Mutations in SELENBP1, encoding a novel human methanethiol oxidase, cause extraoral halitosis.

Selenium-binding protein 1 (SELENBP1) has been associated with several cancers, although its exact role is unknown. We show that SELENBP1 is a methanethiol oxidase (MTO), related to the MTO in methylotrophic bacteria, that converts methanethiol to H2O2, formaldehyde, and H2S, an activity not previously known to exist in humans. We identified mutations in SELENBP1 in five patients with cabbage-like breath odor. The malodor was attributable to high levels of methanethiol and dimethylsulfide, the main odorous compounds in their breath. Elevated urinary excretion of dimethylsulfoxide was associated with MTO deficiency. Patient fibroblasts had low SELENBP1 protein levels and were deficient in MTO enzymatic activity; these effects were reversed by lentivirus-mediated expression of wild-type SELENBP1. Selenbp1-knockout mice showed biochemical characteristics similar to those in humans. Our data reveal a potentially frequent inborn error of metabolism that results from MTO deficiency and leads to a malodor syndrome.

[Halitosis management by the general dental practitioner- results of an International Consensus Workshop*]. / Halitosismanagement für die Zahnarztpraxis. Ergebnisse eines internationalen Konsunsus-Workshops*.

Clinical investigations on patients suffering from halitosis clearly reveal that in the vast majority of cases the source for an offensive breath odor can be found within the oral cavity (90%). Based on these studies, the main sources for intra-oral halitosis where tongue coating, gingivitis/periodontitis and a combination of the two. Thus, it is perfectly logical that general dental practitioners (GDPs) should be able to manage intra-oral halitosis under the conditions found in a normal dental practice. However, GDPs who are interested in diagnosing and treating halitosis are challenged to incorporate scientifically based strategies for use in their clinics. Therefore, the present paper summarizes the results of a consensus workshop of international authorities held with the aim to reach a consensus on general guidelines on how to assess and diagnose patients’ breath odor concerns and general guidelines on regimens for the treatment of halitosis.

The short-term treatment effects on the microbiota at the dorsum of the tongue in intra-oral halitosis patients--a randomized clinical trial.

OBJECTIVES: This study aims to assess the effects of rinsing with zinc- and chlorhexidine-containing mouth rinse with or without adjunct tongue scraping on volatile sulfur compounds (VSCs) in breath air, and the microbiota at the dorsum of the tongue. MATERIAL AND METHODS: A randomized single-masked controlled clinical trial with a cross-over study design over 14 days including 21 subjects was performed. Bacterial samples from the dorsum of the tongue were assayed by checkerboard DNA-DNA hybridization. RESULTS: No halitosis (identified by VSC assessments) at day 14 was identified in 12/21 subjects with active rinse alone, in 10/21 with adjunct use of tongue scraper, in 1/21 for negative control rinse alone, and in 3/21 in the control and tongue scraping sequence. At day 14, significantly lower counts were identified only in the active rinse sequence (p < 0.001) for 15/78 species including, Fusobacterium sp., Porphyromonas gingivalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Tannerella forsythia. A decrease in bacteria from baseline to day 14 was found in successfully treated subjects for 9/74 species including: P. gingivalis, Prevotella melaninogenica, S. aureus, and Treponema denticola. Baseline VSC scores were correlated with several bacterial species. The use of a tongue scraper combined with active rinse did not change the levels of VSC compared to rinsing alone. CONCLUSIONS: VSC scores were not associated with bacterial counts in samples taken from the dorsum of the tongue. The active rinse alone containing zinc and chlorhexidine had effects on intra-oral halitosis and reduced bacterial counts of species associated with malodor. Tongue scraping provided no beneficial effects on the microbiota studied. CLINICAL RELEVANCE: Periodontally healthy subjects with intra-oral halitosis benefit from daily rinsing with zinc- and chlorhexidine-containing mouth rinse.

Halitosis in cystinosis patients after administration of immediate-release cysteamine bitartrate compared to delayed-release cysteamine bitartrate.

Halitosis due to dimethylsulfide (DMS) generation is a major side effect of cysteamine in the treatment of cystinosis. Recently, an enteric coated formulation of cysteamine bitartrate (RP103) administered twice daily was demonstrated to be non-inferior for lowering WBC cystine levels compared to the non-enteric coated formulation (Cystagon®), administered 4 times per day. Since both formulations had different pharmacokinetic profiles, we compared DMS breath levels after administration of either RP103 or Cystagon® in four cystinosis patients. Although cysteamine areas under the curve (AUCs) were comparable, AUC of DMS was lower after the administration of RP103 compared to Cystagon®. This observation is of importance in cystinosis patients, since halitosis hampers compliance with cysteamine therapy.

Standardization of clinical protocols in oral malodor research.

