Efficacy of Early Preventive Dental Services in Primary Medical Care Setting: Results From Alabama's 1st Look Program.

Purpose: To evaluate early preventive dental services (PDS) provided by primary care providers (PCPs) in reducing future caries treatments among Alabama Medicaid recipients. Methods: Data from 2009 to 2019 Alabama Medicaid were used to evaluate effectiveness of 1st Look Program on PDS before age three years and incidence of caries treatments after age three years. PDS groups consisted of 1st Look-involved (PDS claims from PCPs), dentist-only (PDS claims from dental providers), and no early fluoride treatment participants (no PDS claims before age three years). Outcomes included frequency and expenditures of fluoride applications, simple restorations, and extensive treatments. Regression models were used to evaluate associations between PDS groups and outcomes while controlling for covariates. Results: Children in 1st Look- involved received more fluoride (3.0 versus 2.1 times; P<0.001) and were applied earlier (12.1 versus 22.9 months old; P<0.001) than dentist-only group. After adjusting for covariates, compared to dentist-only, 1st Look-involved group received earlier fluoride (beta value equals -11.1 months; 95 percent confidence interval [95% CI] equals -11.25 to -10.97) with greater frequency (incident rate ratio equals 1.49; 95% CI equals 1.47 to 1.51). Caries treatment counts were highest in dentist-only followed by 1st Look-involved and no early fluoride treatment groups in both simple restorations (2.7 versus 2.0 versus 0.2 times; P<0.001) and extensive treatments (2.8 versus 2.3 versus 0.2 times; P<0.001), which were consistent after adjusting for covariates. Conclusions: PDS were provided earlier by PCPs in Medicaid-qualified children, with reduced caries treatments on primary teeth, compared to PDS by dental providers only.

Nutrition and sulfur.

Sulfur is unusual in that it is a mineral that may be taken into the body in both inorganic and organic combinations. It has been available within the environment throughout the development of lifeforms and as such has become integrated into virtually every aspect of biochemical function. It is essential for the nature and maintenance of structure, assists in communication within the organism, is vital as a catalytic assistant in intermediary metabolism and the mechanism of energy flow as well as being involved in internal defense against potentially damaging reactive species and invading foreign chemicals. Recent studies have suggested extended roles for sulfur-containing molecules within living systems. As such, questions have been raised as to whether or not humans are receiving sufficient sulfur within their diet. Sulfur appears to have been the "poor relation" with regards to mineral nutrition. This may be because of difficulties encountered over its multifarious functions, the many chemical guises in which it may be ingested and its complex biochemical interconversions once taken into the body. No established daily requirements have been determined, unlike many minerals, although suggestions have been proposed. Owing to its widespread distribution within dietary components its intake has almost been taken for granted. In the majority of individuals partaking of a balanced diet the supply is deemed adequate, but those opting for specialized or restrictive diets may experience occasional and low-level shortages. In these instances, the careful use of sulfur supplements may be of benefit.

S-Carboxymethyl-l-cysteine: a multiple dosing study using pharmacokinetic modelling.

S-Carboxymethyl-l-cysteine is a mucolytic agent used as adjunctive therapy in the treatment of respiratory disorders. Various mechanisms of action have been proposed but few studies have attempted to link the required in vitro concentrations with those achieved actually in vivo during clinical therapy.The data from several published studies has been re-analysed by WinNonlin using non-compartmental analysis modelling, Phoenix modelling and Classic PK compartmental modelling for both single (500-1500 mg) and multiple oral administration of the drug.Multiple dose modelling indicated maximum peak concentrations (Cmax) ranging from 1.29 to 11.22 µg/ml and those at steady state (Css(av)) from 1.30 to 8.40 µg/ml. For the standard therapeutic regimen of 3 × 750 mg (2250 mg/day) these values were 1.29-5.22 µg/ml (Cmax) and 1.30-3.50 µg/ml (Css(av)). No accumulation was observed.Hence, only the pharmacodynamic studies reporting significant effects below c.10 µg/ml were likely to occur in vivo and these were mainly gene-related mechanisms. The majority of events, although demonstrable in vitro, required levels much greater than possible to achieve in the clinical situation.Such unappreciated disregard for in vitro-in vivo 'concentration matching' may lead to erroneous conclusions regarding mechanisms of action for many drugs as well as for S-carboxymethyl-l-cysteine.

