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Background: The midfacial fat is highly compartmentalized, and the deep fat compartments provide structural support for the midface. Understanding the age-related changes in the midfacial deep fat compartments is important for midfacial rejuvenation physiologically. However, previous studies showed conflicted results of these changes. Objectives: This study aims to quantify the age-related changes of deep fat compartments in the midface using ultrasound. Methods: A cross-sectional study was conducted to evaluate subjects with age more than 25 years old and the subjects were divided into four age groups equally (25–34, 35–44, 45–54, and ≥55). The thickness of the suborbicularis oculi fat compartment (SOOF) and deep medial cheek fat compartment (DMCF) was measured using a portable ultrasound device. Mean thickness differences among different age groups were analyzed by one-way analysis of variance. Multiple linear regression adjusted for body mass index (BMI) and sex was also conducted. Results: A total of 60 subjects were enrolled. The thickness of SOOF and DMCF tends to decrease with age. The mean decrease of SOOF and DMCF from the youngest group to the oldest group was 0.63 mm (36%) and 0.70 mm (25.83%), respectively. The relationship between aging and thickness of SOOF and DMCF remains significant after adjusting for BMI and sex (both P < 0.001). Conclusion: The thickness of deep fat compartments decreases with the natural aging process. The study may offer clinical implications for targeted volume rejuvenation to achieve a more youthful and natural face.

Background and Objectives: Psoriasis is a chronic, long-term, incurable skin inflammatory disease characterized by the excessive proliferation of epidermal keratinocytes, dilation of blood vessels, thickening of the skin, and the formation of visible red patches of variable sizes. The impact on patients differs with the severity of the disease, leading to physiological discomfort and psychological distress, which significantly affect the quality of life. The etiology of psoriasis is not completely clear, but immune cells, including type 1 and type 17 cytokine-producing cells modulated by regulatory T cells (Tregs), play a critical role in driving the disease pathogenesis. With the ability to specifically target inflammatory markers, biologics can efficiently inhibit the spread of inflammation to achieve therapeutic effects. The goal was to explore the changes in body image and quality of life in psoriasis patients undertaking therapies with biologic agents. Materials and Methods: This study employed a quasi-experimental, single-sample, pretest–posttest design. Forty-four psoriasis patients were recruited from the dermatology outpatient clinics at two medical centers in northern Taiwan. A structured questionnaire, including demographic information, the Body Image Scale (BIS), and the Dermatology Life Quality Index (DLQI), was used as a research tool. Questionnaire assessments were conducted both before and three months after the biologic agent intervention. Statistical analyses were performed using SPSS version 22.0. Results: Our results indicated a significant difference in body image between psoriasis patients before and after intervention with biologic agents. In addition, overall quality of life (QoL) also showed significant improvements before and after biologic agent intervention. There was a positive correlation between body image and quality of life in psoriasis patients. Conclusions: The treatment for psoriasis has evolved rapidly in recent years, and biologic agents have proven to be effective therapies to improve the quality of life for psoriasis patients. Our study suggests that health-related education and psychological support can further benefit psoriasis patients to willingly and positively undertake treatment and therefore improve their positive body image and quality of life.

Previous investigations have suggested an association between the PCSK9 common polymorphism E670G and Lipoprotein(a) (Lp(a)) levels, as well as a link between plasma PCSK9 levels and Lp(a) concentrations. However, the causal relationship between plasma PCSK9 and Lp(a) levels remains uncertain. In this study, we explored the association between PCSK9 E670G polymorphism and Lp(a) levels in 614 healthy Taiwanese individuals. Employing a two-sample Mendelian randomization (MR) analysis using openly accessible PCSK9 and Lp(a) summary statistics from the genome-wide association studies (GWAS) and UK Biobank, we aimed to determine if a causal link exists between plasma PCSK9 levels and Lp(a) concentrations. Our findings reveal that the E670G G allele is independently associated with a decreased likelihood of developing elevated Lp(a) levels. This association persists even after adjusting for common cardiovascular risk factors and irrespective of lipid profile variations. The MR analysis, utilizing six PCSK9 GWAS-associated variants as instrumental variables to predict plasma PCSK9 levels, provides compelling evidence of a causal relationship between plasma PCSK9 levels and Lp(a) concentration. In conclusion, our study not only replicates the association between the PCSK9 E670G polymorphism and Lp(a) levels but also confirms a causative relationship between PCSK9 levels and Lp(a) concentrations through MR analysis.

