Efficacy and safety of sitagliptin/metformin fixed-dose combination compared with glimepiride in patients with type 2 diabetes: A multicenter randomized double-blind study.

BACKGROUND: Early initiation of combination therapy using antihyperglycemic agents is recommended for treating type 2 diabetes (T2D). The present multicenter double-blind randomized parallel-group study examined the efficacy and safety of a sitagliptin and metformin fixed-dose combination (Sita/Met) compared with glimepiride in T2D patients as initial treatment. METHODS: Type 2 diabetes patients (aged ≥18 years) were randomized to Sita/Met or glimepiride for 30 weeks after a wash-off run-in period. The primary endpoint was change from baseline (CFB) in HbA1c. Secondary endpoints included the proportion of patients achieving target goal (HbA1c < 7.0 % [53 mmol/mol]) and CFB in fasting plasma glucose (FPG). Safety assessments comprised weight gain from baseline and the incidence of adverse events (AEs). RESULTS: In total, 292 patients were randomized to Sita/Met (n = 147) or glimepiride (n = 145). After 30 weeks, Sita/Met demonstrated superiority over glimepiride in reducing HbA1c (-1.49 % vs -0.71 %, respectively; between-group difference - 0.78 %; P < 0.001). A significantly higher proportion of patients achieved the target goal with Sita/Met (81.2 %) than with glimepiride (40.1 %; P < 0.001). Greater reduction in FPG occurred with Sita/Met than with glimepiride (least-squares mean difference - 23.5 mg/dL; P < 0.001). Both drugs were generally well tolerated. Hypoglycemia events and weight gain were significantly lower in patients with Sita/Met than with glimepiride (5.5 % vs 20.1 % and -0.83 vs +0.90 kg, respectively; both P < 0.001). No serious drug-related AEs or deaths were reported. CONCLUSIONS: Compared with glimepiride, Sita/Met as an initial treatment led to significantly greater improvements in glycemic control and body weight changes, with a lower incidence of hypoglycemia, over 30 weeks.

Dry mouth among the elderly in Korea: a survey of prevalence, severity, and associated factors.

OBJECTIVES: The aim of this study was to investigate the prevalence and severity of dry mouth among elderly population of Korea and to evaluate associate factors and their impact. STUDY DESIGN: Telephone interviews were conducted on a stratified random sample of 1,012 subjects aged ≥ 55 years. Prevalence of dry mouth symptoms, severity of overall oral dryness, and associated factors were assessed using a structured questionnaire. RESULTS: Among the subjects, 70.1% reported to have at least one dry mouth-related symptom and 25.8% were classified with considerable dry mouth. Overall oral dryness severity of each of these groups was 4.30 ± 2.67 and 6.09 ± 2.25, respectively, on a 0-10 scale. Odds ratio of dry mouth increased in women, in smokers, and with increased age and number of medications taken. Women and number of medications taken were significantly associated with overall oral dryness severity. CONCLUSION: A major portion of the Korean elderly reported various dry mouth symptoms, and a wide range of severity and discomfort was caused by these symptoms.

Effect of botulinum toxin injection on nocturnal bruxism: a randomized controlled trial.

OBJECTIVE: To evaluate the effect of botulinum toxin type A on nocturnal bruxism. DESIGN: Twelve subjects reporting nocturnal bruxism were recruited for a double-blind, randomized clinical trial. Six bruxers were injected with botulinum toxin in both masseters, and six with saline. Nocturnal electromyographic activity was recorded in the subject's natural sleeping environment from masseter and temporalis muscles before injection, and 4, 8, and 12 wks after injection and then used to calculate bruxism events. Bruxism symptoms were investigated using questionnaires. RESULTS: Bruxism events in the masseter muscle decreased significantly in the botulinum toxin injection group (P = 0.027). In the temporalis muscle, bruxism events did not differ between groups or among times. Subjective bruxism symptoms decreased in both groups after injection (P < 0.001). CONCLUSIONS: Our results suggest that botulinum toxin injection reduced the number of bruxism events, most likely mediated its effect through a decrease in muscle activity rather than the central nervous system. We controlled for placebo effects by randomizing the interventions between groups, obtaining subjective and objective outcome measures, using the temporalis muscle as a control, and collecting data at three postinjection times. Our controlled study supports the use of botulinum toxin injection as an effective treatment for nocturnal bruxism.