Community dental health coordinators' role in community-based pediatric dental education.

PURPOSE: The University of Alabama at Birmingham (UAB) School of Dentistry utilized a Community Dental Health Coordinator (CDHC) to transform a community-based dental education rotation into a positive learning experience for senior dental students. Based in a county health department's Women, Infant, and Children's (WIC) clinic and dental clinic, the initial rotation before implementation of the CDHC was received poorly by students and community partners. This paper reports how CDHC involvement improved student experiences with pediatric patients. METHODS: In 2018, the CDHC embedded in the WIC clinic where student rotations occur and developed relationships with the community partners to identify key issues. The CDHC then implemented qualitative improvements, including a restructured workflow, preparatory educational modules, and assessment systems to address the issues. Student performance reports, focus group discussions, and a postgraduation questionnaire provided data for evaluation of performance. RESULTS: By year 3, dental appointments for patients under age 6 increased, resulting in 95% of UAB students seeing this age patient; 74% completed four or more. Three-quarters of students reported performing restorative procedures on children. Student and community partner acceptance of the rotation also improved. Postgraduation questionnaires (32% response rate) indicate 35% of graduates continue to treat Medicaid patients after graduation. CONCLUSION: The CDHC's unique skills in community relationship-building, community-based dental screenings, and pediatric dental care coordination produced measurable improvements in community participation and student clinical experiences. The CDHC can be a vital part of dental education, especially in community education settings. Community-based dental education generated measurable improvements in students' clinical experiences.

Pharmacogenetics and drug metabolism: historical perspective and appraisal.

The events leading up to the discovery of genetically controlled polymorphic metabolism of xenobiotics and pharmaceutical chemicals are briefly summarised with the salient historical features being emphasised. Especial attention has been given to seminal works in the then emerging field.The evolving knowledge of such polymorphic metabolism and its role in the quest for personalised medicine and the individualisation of patient drug therapy are appraised. Opinion is offered as to whether or not the full potential has been exploited and if the practical application of this information may be regarded as a success or failure within the present clinical arena.

N-acetyltransferase: the practical consequences of polymorphic activity in man.

Over the years, numerous studies have supported the premise that individuals possessing the "slow acetylator" phenotype are more at risk from developing drug side-effects. Most prominent amongst these reports are those concerned with hepatotoxicity and peripheral neuropathy following treatment with isoniazid, lupus-like symptoms during procainamide therapy and experiencing hypersensitivity reactions to the various sulphonamide derivatives. Similarly, "slow acetylators" undergoing heavy exposure to arylamines and related carcinogens are more likely to develop bladder cancer. Contrariwise, there appears a slight risk of "rapid acetylators" developing pancreatic tumours.Other therapeutic agents for which polymorphic N-acetylation plays a minor role in their metabolism have been investigated but any impact of this metabolic difference on clinical efficacy or associated toxicity is still under question. In the search for clues as to the underlying aetiology, patient groups with many disease states have been examined for association with differences in N-acetylation and the majority have provided data that could be interpreted as equivocal. Studies have given contradictory, often opposing, results, calculated risk factors that are (perhaps) just significant but certainly not high, and patients within the cohorts who are always exceptions. Undoubtedly, other as yet unappreciated factors are at play.

Phenylalanine 4-monooxygenase: the "sulfoxidation polymorphism".

