory evidence of sensitization to mulberries was also collected. CONCLUSIONS: We reason that Ficus and Morus are closely related genera of the Moraceae family and speculate that hypersensitivity to figs and mulberries might be associated as the result of allergen cross-reactivity rather than mere coincidence.

Novel inhibitory effect on 5-lipoxygenase activity by the anti-asthma drug montelukast.

5-Lipoxygenase is the key enzyme in the biosynthesis of leukotrienes, powerful lipid mediators involved in inflammation, cell-cell communication, and other important physiological and pathological conditions. Particularly, cysteinyl-leukotrienes have been recognized as playing a significant role in the pathophysiology of asthma and potent and effective Cys-LT1 receptor antagonists have been developed for the treatment of this illness. Here we report that montelukast, a structural Cys-LT1 receptor antagonist, also exerts a substantial and apparently direct inhibitory effect on 5-lipoxygenase activity in vitro, at concentrations in the lower micromolar range, which are of potential therapeutic relevance. Thus, when human mast cells HMC-1 were stimulated with the Ca ionophore A23187 in the presence of montelukast (up to 100 microM) a substantial decline in 5-lipoxygenase biosynthesis was observed. Similar results were obtained in the rat mast cell-like RBL-1 cell model (IC50 congruent with 2.5 microM) and in human polymorphonuclear leukocytes. Moreover, montelukast directly inhibited human recombinant 5-lipoxygenase. Kinetic experiments revealed that the inhibition was of the non-competitive type, suggesting that montelukast binds a yet undefined allosteric site on 5-lipoxygenase. 5-Lipoxygenase inhibition by montelukast appears to be highly selective since the drug had no effects on other enzymes of the leukotriene cascade, viz. LTC4 synthase and LTA hydrolase.

Occupational irritant and allergic contact dermatitis among healthcare workers.

Contact dermatitis is the most frequent occupational dermatosis and non-specific irritants in addition to specific Type IV sensitization are involved. We reviewed our database for data from 1994 to 1998 and selected 360 consecutive patients working in healthcare environments and experiencing contact dermatitis at their hands, wrists and forearms. We found that allergic contact dermatitis and irritant contact dermatitis were considered to be work-related in 16.5% (72/436) and 44.4% (194/436) of diagnoses, respectively. Occupational irritant contact dermatitis is due to exposure to a wide range of irritants in the workplace, such as soaps, solvents, cleansers and protective gloves, which conspire to remove the surface lipid layer and/or produce cellular damage. In this study the major relevant aetiological agents that induced occupational allergic contact dermatitis were: nickel sulphate (41 patch positivities), components of disinfectants [glutaraldehyde (5) and benzalkonium chloride (7)] and rubber chemicals [thiuram mix (15), carba mix (9) and tetramethylthiuram monosulphide (6)]. The best treatment for allergic contact dermatitis is to avoid those allergens causing the rash. Whenever this is not possible, contact with them needs to be reduced using properly selected protective gloves. Finally, subjects with atopic dermatitis should avoid 'wet work' and contact with irritants, because atopic dermatitis is significantly associated with irritant contact dermatitis.

Atopy and risk factors for latex sensitization in a selected population.

The value of recommending latex allergy screening in allergy departments of the Army's Hospital was studied. The purpose of the study was to evaluate whether atopy was a risk factor for latex sensitization in a specific population such as the young male soldiers of the Italian Army. The study was also aimed to assess the role of other risk factors. One thousand five hundred male subjects (1000 subjects who were atopic and 500 subjects who were nonatopic), visiting the Department of Allergology and Respiratory Physiopathology of the Army's Hospital in Bari, Italy, were enrolled into the study. The protocol included a questionnaire (symptoms of atopy, use of latex gloves and condoms and possible reactions previous surgical procedures), a clinical examination, a skin-prick test to latex and common allergens to evaluate atopy, and in part a latex challenge. Among the 1000 subjects who were atopic, 2.8% had evidence for sensitization to latex compared with 1.2% in the 500 subjects in the nonatopic group. The risk of latex sensitization was 19 times higher for subjects with a history of reactions to latex exposure and had a twofold increase for each surgical procedure and for each skin test positivity for inhalant allergens. Another risk factor was positivity to skin-prick tests for Artemisia vulgaris, cypress, and molds. Atopy significantly relates to an increased risk of latex sensitization. Screening is recommended in the Army's Hospital to identify latex-sensitized subjects and inform them about the risks connected with this condition.

