Accelerator-free gloves as alternatives in cases of glove allergy in healthcare workers.

BACKGROUND: Accelerators in rubber gloves constitute an important group of contact allergens, particularly in healthcare workers. OBJECTIVES: To assess the efficacy of accelerator-free medical gloves in the secondary prevention of allergic contact dermatitis caused by rubber accelerators in healthcare workers. METHODS: Nine healthcare workers with hand eczema were advised to use accelerator-free rubber gloves after a diagnosis of allergic contact dermatitis caused by rubber accelerators. RESULTS: Switching from conventional medical single-use gloves containing accelerators to accelerator-free medical gloves led to improvement in all cases, and more than two-thirds of the patients were completely free of symptoms. CONCLUSION: The use of accelerator-free medical gloves can be an effective alternative in healthcare workers who are allergic to rubber accelerators.

Rubber: new allergens and preventive measures.

Natural rubber latex (NRL) and rubber accelerators are well-known causes of occupational skin diseases. The latest epidemiological data on rubber allergy show that rubber additives are still among the allergens most strongly associated with occupational contact dermatitis, however, a decrease in NRL allergy has been confirmed. A review of recent publications on rubber allergens based on the Pubmed database is presented. New glove manufacturing processes have been developed, such as low-protein natural rubber gloves, vulcanisation accelerator-free gloves, or specific-purpose gloves containing antimicrobial agents or moisturisers. Several websites provide information on allergens found in gloves and/or glove choice according to occupation.

Cellular peptidyl-prolyl cis/trans isomerase Pin1 facilitates replication of feline coronavirus.

Although feline coronavirus (FCoV) causes feline infectious peritonitis (FIP), which is a fatal infectious disease, there are no effective therapeutic medicines or vaccines. Previously, in vitro studies have shown that cyclosporin (CsA) and FK506 inhibit virus replication in diverse coronaviruses. CsA and FK506 are targets of clinically relevant immunosuppressive drugs and bind to cellular cyclophilins (Cyps) or FK506 binding proteins (FKBPs), respectively. Both Cyp and FKBP have peptidyl-prolyl cis-trans isomerase (PPIase) activity. However, protein interacting with NIMA (Pin1), a member of the parvulin subfamily of PPIases that differs from Cyps and FKBPs, is essential for various signaling pathways. Here we demonstrated that genetic silencing or knockout of Pin1 resulted in decreased FCoV replication in vitro. Dipentamethylene thiuram monosulfide, a specific inhibitor of Pin1, inhibited FCoV replication. These data indicate that Pin1 modulates FCoV propagation.

Pin1 inhibitors: Pitfalls, progress and cellular pharmacology.

Compelling data supports the hypothesis that Pin1 inhibitors will be useful for the therapy of cancer: Pin1 deficient mice resist the induction of breast cancers normally evoked by expression of MMTV-driven Ras or Erb2 alleles. While Pin1 poses challenges for drug discovery, several groups have identified potent antagonists by structure based drug design, significant progress has been made designing peptidic inhibitors and a number of natural products have been found that blockade Pin1, notably epigallocatchechin gallate (EGCG), a major flavonoid in green tea. Here we critically discuss the modes of action and likely specificity of these compounds, concluding that a suitable chemical biology tool for probing the function of Pin1 has yet to be found. We conclude by outlining some open questions regarding the target validation of Pin1 and the prospects for identification of improved inhibitors in the future.

Dipentamethylene thiuram monosulfide is a novel inhibitor of Pin1.

Pin1 is involved in eukaryotic cell proliferation by changing the structure and function of phosphorylated proteins. PiB, the Pin1 specific inhibitor, blocks cancer cell proliferation. However, low solubility of PiB in DMSO has limited studies of its effectiveness. We screened for additional Pin1 inhibitors and identified the DMSO-soluble compound dipentamethylene thiuram monosulfide (DTM) that inhibits Pin1 activity with an EC50 value of 4.1 microM. Molecular modeling and enzyme kinetic analysis indicated that DTM competitively inhibits Pin1 activity, with a K(i) value of 0.05 microM. The K(D) value of DTM with Pin1 was determined to be 0.06 microM by SPR technology. Moreover, DTM specifically inhibited peptidyl-prolyl cis/trans isomerase activity in HeLa cells. FACS analysis showed that DTM induced G0 arrest of the HCT116 cells. Our results suggest that DTM has the potential to guide the development of novel antifungal and/or anticancer drugs.

Prevalence of type I allergy to natural rubber latex and type IV allergy to latex and rubber additives in operating room staff with glove-related symptoms.