Validation of the Korean version of the oral health impact profile among the Korean elderly.

OBJECTIVES: This study aimed to validate a Korean version of the oral health impact profile (OHIP) and to develop a short-form of OHIP for the Korean elderly. METHODS: The original English version of OHIP was translated into Korean using a forward-backward method. Internal consistency was measured by Cronbach's alpha among 1098 subjects aged 56 or more. Test-retest reliability was assessed by intraclass correlation coefficients (ICCs) with a 3-month interval among 155 subjects aged 57 or more. The validity of the Korean version of OHIP (OHIP-K) was assessed by comparing OHIP scores with the perceived dental treatment needs and by identifying associations between OHIP scores and the number of natural teeth among 128 subjects aged 54 or more. The short-form of OHIP for the Korean elderly (OHIP-14K) was developed using linear regression models and was also validated and compared with the short-form of OHIP by Slade (OHIP-14S). RESULTS: The Cronbach's alpha value for OHIP-K was 0.97. The ICC for OHIP-K was 0.64. Adults with perceived dental treatment needs had a higher OHIP score than adults without any such needs (P < 0.001). The number of natural teeth was negatively associated with the OHIP score (r = -0.44, P < 0.001). OHIP-14K and OHIP-14S shared seven identical items out of a total of 14 items. OHIP-14K results correlated with OHIP-K almost exactly (r(2) = 0.96), as did OHIP-14S (r(2) = 0.95). CONCLUSIONS: OHIP-K showed excellent reliability and validity. OHIP-14S may be a better choice for the evaluation of oral health-related quality of life among the Korean elderly for an international comparison.

Effects of pilocarpine on the secretory acinar cells in human submandibular glands.

Pilocarpine has been used as a choice of drugs for treatment of impaired salivary flow. Although considerable data are available as to the stimulatory effect of pilocarpine on the salivary secretion in human, its underlying mechanism, at the cellular level, has not been rigorously studied. In this experiment, we studied the effect of pilocarpine on the ion channel activity, cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) and aquaporin (AQP)-5 expression, which play key roles in the secretary process and determine the capacity of fluid secretion. In human submandibular gland (SMG) acinar cells, 10(-5) M pilocarpine activated the outward rectifying-current, which was predominantly K(+) selective in the whole cell patch clamp study. The pilocarpine increased [Ca(2+)](i) in a concentration-dependent manner in the range of 10(-6) M to 10(-4) M. We found that both increases of [Ca(2+)](i) and outward rectifying- K(+) current were inhibited by 10(-5) M U-73122, a specific phospholipase C inhibitor. The magnitudes of pilocarpine-induced [Ca(2+)](i) transients were approximately 55% lower than those with the same concentration of carbachol (CCh). Pilocarpine also increased the amount of AQP-5 protein in the apical membrane (APM) in human SMG acinar cells. Our results suggest that pilocarpine induce salivary secretions in human by activating K(+) channels, increasing [Ca(2+)](i) via phospholipase C dependent pathway, and increasing AQP-5 protein expression in the APM of SMG acinar cells.

Volatile sulfur compounds produced by Helicobacter pylori.