The objective of this study is to standardize protocols for clinical research into oral malodor caused by volatile sulfur compounds (VSCs). To detect VSCs, a gas chromatograph (GC) using a flame photometric detector equipped with a bandpass filter (at 393 nm) is the gold standard (sensitivity: 5 × 10(-11) gS s(-1)). The baselines of VSC concentrations in mouth air varied considerably over a week. When the subjects refrained from eating, drinking and oral hygiene including mouth rinsing, the VSC concentrations remained constant until eating. Over a 6 h period after a meal, VSC concentrations decreased dramatically (p < 0.01). These results point to optimal times and conditions for sampling subjects. Several portable devices were compared with the measurements by the GCs. Portable GCs demonstrated capabilities similar to those of the GCs. We also applied the recommended protocols described below to clinical research testing the efficacy of ZnCl(2) products, and confirmed that using the recommended protocols in a randomized crossover design would provide very clear results. Proposed protocols include: (a) a short-term study rather than a long-term study is strongly recommended, since the VSC concentrations are constant in the short term; (b) a crossover study would be the best design to avoid the effects of individual specificities on each clinical intervention; (c) measurements of VSCs should preferably be carried out using either a GC or portable GCs.

Comparison of different treatment modalities for oral halitosis.

OBJECTIVES: To assess the effects on intra-oral halitosis by a mouth rinse containing zinc acetate (0.3%) and chlorhexidine diacetate (0.025%) with and without adjunct tongue scraping. MATERIALS AND METHODS: Twenty-one subjects without a diagnosis of periodontitis were randomized in a cross-over clinical trial. Organoleptic scores (OLS) were assessed to define intra-oral halitosis by total volatile sulfur compound (T-VSC) measurements and by gas chromatography. RESULTS: Twenty-one subjects with a mean age of 45.7 years (SD: ±13.3, range: 21-66). The OLS were significantly lower following active rinse combined with tongue scraping (p < 0.001) at all time points. Immediately after, at 30 min, and at day 14, the T-VSC values were lower in the active rinse sequence than in the negative rinse sequence (p < 0.001, p < 0.001 and p < 0.05, respectively). At 30 min and at day 14, the hydrogen sulfide (H(2)S) and methyl mercaptan (MM) values were lower in the active rinse sequence compared to the inactive rinse sequence (p < 0.001). The inactive rinse sequence with tongue scraping reduced T-VSC at 30 min (p < 0.001) but not at 14 days. Similar reductions in T-VSC, H(2)S and MM were found in the active rinse sequence with or without tongue scraping. CONCLUSION: The use of a tongue scraper did not provide additional benefits to the active mouth rinse, but reduced OLS and tongue coating index.

Volatile sulphur compounds in morning breath of human volunteers.

OBJECTIVE: morning breath contains elevated concentrations of volatile sulphur components (VSCs). Therefore, morning breath is recognised as a surrogate target for interventions on breath quality. Nevertheless, factors influencing morning breath are poorly understood. Our aim was to evaluate concentrations of VSC at the time of awakening. METHODS: a procedure was developed to collect breath samples at home. Intra- and inter-person variations were determined in two small studies based on measurements of hydrogen sulphide, methyl mercaptan and dimethyl sulphide in healthy volunteers. RESULTS: highest levels of VSC were found directly after waking up, followed by a significant decline afterward. Considerable day-to-day variation was found, but could not be linked to dietary intake. A significantly higher concentration of H(2)S and CH(3)SH was observed in the group of female subjects compared to males. CONCLUSIONS: when morning breath is used as a target for interventions, breath collected at the time of or shortly after waking up is preferred over breath collected later during the morning. Gender plays an important role in VSC levels, and should be taken into account.

Measurement and biological significance of the volatile sulfur compounds hydrogen sulfide, methanethiol and dimethyl sulfide in various biological matrices.

This review deals with the measurement of the volatile sulfur compounds hydrogen sulfide, methanethiol and dimethyl sulfide in various biological matrices of rats and humans (blood, serum, tissues, urine, breath, feces and flatus). Hydrogen sulfide and methanethiol both contain the active thiol (-SH) group and appear in the free gaseous form, in the acid-labile form and in the dithiothreitol-labile form. Dimethyl sulfide is a neutral molecule and exists only in the free form. The foul odor of these sulfur volatiles is a striking characteristic and plays a major role in bad breath, feces and flatus. Because sulfur is a biologically active element, the biological significance of the sulfur volatiles are also highlighted. Despite its highly toxic properties, hydrogen sulfide has been lately recommended to become the third gasotransmitter, next to nitric oxide and carbon monoxide, based on high concentration found in healthy tissues, such as blood and brain. However, there is much doubt about the reliability of the assay methods used. Many artifacts in the sulfide assays exist. The methods to detect the various forms of hydrogen sulfide are critically reviewed and compared with findings of our group. Recent findings that free gaseous hydrogen sulfide is absent in whole blood urged the need to revisit its role as a blood-borne signaling molecule.

Intra- and extra-oral halitosis: finding of a new form of extra-oral blood-borne halitosis caused by dimethyl sulphide.