1. Consistent differences in the proportion of an orally administered dose of S-carboxymethyl-l-cysteine subsequently excreted in the urine as S-oxide metabolites were reported 40 years ago. This observation suggested the existence of inter-individual variation in the ability to undertake the enzymatic S-oxygenation of this compound. Pedigree studies and investigations employing twin pairs indicated a genetically controlled phenomenon overlaid with environmental influences. It was reproducible and not related to gender or age.2. Studies undertaken in several healthy volunteer cohorts always provided similar results that were not significantly different when statistically analysed. However, when compared to these healthy populations, a preponderance of subjects exhibiting the characteristic of poor sulfoxidation of S-carboxymethyl-l-cysteine was found within groups of patients suffering from various disease conditions. The most striking of these associations were witnessed amongst subjects diagnosed with neurodegenerative disorders; although, underlying mechanisms were unknown.3. Exhaustive investigation has identified the enzyme responsible for this S-oxygenation reaction as the tetrahydrobiopterin-dependent aromatic amino acid hydroxylase, phenylalanine 4-monooxygenase classically assigned the sole function of converting phenylalanine to tyrosine. The underlying principle is discussed that enzymes traditionally associated solely with intermediary metabolism may have as yet unrecognised alternative roles in protecting the organism from potential toxic assault.

Drug S-oxidation and phenylalanine hydroxylase: a biomarker for neurodegenerative susceptibility in Parkinson's disease and amyotrophic lateral sclerosis.

Background The S-oxidation of S-carboxymethyl-L-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson's disease and amyotrophic lateral sclerosis. In the present investigation, the original observations have been extended and confirmed. Methods Meta-analysis of previously published investigations into the S-oxidation polymorphism together with new subject data was evaluated. Results The incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) was found to be 3%-7% within healthy and non-neurological disease populations, whereas 38% of the Parkinson's disease subjects and 39% of the amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson's disease was calculated to be 33.8 [95% confidence interval (CI), 13.3-86.1] and for amyotrophic lateral sclerosis was 35.2 (95% CI, 13.0-85.1). Conclusions The possible involvement of the enzyme responsible for this S-oxidation biotransformation reaction, phenylalanine hydroxylase, should be further investigated to elucidate its potential role in the mechanism(s) of toxicity in susceptible individuals displaying these diseases. The "Janus hypothesis," possibly explaining why phenylalanine hydroxylase is a biomarker of neurodegenerative disease susceptibility, together with the general theme that this concept may apply to many other hitherto unsuspected enzyme systems, is presented.

Dental Students' Attitudes About Treating Populations That Are Low-Income Rural, Non-White, and with Special Needs: A Survey of Four Classes at a U.S. Dental School.

The aim of this study was to explore dental students' attitudes about treating populations that are low-income rural, non-white, and with special needs. All 259 students in all four years at one U.S. dental school were invited in January 2018 to participate in a survey with questions about treating these three populations in the following areas: personal value, perceived preparedness, comfort, future intent to treat, and professional responsibility. A total of 227 students completed the survey, for an overall 87.6% response rate. By class, participants were as follows: D1 n=63, 100% response rate; D2 n=60, 98.4% response rate; D3 n=67, 98.5% response rate; and D4 n=37, 53.6% response rate. The results showed that dental school class did not predict willingness to treat the specified populations. Regarding populations that are rural and non-white, personal value and professional responsibility significantly correlated with intent to treat. Women perceived stronger professional responsibility regarding treatment of populations that are low-income rural (M=1.97, SD=1.09; p=0.004) and non-white (M=1.95, SD=1.07; p=0.013) than did men (M=2.44, SD=1.23; M=2.34, SD=1.22, respectively). More advanced students reported greater preparedness regarding populations that are rural and non-white, but not patients with special needs. Preparedness correlated with intent to treat for patients with special needs only. Women were less comfortable than men in treating patients with special needs (χ2=6.10, p=0.014). Hometown residence had a limited effect for patients with special needs only. Rural residence did not predict students' attitudes about serving rural patients. Overall, the students reported positive intentions to serve populations that are low income, but showed less confidence and willingness in treating patients with special needs, especially among women. These results suggest that the students' comfort in serving patients with low income was more static and less malleable than preparedness. As preparedness and personal value were positively correlated, students may have found worthwhile what they felt prepared to do.