GOALS: To assess the volatile sulfur compounds produced by three strains of Helicobacter pylori in broth cultures mixed with sulfur-containing amino acids. BACKGROUND: Halitosis has been reported in H. pylori-positive patients, and volatile sulfur compounds such as hydrogen sulfide and methyl mercaptan are known to be responsible for inducing oral malodor. Whether H. pylori produces these volatile sulfur compounds has yet to be established. STUDY: Three strains of H. pylori (ATCC 43504, SS 1, DSM 4867) were cultured with 5 mM cysteine and methionine. After 72 hours of incubation, the headspace air was aspirated and injected directly into a gas chromatograph. The concentrations of hydrogen sulfide and methyl mercaptan were analyzed and compared between experimental and control cultures RESULTS: In broth containing 5 mM cysteine, hydrogen sulfide was increased by ATCC 43504 (P < 0.01) and SS 1 (P < 0.05), while methyl mercaptan was elevated only by SS 1 (P < 0.05). In broth containing 5 mM methionine, methyl mercaptan increases were significant for SS 1 (P < 0.05) and DSM 4867 (P < 0.05). In broth containing 5 mM cysteine and 5 mM methionine, the concentration of hydrogen sulfide was higher than in controls for all three strains (P < 0.01); that of methyl mercaptan was higher only for SS 1 (P < 0.01). Cysteine addition to cultures containing methionine increased hydrogen sulfide and methyl mercaptan for ATCC 43504 (P < 0.05) and SS 1 (P < 0.05). Conversely, addition of methionine to cultures containing cysteine increased methyl mercaptan only for DSM 4867 (P < 0.01). CONCLUSIONS: The production of volatile sulfur compounds by H. pylori is not only very complicated but also strain-specific. Nevertheless, H. pylori was shown to produce hydrogen sulfide and methyl mercaptan, which suggests that this microorganism can contribute to the development of halitosis.

Influences of animal mucins on lysozyme activity in solution and on hydroxyapatite surfaces.

The purpose of this study was to investigate the influence of animal mucins on lysozyme activity in solution and on the surface of hydroxyapatite (HA) beads. The effects of animal mucins on lysozyme activity in solution were examined by incubating porcine gastric mucin (PGM) or bovine submaxillary mucin (BSM) with hen egg-white lysozyme (HEWL) or salivary samples. HA-immobilised animal mucins or lysozyme were used to determine the influence of animal mucins on lysozyme activity on HA surfaces. Lysozyme activity was determined by turbidity measurement of a Micrococcus lysodeikticus substrate suspension. Protein concentration was determined by ninhydrin assay. PGM inhibited the activity of HEWL and salivary lysozyme in solution. The amount of inhibition was dependent on mucin concentration, incubation time and temperature, and the structural integrity of the mucin. The inhibition of salivary lysozyme activity by PGM was greater in submandibular/sublingual saliva than in parotid saliva. The inhibition of lysozyme activity by PGM was markedly dependent on pH. However, BSM did not inhibit the in-solution lysozyme activities of HEWL and clarified saliva. Both PGM and BSM bound to HA surfaces, and HA-adsorbed animal mucins increased the subsequent adsorption of lysozyme. When HA beads were exposed to a mixture of HEWL and PGM or BSM, lysozyme activity on the HA surfaces was significantly increased. The results suggest that animal mucins affect lysozyme activity, and the effects are different on HA surfaces compared with in solution. Further research is needed to determine the effect of animal mucins on lysozyme activity in vivo.

The relationship between phenylthiocarbamide (PTC) and 6-n-propylthiouracil (PROP) taster status and taste thresholds for sucrose and quinine.