There is lack of data on the prevalence of latex allergy in the health care setting in Iran. This study was performed to determine the prevalence of type I latex allergy and type IV allergy to latex and rubber additives among the operating room staff with glove-related symptoms in 13 general hospitals in Tehran. Skin-prick tests with commercial latex extract, patch tests with latex and 25 rubber additive series, and total and latex-specific IgE detection were performed on the operating room staff who reported latex glove-related symptoms. Five hundred twelve self-administered questionnaires (100%) were completed by all operating room staff and latex glove-related symptoms were reported by 59 (11.5%) employees. Among all symptomatic operating room staff tested, the prevalence of type I latex allergy was 30.5% and the prevalence rates of type IV allergy to latex and rubber additives were 16.7 and 14.6%, respectively. The most positive patch test result with rubber additives was related to tetramethylthiuram monosulfide (38.5%). The risk factors for type I latex allergy were female sex (p = 0.009) and positive patch test with rubber additives (p = 0.012). Subjects who had positive patch test with latex were significantly more likely to have positive patch test with rubber additives (p < 0.0001). Our results showed a high prevalence of type I latex allergy and type IV allergy to latex and rubber additives. Based on this study, we recommend eliminating powdered latex gloves from the operating rooms of the 13 studied general hospitals and support the substitution of powder-free latex gloves.

Contact allergy and exposure patterns to thiurams and carbamates in consecutive patients.

Sensitization to rubber is most often due to sensitization to thiurams. Positive patch test reactions to carbamates are less frequent, and usually only diagnosed in patients with positive patch test reactions to thiurams as well. The aim of the present study was to describe the relative frequency of sensitization to thiuram mix (TH mix) and zinc diethyldithiocarbamate (ZDC) in a population where the exposure to these chemicals from rubber gloves was previously studied and considered to be of approximately the same order of magnitude. The thiuram derivatives seemed to be the most important sensitized (frequency 2.8%) compared to ZDC (frequency 0.5%), which has been the most frequently reported sensitizer among the carbamates in rubber gloves. An interesting observation was that the probability that the patient was reacting to ZDC was strongly associated with the strength of the patch test reaction to TH mix. This observation may add a new aspect to the discussion about cross-reactivity versus concomitant sensitization of thiurams and carbamates.

Elicitation thresholds for thiuram mix using petrolatum and ethanol/sweat as vehicles.

An estimate of amounts of thiurams that may be released from rubber gloves into synthetic sweat, has previously been generated. These amounts should be compared to elicitation thresholds of patch tests performed with serial dilutions of thiuram mix using synthetic sweat as vehicle. Because of solubility properties of thiurams in aqueous media, such dilutions cannot directly be prepared. In this study, a stem solution was prepared in ethanol. This solution was then further diluted with synthetic sweat. Thiuram mix 0.5 w/v% was the most concentrated solution in ethanol achievable. The patch test reactions were compared to reactions to serial dilutions using petrolatum as vehicle. The experiment revealed that endpoint dilution with synthetic sweat was not achieved in this study. The threshold for elicitation of positive patch test reactions seemed to be lower for ethanol/sweat as vehicle compared to petrolatum: 32% reacted to ethanol/synthetic sweat 0.001 mg/cm2 compared to 14% reacting to thiuram in pet. 0.002 mg/cm2. Based on these results, synthetic sweat may be considered a more relevant medium for threshold finding studies than petrolatum. Because of expected instability of the aqueous solutions, petrolatum is probably a more suitable vehicle for routine testing. The study does not permit final conclusions concerning acceptable thresholds for leachable thiurams in rubber gloves, but it is likely that an acceptable threshold would be substantially less than 0.001 mg/ cm2.

Evaluation of contact sensitivity to formaldehyde and tetramethylthiuram monosulfide using a modified lymphocyte transformation test.

To examine the validity of a modified lymphocyte transformation test for evaluating contact hypersensitivity from weak sensitizers, guinea pigs were sensitized with formaldehyde (F) or tetramethylthiuram monosulfide (TMTM) using the maximization test procedure. Lymph node cells from the animals were then cultured with F or TMTM, in the presence or absence of epidermal cells (EC). Transformed lymphocyte counts were evaluated by uptake of 3H-thymidine. Nonsensitized guinea pigs were used as controls. The lymphocytes from sensitized guinea pigs showed stronger blastogenesis when cultured with F or TMTM in the presence of EC than when the sensitizers were not added to the culture and the response depended on the concentration of F or TMTM. Cultures in the absence of EC also showed significant enhancement of blastogenesis by F or TMTM, but the responses were significantly weaker than those in the presence of EC. Lymphocytes from the control animals did not show significantly enhanced blastogenesis in response to F or TMTM, even when EC was added to the cultures. The results suggested that contact sensitivity for weak sensitizers can be evaluated by this modified lymphocyte transformation test, especially when lymph node cells were co-cultured with EC.

Lymphocyte transformation and thiuram sensitization.

The use of a lymphocyte transformation test (LTT) to confirm allergic contact dermatitis from thiurams has been investigated. The responses of peripheral blood mononuclear cells (PBMC) from thiuram-sensitive and non-sensitive individuals following culture with dimethylcarbamoyl-protein (human serum albumin; HSA) and dimethylthiocarbamoyl-HSA conjugates has been compared. Only PBMC from those patients who were patch-test-positive with thiuram-mix and sensitized to tetramethylthiuram monosulphide (TMTM) or TMTM and tetramethylthiuram disulphide (TMTD) exhibited significant proliferative responses to these conjugates. Thiuram-patch-test-negative patients and control donors with no history of allergic contact dermatitis failed to mount a significant response to any concentration of either conjugate. Two of the thiuram-sensitive patients were also nickel-patch-test-positive, and PBMC isolated from these donors, but not from nickel-patch-test-negative patients, proved positive in a nickel LTT. The data reveal that relevant hapten-protein conjugates are capable of provoking specific human lymphocyte proliferative responses in vitro, and that, using this technique, the LTT can, in principle, be used for the investigation and/or diagnosis of skin sensitization to lipophilic contact allergens.