Dental Team's Role in Maternal and Child Oral Health During and After Pregnancy.

For a mother-to-be, pregnancy presents an opportunity to improve not only her health and well being but also that of the immediate family, particularly the newborn infant. The National Consensus Statement of the Oral Health Care During Pregnancy Expert Group together with both governmental and non-governmental guidelines indicate that dental care is both safe and effective during pregnancy. These statements and guidelines may not be widely understood across all healthcare providers that form the perinatal care team, and confusion seems to exist among the general public regarding the safety of and necessity for dental care during pregnancy. Only about half of pregnant patients seek care, even those with dental problems. Previous articles in this series have reviewed appropriateness of dental care during a healthy pregnancy and specific steps to be taken in consideration of the altered physiology brought on by pregnancy and the increased risk associated with oral diseases such as changes in periodontal status, dental caries, and acid erosion; communication through the technique of motivational interviewing with patients who are either planning to become or are pregnant; and collaboration with the perinatal team of providers to ensure improved health outcomes for mother and baby. This final article in the series addresses considerations during and after pregnancy to ensure mother and child may follow a pathway to a future of good oral health.

The S-oxidation of S-carboxymethyl-L-cysteine in hepatic cytosolic fractions from BTBR and phenylketonuria enu1 and enu2 mice.

Mice that were heterozygous dominant for the enu1 and enu2 mutation in phenylalanine monooxygenase/phenylalanine hydroxylase (PAH) resulted in hepatic PAH assays for S-carboxymethyl-L-cysteine (SCMC) that had significantly increased calculated Km (wild type (wt)/enu1, 1.84-2.12 fold increase and wt/enu2 a 2.75 fold increase in PAH assays). The heterozygous dominant phenotypes showed a significantly reduced catalytic turnover of SCMC (wt/enu1, 6.11 fold decrease and wt/enu2 an 11.25 fold decrease in calculated Vmax). Finally, these phenotypes also had a significantly reduced clearance, CLE (wt/enu1, 13.02 fold and wt/enu2, a 30.80-30.94 fold decrease) The homozygous recessive phenotype (enu1/enu1) was also found to have significantly increased calculated Km (2.16 fold increase), a significantly reduced calculated Vmax (11.35-12.33 fold decrease) and CLE (24.75-25.00 fold decrease). The enu2/enu2, homozygous recessive phenotype had no detectable PAH activity using SCMC as substrate. The identity of the enzyme responsible for the C-oxidation of L-phenylalanine (L-Phe) and the S-oxidation of SCMC in wt/wt (BTBR) mice was identified using monoclonal antibody and selective chemical inhibitors and was found to be PAH. This in vitro mouse hepatic cytosolic fraction metabolism investigation provides further evidence to support the hypothesis that an individual possessing one variant allele for PAH will result in a poor metaboliser phenotype that is unable to produce significant amounts of S-oxide metabolites of SCMC.

Xenobiotic Conjugation with Dicarboxylic Acids.