The increased proliferation and activation of hepatic stellate cells (HSCs) are associated with liver fibrosis development. To date, there are no FDA-approved drugs for the treatment of liver cirrhosis. Augmentation of HSCs apoptosis is one of the resolutions for liver fibrosis. In this study, we extracted α-mangostin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methyl-2-butenyl)-9H-xanthen-9-one) from the fruit waste components of mangosteen pericarp. The isolated α-mangostin structure was determined and characterized with nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) and compared with those known compounds. The intracellular signaling pathway activities of α-mangostin on Transforming growth factors-beta 1 (TGF-β1) or Platelet-derived growth factor subunit B (PDGF-BB) induced HSCs activation and were analyzed via Western blot and Real-time Quantitative Polymerase Chain Reaction (Q-PCR). α-Mangostin-induced mitochondrial dysfunction and apoptosis in HSCs were measured by seahorse assay and caspase-dependent cleavage. The in vivo anti-fibrotic effect of α-mangostin was assessed by carbon tetrachloride (CCl4) treatment mouse model. The data showed that α-mangostin treatment inhibited TGF-β1-induced Smad2/3 phosphorylation and alpha-smooth muscle actin (α-SMA) expression in HSCs in a dose-dependent manner. Regarding the PDGF-BB-induced HSCs proliferation signaling pathways, α-mangostin pretreatment suppressed the phosphorylation of extracellular-signal-regulated kinase (ERK) and p38. The activation of caspase-dependent apoptosis and dysfunction of mitochondrial respiration (such as oxygen consumption rate, ATP production, and maximal respiratory capacity) were observed in α-mangostin-treated HSCs. The CCl4-induced liver fibrosis mouse model showed that the administration of α-mangostin significantly decreased the expression of the fibrosis markers (α-SMA, collagen-a2 (col1a2), desmin and matrix metalloproteinase-2 (MMP-2)) as well as attenuated hepatic collagen deposition and liver damage. In conclusion, this study demonstrates that α-mangostin attenuates the progression of liver fibrosis through inhibiting the proliferation of HSCs and triggering apoptosis signals. Thus, α-mangostin may be used as a potential novel therapeutic agent against liver fibrosis.

Abstract The automated blister epidermal micrograft (ABEM) is a newly introduced surgical transplantation for refractory vitiligo. Comparative analysis of other surgical methods is lacking. We conducted a retrospective study to compare the efficacy, safety, and experience of ABEM with conventional suction blister epidermal graft (SBEG). A total of 118 anatomically based vitiligo lesions from 75 patients were included. The primary outcome was the degree of repigmentation; the patient and operator experience were evaluated. SBEG had a significantly greater incidence of repigmentation (p

Background: Although alcohol use has been determined as a predisposing factor for psoriasis, research findings have been inconsistent. Objectives: This study investigated whether alcohol intake is causally linked to psoriasis. Methods: The presence of rs671 polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene was investigated in 258 psoriasis patients and 605 healthy controls. The rs671 was employed as an instrumental variable for predicting alcohol use. Mendelian randomization (MR) was utilized to assess the causality between genetically determined alcohol consumption and psoriasis using the two-stage least-square (2SLS) approach. A replication study of MR analysis with inverse-variance weighting (IVW), MR-Egger regression, and weighted median methods was performed using openly accessible alcohol consumption and psoriasis summary statistics from the UK Biobank. Results: Between psoriasis and controls, there were no significant differences in genotype and allele frequencies for the ALDH2 rs671 polymorphism. The G allele of the rs671 was positively linked with alcohol intake. The ALDH2 rs671 genetically determined alcohol intake was not linked to the risk of psoriasis in the 2SLS analysis (β = −0.011, P = 0.960). The MR replication study also found no evidence of genetic propensity to greater alcohol consumption increasing the risk of psoriasis (β = −0.00065, P = 0.6002 in IVW; β = −0.00099, P = 0.6851 in MR-Egger; and β = −0.00181, P = 0.3558 in weighted median analysis). Conclusion: ALDH2 rs671 may not have a role in psoriasis susceptibility in Taiwanese. The MR analysis found no causality between alcohol consumption and psoriasis.