OBJECTIVE: The aim of this study was to investigate the relationship of taster status with taste detection and recognition thresholds for sucrose and quinine. DESIGN: Sixty-nine subjects (35 men and 34 women; mean age, 23.9+/-1.2 years) were included. Stimulus fluids were prepared, one each for phenylthiocarbamide (PTC), 6-n-propylthiouracil (PROP), sucrose and quinine HCl. In each series, successive solutions, which comprised a total of 15 grades, differed by 0.25log units of the molar concentration. Two concentrations of NaCl (0.32 and 1.0 M) were prepared. The subjects were classified as nontasters and tasters using their PTC and PROP perceptions. Tasters were classified as medium-tasters and supertasters by the ratio of perceived bitterness of above-threshold PROP relative to the perceived saltiness of NaCl (PROP ratio). Taste detection and recognition thresholds for sucrose and quinine were determined by standard two-alternative forced choice trials. A Student's t-test, a Pearson's correlation analysis and linear contrasts in a one-way analysis of variance (ANOVA) were used. RESULTS: The percentages of nontaster, medium-taster and supertaster were 13, 70 and 17%, respectively. There were no significant gender differences in the taste detection and recognition thresholds for sucrose and quinine. The threshold for PTC and PROP showed significant correlations with taste threshold for quinine. Linear contrast in one-way ANOVA showed that the greater the value of PROP ratio, the more sensitive to sweet and bitter tastes (p<0.001). CONCLUSION: The PTC and PROP taster status is closely related with taste detection and recognition thresholds for sucrose and quinine.

The relationship between PTC taster status and taste thresholds in young adults.

OBJECTIVE: The aim of this study was to compare taste detection and recognition thresholds of young males and females, and young phenylthiocarbamide (PTC) "tasters" and "nontasters" for stimuli representing sweet, sour, bitter, salty, and umami classes of taste sensations. STUDY DESIGN: Thirty-eight men and 37 women (mean [SD] age = 24.5 [2.5] years) were classified as PTC tasters and nontasters according to their PTC recognition thresholds. Detection and recognition thresholds for the non-PTC stimuli were determined using a 2-alternative, forced choice procedure. RESULTS: The detection thresholds for quinine-HCl and sucrose and the recognition threshold for quinine-HCl were significantly higher in the PTC nontasters than in the tasters. The PTC threshold showed significant correlations with detection or recognition thresholds for sucrose, sodium chloride, quinine-HCl, and monosodium glutamate. The sucrose recognition threshold was lower in women than in men. CONCLUSION: In this study, gender and PTC taster status were found to be associated with thresholds for sucrose and quinine-HCl.

Intracellular glutathione status regulates mouse bone marrow monocyte-derived macrophage differentiation and phagocytic activity.

Although a redox shift can regulate the development of cells, including proliferation, differentiation, and survival, the role of the glutathione (GSH) redox status in macrophage differentiation remains unclear. In order to elucidate the role of a redox shift, macrophage-like cells were differentiated from the bone marrow-derived monocytes that were treated with a macrophage colony stimulating factor (M-CSF or CSF-1) for 3 days. The macrophagic cells were characterized by a time-dependent increase in three major symptoms: the number of phagocytic cells, the number of adherent cells, and the mRNA expression of c-fms, a M-CSF receptor that is one of the macrophage-specific markers and mediates development signals. Upon M-CSF-driven macrophage differentiation, the GSH/GSSG ratio was significantly lower on day 1 than that observed on day 0 but was constant on days 1-3. To assess the effect of the GSH-depleted and -repleted status on the differentiation and phagocytosis of the macrophages, GSH depletion by BSO, a specific inhibitor of the de novo GSH synthesis, inhibited the formation of the adherent macrophagic cells by the down-regulation of c-fms, but did not affect the phagocytic activity of the macrophages. To the contrary, GSH repletion by the addition of NAC, which is a GSH precursor, or reduced GSH in media had no effect on macrophage differentiation, and led to a decrease in the phagocytic activity. Furthermore, we observed that there is checkpoint that is capable of releasing from the inhibition of the formation of the adherent macrophagic cells according to GSH depletion by BSO. Summarizing, these results indicate that the intracellular GSH status plays an important role in the differentiation and phagocytosis of macrophages.

Chronic orofacial pain among Korean elders: prevalence, and impact using the graded chronic pain scale.