BACKGROUND: Although it is believed widely that the various routes of xenobiotic metabolism are now all known and effectively understood, occasionally there emerges a metabolite that signals a novel biotransformation pathway, especially where the xenobiotic may in some way interact with the myriad processes of intermediary metabolism. There are a few reports in the literature where saturated short-chain dicarboxylic acids have been exploited as conjugating agents and these unusual xenobiotic metabolites subsequently excreted intact in the urine. METHOD: Initially suggested by unpublished observations bolstered by extensive experience of the authors and colleagues in the field of xenobiochemistry, this narrative review has been supplemented by a search of bibliographic databases and the subsequent scrutiny of numerous peer-reviewed research articles. The resultant sparse and widely dispersed information has been examined, analysed and presented in this review. RESULTS: Xenobiotic conjugation with dicarboxylic acids has been demonstrated to occur within several domains of life; microorganisms, plants, invertebrates and mammals. However, considering the number of xenobiotic metabolism investigations that have been undertaken reports of such conjugations are exceedingly rare. CONCLUSION: Dicarboxylic acid condensation with xenobiotic molecules may occur at nitrogen centres, or more precisely with a primary or secondary amine, that is at nitrogen still possessing a replaceable hydrogen atom. Both aliphatic amines and arylamines may be substrates with many of the free amino groups being formed by previous Ndealkylation reactions. Hopefully, awareness of this metabolic route will be raised and researchers will be enthused to search for this type of conjugate.

Phenylalanine hydroxylase: A biomarker of disease susceptibility in Parkinson's disease and Amyotrophic lateral sclerosis.

The S-oxidation of S-carboxymethyl-l-cysteine has been reported previously to be a biomarker of disease susceptibility in Parkinson's disease and Amyotrophic lateral sclerosis. In this investigation, the original observations have been confirmed with the incidence of the poor metaboliser phenotype (no urinary recovery of S-oxide metabolites) being found to be 3.9% within healthy control population. However, 38.3% of the Parkinson's disease subjects and 39.0% of the Amyotrophic lateral sclerosis group were phenotyped as poor metabolisers. The consequent odds risk ratio of developing Parkinson's disease was calculated to be 15.5 (95% CI 9.5-25.3) and for Amyotrophic lateral sclerosis was 15.2 (95% CI 8.8-26.5). Thus, the possible role of the enzyme responsible for the S-oxidation biotransformation reaction, phenylalanine hydroxylase, must be further investigated to elucidate the mechanism(s) of toxicity in susceptible individuals displaying these diseases. A dual role potentially explaining of the role of phenylalanine hydroxylase as a biomarker of disease susceptibility is presented together with the observation that metabolomics is a possible way forward in the identification of potential pro-toxins/toxins in those individuals phenotyped as poor metabolisers (Controls, Parkinson's disease and Amyotrophic lateral sclerosis subjects).

Comparison of the sulfur-oxygenation of cysteine and S-carboxymethyl-l-cysteine in human hepatic cytosol and the rôle of cysteine dioxygenase.

OBJECTIVES: To determine the Km , Vmax , cofactor, activator and inhibitor requirements of human cysteine dioxygenase and S-carboxymethyl-l-cysteine S-oxygenase with respect to both l-Cysteine and S-carboxymethyl-l-cysteine as substrates. METHODS: In vitro human hepatic cytosolic fraction enzyme assays were optimised for cysteine dioxygenase activity using l-Cysteine as substrate and the effect of various cofactors, activators and inhibitors on the S-oxidations of both l-Cysteine and S-carboxymethyl-l-cysteine were investigated. KEY FINDINGS: The results of the in vitro reaction phenotyping investigation found that although both cysteine dioxygenase and S-carboxymethyl-l-cysteine S-oxygenase required Fe2+ for catalytic activity both enzymes showed considerable divergence in cofactor, activator and inhibitor specificities. Cysteine dioxygenase has no cofactor but uses NAD+ and NADH(H+ ) as pharmacological chaperones and is not inhibited by S-carboxymethyl-l-cysteine. S-carboxymethyl-l-cysteine S-oxygenase requires tetrahydrobiopterin as a cofactor, is not activated by NAD+ and NADH(H+ ) but is activated by l-Cysteine. Additionally, the sulfydryl alkylating agent, N-ethylmaleimide, activated carboxymethyl-l-cysteine S-oxygenase but inhibited cysteine dioxygenase. CONCLUSIONS: Human hepatic cytosolic fraction cysteine dioxygenase activity is not responsible for the S-oxidation of the substituted cysteine, S-carboxymethyl-l-cysteine.