Cytotoxic effects of the mycotoxin beauvericin to human cell lines of myeloid origin.

Beauvericin, a cyclic hexadepsipeptide of potential importance to the health of humans and domestic animals, has been reported to exert cytotoxic effects on several mammalian cell types and to induce apoptosis. We investigated the cytotoxicity of this compound to two human cell lines of myeloid origin: the monocytic lymphoma cells U-937 and the promyelocytic leukemia cells HL-60. In some experiments HL-60 cells partially differentiated towards the eosinophilic phenotype were also used. Cultures of U-937 cells and HL-60 cells in stationary phase were exposed to beauvericin at concentrations ranging from 100 nM to 300 microM for periods of time of 4 and 24h, respectively. The effects of beauvericin on cell viability were assessed by the Trypan blue exclusion method. In another set of experiments, performed with U-937 cells, the mycotoxin was included in the culture medium at passaging, in order to assess its possible effects on cell growth. Viability of both U-937 cells and HL-60 cells was not affected by beauvericin at concentrations up to 3 microM, after 4h exposure, whereas a steady decline was seen at higher concentrations. Similarly, after an exposure time of 24h, a decline in viability was observed in cultures exposed to beauvericin at a concentration of 10 microM or higher. Thus, 50% cytotoxic concentrations at 24h of congruent with 30 microM and congruent with 15 microM were estimated for U-937 cells and HL-60 cells, respectively.Similar experiments were performed with cultures of HL-60 cells partially differentiated towards the eosinophilic phenotype, revealing that, in 4h exposure experiments (but not in 24h experiments), the viability of these cultures underwent a significantly less pronounced decline, in comparison to undifferentiated HL-60 cultures. Interestingly, when U-937 cells were allowed to proliferate in the presence of the mycotoxin, included in the culture medium at passaging, a substantial cytotoxicity was observed at lower concentrations, compared with prevalently resting, stationary phase cultures. Accordingly, a definite inhibition of the proliferative capability of the cells was detected. The information provided by this work may be useful in selecting appropriate myeloid cell models for the development of biossays aimed at detecting beauvericin (and, possibly, other mycotoxins) in foods and other commodities.

Role of cytokines in gonarthrosis and knee prosthesis aseptic loosening.

Cytokines, which have been demonstrated in synovial fluids during various joint diseases, play an important role in mediating synovial inflammation and in regulating the immune response of many inflammatory processes. We studied synovial fluid, serum, and synovial fragments obtained from 33 patients--10 affected by serious gonarthrosis re-quiring a prosthetic implant, 8 with knee prosthesis aseptic loosening, and (as controls) 15 affected by degenerative meniscopathies--to evaluate the degree of inflammation and level of interleukins (IL-2, IL-4, IL-6, IL-10) and interferon gamma secretion. Histological analysis revealed slightly more infiltration by inflammatory cells in the synovial tissue of patients with gonarthrosis and knee prosthesis aseptic loosening than in that of the control group, with a high prevalence of macrophages. Moreover, we observed enhanced production of the studied cytokines, especially in synovial fluid as compared to serum, indicating that in the pathological conditions examined the inflammatory events are mainly localized. Because the role of these cytokines is to modulate inflammation, better knowledge of the involvement of cells and their soluble mediators in articular damage could guide immunomodulating treatment.