Allergic contact dermatitis due to rubber chemicals in haemodialysis equipment.

6 of 80 haemodialysed patients developed a sub-acute eczematous dermatitis of the area surrounding the arteriovenous shunt in the forearm. Patch tests were positive to rubber chemicals: 6 patients reacted to the thiuram group, 4 of them also to carba compounds. Since the equipment contained only small pieces of rubber, the cause of the allergy remains obscure. It is possible that allergy was caused by short and intermittent contact of the skin with the rubber gloves used by the nursing personnel.

Activities of hepatic epoxide hydrolase and glutathione S-transferase in rats under the influence of tetramethyl thiuramdisulfide, tetramethyl thiurammonosulfide or dimethyl dithiocarbamate.

The epoxide hydrolase (EH) activity in the liver of adult female Wistar rats significantly increased 18 h after the administration by gavage of tetramethyl thiuramdisulfide (TMTD, 1 mmol/kg) or tetramethyl thiurammonosulfide (TMTM, 2 mmol/kg). No increase was observed 5 h after administration of Na-dimethyl dithiocarbamate (Na-DMDTC, 4 mmol/kg). The glutathione S-transferase (GST) activity in the cytosol and microsomes of the liver was slightly enhanced after oral (gavage) administration of TMTD, TMTM or Na-DMDTC (doses up to 4 mmol/kg). In vitro, TMTD, TMTM, and Na-DMDTC significantly enhanced the hepatic activity of EH prepared from adult female Wistar rats. Cytosolic and microsomal GST activities from the liver were significantly raised in vitro by Na-DMDTC. The results have a bearing on the evaluation of the risk to health of these chemicals in the workplace.

Enzyme inhibition as a possible mechanism of the mutagenicity of dithiocarbamic acid derivatives in Salmonella typhimurium.

In recent years data have accumulated regarding genotoxic properties of dithiocarbamic acid derivatives. The results from the present work indicate that the mutagenicity of these compounds depends on an indirect effect via oxygen radicals. Mutagenicity of tetramethylthiuram disulfide ( TMTD ), that was used as a model substance, was established with both frameshift and base substitution sensitive strains of Salmonella typhimurium. Addition of copper ions resulted in a decreased survival at low dithiocarbamate doses. The dose response curves seem to correlate with the formation of two types of metal dithiocarbamate complexes. At low doses charged complexes are formed, while the formation of uncharged complexes is favoured at higher dosages. The data suggest that this formation of uncharged metal complexes implies a decreased toxicity but at the same time an increased mutagenicity. The mutagenicity of both TMTD and its ethyl analogue TETD was enhanced by oxygen. Furthermore, TMTD potentiates the mutagenic action of menadione, a substance that produces O(2) and H2O2 by redox cycling with molecular oxygen. Interaction of uncharged metal dithiocarbamate complexes with both production and detoxification of reactive forms of oxygen is suggested to be responsible for the direct mutagenic effects via oxidative damage to DNA. A further enhancement of the oxygen radical content of the cells by adding microsomes that produce oxygen radicals via autoxidation of cytochrome P-450 is proposed as the mechanism for the 'metabolic activation of TMTD '.

Blood acetaldehyde levels in alcohol-dosed rats after treatment with ANIT, ANTU, dithiocarbamate derivatives, or cyanamide.

In adult female Wistar rats, pretreated by gavage with two doses - 16 or 256 mumol/kg - of cyanamide, TMTD (tetramethylthiuram disulfide), TMTM (tetramethylthiuram monosulfide), Ziram or Zineb at 90 min or 18 h before administration of 2 g of ethanol/kg i.p., the blood acetaldehyde levels were significantly increased for 90 - 240 min after ethanol administration (exceptions were noted after exposure to Zineb for 90 min or to low-dosed cyanamide for 18 h). After pretreatment for identical periods with ANTU (N-1-naphthylthiourea) or ANIT (1-naphthylisothiocyanate) at doses extending into the LD50 range, the blood acetaldehyde levels of rats given the same dose of ethanol remained uninfluenced. The increase in blood acetaldehyde recorded after 16 mumol/kg p.o. of TMTM and TMTD remained detectable for up to 48 h. Onset of the cyanamide action occurred already after 45 min. While recognizing that results from animal experiments cannot be transposed without restriction to the human situation, it is concluded that occupational contacts with ANTU or ANIT are not likely to elicit increased blood acetaldehyde levels in man after ingestion of alcohol. The risk of an ethanol intolerance reaction due to a rise in blood acetaldehyde therefore does not appear to be warranted. The present findings indicate, however, that exposure to TMTD, TMTM, Ziram, Zineb or cyanamide is associated with a definite health risk; because of the long persistence of these substances in the body, the risk exists for a long time post-exposure.