The aims of this study were to investigate the prevalence of orofacial pain symptoms in the Korean elderly population, and to evaluate factors associated with orofacial pain and graded chronic pain. Of 4,342 Korean elders from the cohort of Korean National Interview Survey of Oral Health Status in 2000, telephone interviews were conducted on a stratified random sample of 1,032 people aged 55 years or older. Prevalence of five orofacial pain symptoms (jaw joint pain, face pain, toothache, oral sores, and burning mouth) in the past 6 months along with questions from the graded chronic pain scale were assessed by telephone using a structured questionnaire. The results suggested that the 6-month prevalence of joint pain (15.5%), face pain (9.3%), toothache (26.8%), oral sores (26.2%), and burning mouth (14.2%) in Korean elders were higher than in studies on Caucasian populations. Painful oral sores and burning mouth had higher prevalence for females than for males. Subjects with joint pain, burning mouth or toothache pain were more likely to report high levels of a pain-related disability compared with subjects not reporting those symptoms. There were no age group differences in pain intensity, but the older age group reported a higher number of disability days because of their pain. Chronic orofacial pain is a substantial health problem in the elderly population.

Elevation of urinary betaig-h3, transforming growth factor-beta-induced protein in patients with type 2 diabetes and nephropathy.

Transforming growth factor-beta (TGF-beta) is a pro-sclerotic growth factor implicated in the pathogenesis of diabetic nephropathy. betaig-h3 is an extracellular matrix protein which is induced in many cells by TGF-beta. This study examined urinary betaig-h3 excretion in diabetic patients with elevated urinary albumin excretion and the clinical application of urinary betaig-h3 as a marker of diabetic nephropathy. Urinary and serum betaig-h3 levels were determined by enzyme-linked immunosorbent assay in 163 type 2 diabetic patients and 101 healthy control subjects of comparable age and weight. The ratio of urinary betaig-h3 and TGF-beta to creatinine was analyzed in patients with different degree of nephropathy. The betaig-h3 to creatinine ratio in urine was elevated in all groups of type 2 diabetics with normoalbuminuria (101.6 +/- 9.27), microalbuminuria (120.2 +/- 14.48), and overt proteinuria (146.3 +/- 16.34), when compared with control subjects (64.8 +/- 7.14) (P < 0.01). There was a positive correlation between urinary betaig-h3 and TGF-beta excretion rate and a positive correlation between urinary betaig-h3 and albumin excretion rate (AER). These data show that urinary levels of betaig-h3 are elevated in type 2 diabetic patients with nephropathy and may be used as a marker of diabetic nephropathy.

Common genes responsible for differentiation and senescence of human mucosal and epidermal keratinocytes.

Serial subcultures of normal human oral keratinocytes (NHOKs) and normal human epidermal keratinocytes (NHEKs) to the postmitotic stage result in terminal differentiation and replicative senescence. In order to investigate the common mode of differentiation and/or senescence between mucosal and epidermal keratinocytes, gene expression profiling on both NHOKs and NHEKs was performed by a cDNA microarray analysis. Primary NHOKs and NHEKs were serially subcultured, and the expression level of 3,063 genes was compared between the exponentially growing and senescent cultures. The senescent NHOKs and NHEKs highly expressed 55 and 37 genes, respectively. Among these genes, 16 genes were common in both NHOKs and NHEKs while the other genes were upregulated either in the NHOKs or in the NHEKs. Furthermore, the expression levels of the common genes did not change in the human diploid fibroblasts during the subcultures. These results suggest that subculture-induced differentiation and/or replicative senescence in NHOKs and NHEKs has similar characteristics, but that the pathways leading to these processes are distinct and keratinocyte specific.

The relationship between oral Candida carriage and the secretor status of blood group antigens in saliva.

OBJECTIVE: The aim of the study was to investigate the relationship between oral Candida carriage and the secretor status of blood group antigens. STUDY DESIGN: Unstimulated whole saliva and oral rinse samples were obtained from 180 healthy subjects. These samples were plated on Sabouraud's dextrose agar media to determine oral Candida carriage. Sodium dodecylsulfate polyacrylamide gel electrophoresis and immunoblotting were performed on whole saliva samples to determine the secretor status of blood group antigens. RESULTS: The oral Candida carriage rate was found to be 45.0%. The sensitivity of the concentrated rinse culture proved to be superior. Oral Candida carriage was not significantly related to the blood group or secretor status of ABH or Lewis antigens. No significant relationship was found between oral Candida carriage and salivary flow rate. However, smoking affected oral Candida carriage. CONCLUSION: Oral Candida carriage in healthy individuals is not significantly related to blood group or secretor status.