Vancomycin is a commonly used antibiotic; however, it can cause life-threatening severe cutaneous adverse reactions, such as drug reaction with eosinophilia and systemic symptoms (DRESS). A previous study has reported a strong association between HLA-A*32:01 and vancomycin-induced DRESS in European ethnicity. Herein, we aim to investigate the genetic predisposition of vancomycin-induced DRESS in the Han-Chinese population. In this study, we enrolled a total of 26 patients with vancomycin-induced DRESS, 1,616 general population controls, and 51 subjects tolerant to vancomycin. In vitro granulysin-based lymphocyte activation tests (LAT) were conducted among 6 vancomycin-induced DRESS patients who were concomitantly receiving other medicines. HLA-A and HLA-B genotypes were determined by sequencing-based typing. Our results found that vancomycin-induced DRESS was associated with HLA-A*32:01 [odds ratio (OR) = 7.8, 95% confidence interval (CI) = 1.7–35.8; p-value = 0.035], HLA-B*07:05 (OR = 32.3, 95% CI = 2.8–367.7; p-value = 0.047), HLA-B*40:06 (OR = 4.7, 95% CI = 1.3–16.1; p-value = 0.036) and HLA-B*67:01 (OR = 44.8, 95% CI = 7.2–280.4; p-value = 0.002) when comparing the vancomycin-induced DRESS patients with the general population controls. LAT results showed that granulysin significantly increased in the vancomycin-induced DRESS patients upon vancomycin stimulation (4.7 ± 3.7 fold increased), but not upon other co-medicines. This study identified that, in addition to HLA-A*32:01, HLA-B*07:05, HLA-B*40:06, and HLA-B*67:01 were also genetic markers for vancomycin-induced DRESS in the Han-Chinese population. Associations of ethnic variances in HLA with vancomycin-DRESS were observed.

The efficacy and the safety of psoriasis medications have been proved in trials, but unideal responses and side effects are noted in clinical practice. Genetic predisposition is known to contribute to the pathogenesis of psoriasis. Hence, pharmacogenomics gives the hint of predictive treatment response individually. This review highlights the current pharmacogenetic and pharmacogenomic studies of medical therapy in psoriasis. HLA-Cw*06 status remains the most promising predictive treatment response in certain drugs. Numerous genetic variants (such as ABC transporter, DNMT3b, MTHFR, ANKLE1, IL-12B, IL-23R, MALT1, CDKAL1, IL17RA, IL1B, LY96, TLR2, etc.) are also found to be associated with treatment response for methotrexate, cyclosporin, acitretin, anti-TNF, anti-IL-12/23, anti-IL-17, anti-PDE4 agents, and topical therapy. Due to the high throughput sequencing technologies and the dramatic increase in sequencing cost, pharmacogenomic tests prior to treatment by whole exome sequencing or whole genome sequencing may be applied in clinical in the future. Further investigations are necessary to manifest potential genetic markers for psoriasis treatments.

Alterations in the gut microbiota composition and their associated metabolic dysfunction exist in psoriasis. However, the impact of biologics on shaping gut microbiota is not well known. This study aimed to determine the association of gut microorganisms and microbiome-encoded metabolic pathways with the treatment in patients with psoriasis. A total of 48 patients with psoriasis, including 30 cases who received an IL-23 inhibitor (guselkumab) and 18 cases who received an IL-17 inhibitor (secukinumab or ixekizumab) were recruited. Longitudinal profiles of the gut microbiome were conducted by using 16S rRNA gene sequencing. The gut microbial compositions dynamically changed in psoriatic patients during a 24-week treatment. The relative abundance of individual taxa altered differently between patients receiving the IL-23 inhibitor and those receiving the IL-17 inhibitor. Functional prediction of the gut microbiome revealed microbial genes related to metabolism involving the biosynthesis of antibiotics and amino acids were differentially enriched between responders and non-responders receiving IL-17 inhibitors, as the abundance of the taurine and hypotaurine pathway was found to be augmented in responders treated with the IL-23 inhibitor. Our analyses showed a longitudinal shift in the gut microbiota in psoriatic patients after treatment. These taxonomic signatures and functional alterations of the gut microbiome could serve as potential biomarkers for the response to biologics treatment in psoriasis.