AIM: The aim of this study was to unravel the origen and cause of intra-oral and extra-oral halitosis. MATERIAL AND METHODS: We studied 58 patients complaining of halitosis, using gas chromatography of volatile sulphur compounds (VSCs) in mouth and nose breath, organoleptic scoring of mouth and nose breath, Halimeter readings of mouth air and tongue-coating inspection. Subjects had no precence or history of periodontitis. RESULT: Of 58 patients, 47 patients had halitosis of oral origin, six had halitosis of extra-oral origin and five had no halitosis (halitophobia). A strong correlation was found between the degree of intra-oral halitosis as measured by organoleptic scoring of mouth breath and the concentration of the VSCs hydrogen sulphide (H(2)S) and methyl mercaptan (CH(3)SH) in mouth breath. Taking into account the much larger odour index of CH(3)SH, it was concluded that CH(3)SH is the main contributor to intra-oral halitosis. In all six cases of extra-oral halitosis, halitosis was caused by the presence of elevated levels of dimethyl sulphide (CH(3)SCH(3)) in mouth and nose breath. CONCLUSION: Our study provides evidence that the VSC, CH(3)SH and to a lesser extent H(2)S are the main contributors to intra-oral halitosis and that CH(3)SCH(3) is the main contributor to extra-oral or blood-borne halitosis, due to a hitherto unknown metabolic disorder.

The origin of halitosis in cystinotic patients due to cysteamine treatment.

INTRODUCTION: Cystinosis is a rare autosomal recessive disorder characterized by the intralysosomal accumulation of cystine. Cysteamine removes cystine from the lysosome and slows down the progression of the disease. One of its side effects is the induction of halitosis, which can interfere with patients' willingness to comply with cysteamine treatment. OBJECTIVE: To identify breath sulphur compounds causing halitosis induced by cysteamine therapy in patients with cystinosis. STUDY DESIGN: After the ingestion of 15mg/kg cysteamine whole blood (n=4), urine (n=4) and breath (n=8) volatile sulphur compounds levels were measured every 60min over a 360min period by gas chromatography and the cysteamine plasma concentrations (n=4) were measured by high-performance liquid chromatography. RESULTS: The expired air of cystinotic patients contained elevated concentrations of methanethiol (MT, median maximum value 0.5 (range 0-11)nmol/L) and, in particular, dimethylsulphide (DMS, median maximum value 15 (range 2-83)nmol/L). DMS concentrations higher than 0.65nmol/L are known to cause halitosis. Maximal plasma values of cysteamine (median 46 (range 30-52)micromol/L) preceded those of MT and DMS, confirming that cysteamine is converted to MT and DMS. Less than 3% of the amount of cysteamine ingested was excreted as MT and DMS via expired air and 0.002% via urine. CONCLUSION: Halitosis induced by cysteamine intake is caused by DMS and to a lesser extent by MT, excreted via the expired air. Further studies should focus on the possibilities of reducing the formation of these volatile sulphur compounds or masking their odour, which would improve the rates of compliance with cysteamine treatment.

Dimethyl sulfone in human cerebrospinal fluid and blood plasma confirmed by one-dimensional (1)H and two-dimensional (1)H-(13)C NMR.

(1)H-NMR spectroscopy at 500 MHz was used to confirm that a previously unidentified singlet resonance at 3.14 ppm in the spectra of cerebrospinal fluid and plasma samples corresponds to dimethyl sulfone (DMSO(2)). A triple resonance inverse cryogenic NMR probe, with pre-amplifier and the RF-coils cooled to low temperature, was used to obtain an (1)H-(13)C HSQC spectrum of CSF containing 8 microM (753 ng/ml) DMSO(2). The (1)H-(13)C correlation signal for DMSO(2) was assigned by comparison with the spectrum from an authentic reference sample. In plasma and CSF from healthy controls, the concentration of DMSO(2) ranged between 0 and 25 micromol/l. The concentration of DMSO(2) in plasma from three of four patients with severe methionine adenosyltransferase I/III (MAT I/III) deficiency was about twice the maximum observed for controls. Thus, DMSO(2) occurs as a regular metabolite at low micromolar concentrations in cerebrospinal fluid and plasma. It derives from dietary sources, from intestinal bacterial metabolism and from human endogenous methanethiol metabolism.

Halitosis in medicine: a review.

This review deals with the different forms of halitosis. Halitosis can be subdivided according to its original location. At present, halitosis of oral origin is quite well understood and some excellent reviews have already appeared in the literature. Special attention is given here to extra-oral halitosis. Extra-oral halitosis can be subdivided into: halitosis from the upper respiratory tract including the nose; halitosis from the lower respiratory tract; blood-borne halitosis. In blood-borne halitosis, malodourant compounds in the bloodstream are carried to the lungs where they volatilise and enter the breath. Potential sources of blood-borne halitosis are some systemic diseases, metabolic disorders, medication and certain foods. The methods of analysis of halitosis are critically reviewed. Attention is also given to odour characterisation of various odourants.

Adverse event associated with methionine loading test: a case report.

The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.

Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.

Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control.