The relationship between volatile sulfur compounds and major halitosis-inducing factors.

BACKGROUND: Although tongue coating and periodontal conditions have been reported to be major halitosis-inducing factors, the relationship between volatile sulfur compounds (VSC) and these 2 major factors is not yet fully understood. The aim of this study was to investigate the relationship of VSC concentrations to tongue coating and periodontal health. METHODS: Forty subjects (mean age 33.3 years, range 14 to 64 years) were enrolled in this study. Gas chromatography was performed to analyze each VSC component from the mouth air sampled prior to tongue scraping, after tongue scraping, and after a subsequent prophylaxis on the interdental spaces. RESULTS: CH3SH was the most malodorous component among the 3 major VSC from the mouth air. The high CH3SH group showed a significantly higher organoleptic rating (P < 0.01), gingival index (P < 0.01), bleeding index (P < 0.01), probing depth (P < 0.05), and VSC concentrations prior to tongue scraping (P < 0.01), except for the amount of tongue coating, compared to the low CH3SH group. All VSC concentrations were vastly reduced by tongue scraping in both groups, and the remaining contents were nearly all removed by the subsequent prophylaxis. The VSC contents produced by the tongue coating played a major role [H2S: 76%; CH3SH: 52%; (CH3)2S: 55%] in the low CH3SH group. In the high CH3SH group which had poor periodontal health, the tongue coating still played a major role [H2S: 67%; CH3SH: 59%; (CH3)2S: 48%], but the interdental spaces also contributed to VSC production [H2S: 26%; CH3SH: 32%; (CH3)2S; 36%]. CONCLUSIONS: The tongue coating was demonstrated to be a primary halitosis-inducing factor. Periodontal health was also shown to contribute to VSC production.

Analysis of residual saliva and minor salivary gland secretions in patients with dry mouth.

The importance of oral mucosal wetness in the condition of dry mouth and the role of salivary proteins in proper oral function are acknowledged. A negative correlation between mucosal wetness and the protein concentration of residual saliva has been reported in normosalivators. Here, to examine the suggestion that a reduction in residual salivary volume leads to a concomitant elevation of its protein concentration, the amount of residual saliva and minor salivary gland secretions, and their protein concentrations, were measured in hyposalivators and normosalivator controls. A Periotron 8000 micro-moisture meter was used to measure the thickness of the mucosal film at six selected mucosal surfaces and the minor salivary gland secretion rate at two mucosal surfaces. The unstimulated whole salivary flow rate was measured by the spitting method. The total protein concentration of all salivary samples was measured by bicinchoninic acid assay. The hyposalivators had significantly lower amounts of residual saliva and minor salivary gland secretions than the normosalivators at all selected mucosal sites except the soft palate. In both groups, the site with the thinnest coat of residual saliva was the anterior hard palate and the wettest site was the anterior dorsal mucosa of the tongue. The protein concentration of residual saliva was significantly higher in hyposalivators than normosalivators. In the minor salivary gland secretions there was no significant difference in protein concentration between the normo- and hyposalivators. When the hyposalivators were divided into two subgroups according to their severity of dryness, the reduction of residual salivary volume and the elevation of protein concentration were more apparent in the group with the more severe dry mouth. Collectively, these results indicate that oral mucosal wetness is associated with the flow rate of unstimulated whole saliva. The function of the minor salivary glands was less affected and relatively well preserved in patients with dry mouth. The increased protein concentration of residual saliva in the hyposalivators appeared to be the result of decreased salivary volume.