Background/Purpose: Basic fibroblast growth factor (bFGF) exhibits multiple biological functions in various tissues. Stem cells from apical papilla (SCAP) can be isolated from human apical papilla tissues in developmental teeth of children. The purposes of this study were to investigate the expression of FGF receptors (FGFRs) and the effects of bFGF on SCAP and related MEK/ERK signaling. Methods: SCAP cells were treated under different concentrations of bFGF with or without U0126 (an inhibitor of MEK/ERK). Expression of FGFR1 and FGFR2 in SCAP was analyzed by RT-PCR. Cell proliferation was measured by MTT assay. The expressions of type I collagen, cdc 2, cyclin B1, TIMP-1 and p-ERK proteins were examined by Western blot. Results: SCAP cells expressed FGFR1 and FGFR2. Exposure of SCAP to bFGF enhanced cell proliferation, and the expression cyclinB1, cdc 2, and TIMP-1, but not type I collagen. U0126 pretreatment and co-incubation attenuated the bFGF-induced proliferation, cdc2, cyclin B1 and TIMP-1 proteins’ expression, but not type I collagen in SCAP. Conclusion: SCAP cells express FGFRs. bFGF may stimulate proliferation and affect the matrix turnover of SCAP cells, possibly via stimulation of FGFRs and MEK/ERK signaling pathway. These results are useful for clinical therapies for apexogenesis and regeneration of pulpo-dentin complex.

Background: The associations between psoriasis, metabolic syndrome, and cardiovascular events are increasingly recognized. Studies have shown decreased cardiovascular events with the treatment of methotrexate and anti-tumor necrosis factor-α. However, effects of interleukin (IL)-12/23 blockade remain debatable. Objectives: Our study sought to investigate the effect of IL-12/23 blockade on the metabolic parameters in patients with psoriasis. Methods: We performed a retrospective cohort study to assess 93 consecutive patients with moderate-to-severe plaque-type psoriasis who received IL-12/23 blockade (ustekinumab) for 24 weeks between January 2012 and May 2016. Results: Metabolic parameters and disease activity (psoriasis area severity index score) at baseline and 24 weeks of treatment were collected. At week 24 (wk24), the disease activity improved significantly (mean: baseline, wk0: 21.35 ± 11.55 to wk24: 6.87 ± 6.81, P < 0.0001), with a significant reduction of erythrocyte sedimentation rate. Conversely, body mass index was significantly elevated in PASI-75 responders at wk24 of treatment and was independent of disease severity. Fasting sugar and triglyceride level were elevated at wk24. Cholesterol (Chol), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) remained unchanged. These metabolic parameters were not correlated with the improvement in disease severity after ustekinumab treatment. Nonetheless, the atherogenic index, LDL/HDL ratio, and Chol/HDL ratio remained unchanged. Male gender is a predictor of elevated plasma triglyceride level. Conclusion: Our results suggest that despite tremendous improvement in disease activity after ustekinumab treatment, obesity, fasting sugar, and hypertriglyceridemia are still present in these patients. Regular screening of lipid profile and obesity control is advised during the treatment of ustekinumab, especially in male psoriasis patients with predisposing cardiovascular risks.

We report a case of idiopathic lymphoplasmacellular mucositis (ILPM) of the vulva in a 48-year-old woman with partial interferon-γ receptor 1 (IFN-γR1) deficiency. The lesion had an unusual ulcerovegetative presentation. Remarkable response was observed with oral and topical steroids in the first 3 weeks. However, the lesion recurred after tapering oral steroids and continuous low-dose oral steroids were required to suppress recurrence. To the best of our knowledge, this is the first case report of ILPM in a patient with partial IFN-γR1 deficiency. ILPM should be included in the differential diagnosis of persistent vulvar ulcerovegetative lesions.

TGF-β1 is an important growth factor that may influence the odontoblast differentiation and matrix deposition in the reactionary/reparative dentinogenesis to dental caries or other tooth injuries. TGF-β1 exerts its effects through various signaling pathways, such as Smads and MAPKs. Cyclooxygenase-2 (COX-2) is a membrane-associated enzyme that produces prostaglandin E2 (PGE2) at sites of pulpal injury and inflammation, which leads to tissue swelling, redness and pain. The purposes of this study were to investigate the differential signal transduction pathways of TGF-β1 that mediate COX-2 stimulation and PGE2 production in dental pulp cells. Methods: Pulp cells were exposed to TGF-β1 with/without SB431542 (an ALK5/Smad2 inhibitor) and U0126 (a MEK/ERK inhibitor). MTT assay was used to estimate cell viability. Enzyme-linked immunosorbent assay (ELISA) was used for measurement of PGE2 levels. RT-PCR and western blot were used to determined COX-2 mRNA and protein, respectively. Results: Exposure to TGF-β1 (1–10 ng/ml) increased the COX-2 mRNA and protein level of cultured pulp cells. Exposure to TGF-β1 (0.1–10 ng/mL) significantly stimulated PGE2 production of dental pulp cells. Under the pretreatment of SB431542, the stimulatory effect of TGF-β1 on COX-2 level of pulp cells was inhibited. Similarly, U0126 also partly inhibited the TGF-β1-induced COX-2 expression. Conclusion: TGF-β1 increased the COX-2 and PGE2 level of cultured pulp cells. The effect of TGF-β1 on COX-2 protein expression was associated with ALK5/Smad2/3 and MEK/ERK pathways. These events are important in the early inflammation, repair and regeneration of dental pulp in response to injury.