Xenobiotic C-sulfonate derivatives; metabolites or metabonates?

1. The production of sulfate conjugates is a well-known and established pathway within the field of xenobiotic metabolism. In addition to the usual attachment of a sulfonate grouping via an oxygen atom (O-sulfonates) to yield a sulfate conjugate, so-called "N-sulfates" (N-sulfonates) have been reported and "S-sulfates" (S-sulfonates) mooted to exist. 2. The few examples cited in the literature where the sulfur atom of the sulfonate group was attached directly to a carbon atom of the xenobiotic (C-sulfonates) and subsequently excreted as a metabolite have been collated, examined and reviewed. 3. The potential mechanisms of formation of these C-sulfonates are discussed, both biological and chemical; the potential role of the gut microbiome raised and hopefully by highlighting this curiosity further fruitful investigation will be stimulated.

Trimethylamine-The Extracorporeal Envoy.

One of the most widespread and efficient mechanisms that has evolved to enable communication between discrete and spatially separate living organisms is the use of specific chemical messengers. The organoleptic properties of certain molecules, even at concentrations that do not necessarily evoke a conscious response, have been exploited to transmit information across relatively large distances. The trimethylated derivative of ammonia is one such molecule that is ideally suited to this function and several species are known to respond to its presence. This review uniquely collects together and integrates widely dispersed data to show that trimethylamine also may serve a communicatory role in man, with its influence extending outside of the body.

Sulphate absorption across biological membranes.

1. Sulphonation is unusual amongst the common Phase II (condensation; synthetic) reactions experienced by xenobiotics, in that the availability of the conjugating agent, sulphate, may become a rate-limiting factor. This sulphate is derived within the body via the oxygenation of sulphur moieties liberated from numerous ingested compounds including the sulphur-containing amino acids. Preformed inorganic sulphate also makes a considerable contribution to this pool. 2. There has been a divergence of opinion as to whether or not inorganic sulphate may be readily absorbed from the gastrointestinal tract and this controversy still continues in some quarters. Even more so, is the vexing question of potential absorption of inorganic sulphate via the lungs and through the skin. 3. This review examines the relevant diverse literature and concludes that sulphate ions may move across biological membranes by means of specific transporters and, although the gastrointestinal tract is by far the major portal of entry, some absorption across the lungs and the skin may take place under appropriate circumstances.

Phenylalanine monooxygenase and the sulfur oxygenation of S-carboxymethyl-L-cysteine in mice.

1. The extent of sulfoxidation of the drug, S-carboxymethyl-L-cysteine, has been shown to vary between individuals, with this phenomenon being mooted as a biomarker for certain disease states and susceptibilities. Studies in vitro have indicated that the enzyme responsible for this reaction was phenylalanine monooxygenase but to date no in vivo evidence exists to support this assumption. Using the mouse models of mild hyperphenylalaninamia (enu1 PAH variant) and classical phenylketonuria (enu2 PAH variant), the sulfur oxygenation of S-carboxymethyl-L-cysteine has been investigated. 2. Compared to the wild type (wt/wt) mice, both the heterozygous dominant (wt/enu1 and wt/enu2) mice and the homozygous recessive (enu1/enu1 and enu2/enu2) mice were shown to have significantly increased Cmax, AUC(0-180 min) and AUC(0-∞ min) values (15 - to 20-fold higher). These results were primarily attributable to the significantly reduced clearance of S-carboxymethyl-L-cysteine (13 - to 22-fold lower). 3. Only the wild type mice produced measurable quantities of the parent S-oxide metabolites. Those mice possessing one or more allelic variant showed no evidence of blood SCMC (R/S) S-oxides. These observations support the proposition that differences in phenylalanine hydroxylase activity underlie the variation in S-carboxymethyl-L-cysteine sulfoxidation and that no other enzyme is able to undertake this reaction.