Background: Genetic predisposition of the inflammatory-host response may affect the development of psoriasis. Previous studies have shown that copy number variations (CNVs) of β-defensin genes (DEFB) are associated with the susceptibility of psoriasis in Caucasian populations. Objectives: This study aimed to assess the role of the CNVs of the DEFB4 gene and functional variants in the DEFB1 gene in Taiwanese patients with psoriasis. Methods: In total, 196 patients with psoriasis and 196 control individuals were analyzed for the presence of the DEFB4 CNVs using the paralogue ratio test, and also for the DEFB1 polymorphisms rs11362, rs1800972, and rs1799946, using a polymerase chain reaction. Results: None of the polymorphisms were found to be associated with psoriasis. The distribution of DEFB4 genomic CNVs did not significantly differ between the control group and psoriasis group. The frequencies of patients who carried a greater than the median (≥ 5) number of copies did not significantly differ in patients with psoriasis and controls. The multivariate analysis similarly revealed that the DEFB4 CNVs were not associated with psoriasis (odds ratio = 1.03, 95% confidence interval = 0.89–1.19, p = 0.720). No significant difference was detected in the genotype and allele distribution for any of the individual DEFB1 polymorphisms between the cases and the controls. Finally, the overall haplotype frequency profiles derived from the three polymorphisms did not significantly differ between the cases and the controls. Conclusion: Our results do not suggest that these genetic variants of the β-defensin genes contribute to the genetic background of psoriasis in Taiwanese patients.

Non-small cell lung cancer (NSCLC) accounts about 80% of all lung cancers. More than two-thirds of NSCLC patients have inoperable, locally advanced or metastatic tumors. Non-toxic agents that synergistically potentiate cancer-killing activities of chemotherapeutic drugs are in high demand. YL-9 was a novel and non-cytotoxic compound with the structure related to sildenafil but showing much less activity against phosphodiesterase type 5 (PDE5). NCI-H460, an NSCLC cell line with low PDE5 expression, was used as the cell model. YL-9 synergistically potentiated vinorelbine-induced anti-proliferative and apoptotic effects in NCI-H460 cells. Vinorelbine induced tubulin acetylation and Bub1-related kinase (BUBR1) phosphorylation, a necessary component in spindle assembly checkpoint. These effects, as well as BUBR1 cleavage, were substantially enhanced in co-treatment with YL-9. Several mitotic arrest signals were enhanced under combinatory treatment of vinorelbine and YL-9, including an increase of mitotic spindle abnormalities, increased cyclin B1 expression, B-cell lymphoma 2 (Bcl-2) phosphorylation and increased phosphoproteins. Moreover, YL-9 also displayed synergistic activity in combining with vinorelbine to induce apoptosis in A549 cells which express PDE5. In conclusion. the data suggest that YL-9 is a novel agent that synergistically amplifies vinorelbine-induced NSCLC apoptosis through activation of spindle assembly checkpoint and increased mitotic arrest of the cell cycle. YL-9 shows the potential for further development in combinatory treatment against NSCLC.

Cutaneous adverse drug reactions are commonly seen in patients with anticancer drug treatment. Anticancer drugs, including chemotherapy, target therapy, and recent immunotherapy causing skin reactions ranging from mild skin rash to life-threatening severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) with increase morbidity and mortality while they are receiving cancer treatments, have been proposed to be a result of direct skin toxicity or drug hypersensitivity reactions (these are proposed mechanism, not definite). Differentiating SCARs from other more commonly seen reactions with a better outcome help prevent discontinuation of therapy and inappropriate use of systemic immunosuppressants for presumable allergic reactions, of which will affect the clinical outcome. In this article, we have reviewed published articles from 1950 to August 2017 for SJS/TEN associated with anticancer drugs, including chemotherapy, targeted therapy, and immunotherapy. We aimed to provide an overview of SJS/TEN associated with anticancer drugs to increase clinician recognition and accelerate future studies on the pathomechanism and managements.

Objectives: Sudden neurosensory deafness is the second debilitating disease in China. In fact, the current treatment is limited to hearing aids, assistive devices and cochlear implants. However, some patients might not be suitable for surgery or even hearing aids. Methods: Hereby, we report a pediatric case of sudden sensorineural hearing loss accompanied by otalgia and blocked ear sensation. Results: He firstly failed with conventional treatment but later his hearing symptoms were improved with our electro-acupuncture therapy according to pure tone audiometry findings and clinical responses. Conclusions: It may be worth trying in patients with sudden neurosensory deafness, who do not respond to routine medical treatment. In line with previous studies, the current report indicates that future observational studies or even clinical trials are needed to prove the efficacy of acupuncture on hearing loss and the accompanying symptoms.

Adverse drug reactions (ADRs) remain a common and major problem in healthcare. Severe cutaneous adverse drug reactions (SCARs), such as Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) with mortality rate ranges from 10% to more than 30%, can be life threatening. A number of recent studies demonstrated that ADRs possess strong genetic predisposition. ADRs induced by several drugs have been shown to have significant associations with specific alleles of human leukocyte antigen (HLA) genes. For example, hypersensitivity to abacavir, a drug used for treating of human immunodeficiency virus (HIV) infection, has been proposed to be associated with allele 57:01 of HLA-B gene (terms HLA-B∗57:01). The incidences of abacavir hypersensitivity are much higher in Caucasians compared to other populations due to various allele frequencies in different ethnic populations. The antithyroid drug- (ATDs- ) induced agranulocytosis are strongly associated with two alleles: HLA-B∗38:02 and HLA-DRB1∗08:03. In addition, HLA-B∗15:02 allele was reported to be related to carbamazepine-induced SJS/TEN, and HLA-B∗57:01 in abacavir hypersensitivity and flucloxacillin induced drug-induced liver injury (DILI). In this review, we summarized the alleles of HLA genes which have been proposed to have association with ADRs caused by different drugs.

Cervical invasive root resorption is a type of external inflammatory root resorption that is relatively uncommon and aggressive, and leads to loss of tooth structure. A diagnosis of cervical invasive root resorption depends on careful routine clinical and radiographic examinations. This report describes the diagnosis and successful treatment of a 41-year-old male patient with invasive cervical root resorption at tooth #21. The distinctive feature was a large resorptive defect at the cervicopalatal aspect of the maxillary central incisor involving the root-canal space. A radiographic examination revealed a large periradicular lesion and severe periodontal damage around this tooth. The defect was surgically repaired using resin-reinforced glass ionomer cement (GIC) and mineral trioxide aggregate (MTA) to restore the coronal half and apical half of the resorption cavity, respectively. Thereafter, conventional root-canal treatment was performed. The 11-month recall revealed good healing of both the periodontal and periradicular conditions and no obvious clinical symptoms. This case provides a new treatment modality to repair defects of cervical invasive root resorption and promote the healing of periodontal defects.

The acquisition of transition metal ions is essential for the viability and in some cases the expression of virulence genes in bacteria. The fimCBA operon of Streptococcus parasanguinis FW213 encodes a Mn(2+)/Fe(2+)-specific ATP-binding cassette transporter. FimA, a lipoprotein in the system, is essential for the development of endocarditis, presumably by binding to fibrin monolayers on the damaged heart tissue. Recent sequence analysis revealed that Spaf_0344 was homologous to Streptococcus gordonii scaR, encoding a metalloregulatory protein for the Sca Mn(2+)-specific transporter. Based on the homology, Spaf_0344 was designated fimR. By using various fim promoter (p fim ) derivatives fused with a promoterless chloramphenicol acetyltransferase gene, the functions of the cis-elements of p fim were analyzed in the wild-type and fimR-deficient hosts. The result indicated that FimR represses the expression of p fim and the palindromic sequences 5' to fimC are involved in repression of p fim . A direct interaction between FimR and the palindromic sequences was further confirmed by in vitro electrophoresis gel mobility shift assay and in vivo chromatin immunoprecipitation assay (ChIP)-quantitative real-time PCR (qPCR). The result of the ChIP-qPCR analysis also indicated that FimR is activated by Mn(2+) and, to a lesser degree, Fe(2+). Functional analysis indicated that the expression of FimA in S. parasanguinis was critical for wild-type levels of survival against oxidative stress and within phagocytes, but not for acid tolerance. Taken together, in addition to acting as an adhesin (FimA), the expression of the fim operon is critical for the pathogenic capacity of S. parasanguinis.