Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing.

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+ CD27+ immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+ CD27+ IgD- memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+ CXCR3- CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.

Cherubism: panoramic and CT features in adults.

OBJECTIVES: To describe the panoramic radiographic and CT features of cherubism in an unselected series of 15 adults. METHODS: In this cross-sectional study, 15 individuals aged 29-84 years with familial non-syndromal molecularly confirmed cherubism were examined with panoramic radiography and CT. Bone abnormalities were analysed and described. RESULTS: 11 (73%) of the 15 adults had mandibular abnormalities. These abnormalities ranged from subtly detectable to severe, and were less prevalent and expansive but could be rather similar to the characteristic image features in children. Unilocular radiolucencies were more common than multilocular radiolucencies, and a specific feature of these abnormalities was that they were exclusively found in the anterior mandible. CONCLUSIONS: The radiographic and CT abnormalities of cherubism in adults were frequent and extremely heterogeneous, with some distinct features.

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

Oligodontia is associated with extra-oral ectodermal symptoms and low whole salivary flow rates.

INTRODUCTION: Ectodermal dysplasias (EDs) involve abnormal development of hair, teeth, nails, and sweat glands. OBJECTIVES: (1) To investigate the frequency of extraoral ectodermal symptoms in persons with oligodontia (>6 congenitally missing teeth). (2) To examine whole salivary flow rates in oligodontia patients, with special emphasis on persons with EDs. SURVEY GROUP AND METHODS: Sixty-eight persons with oligodontia and 39 healthy control persons were included. All participants underwent an interview, general and oral examinations, and whole salivary secretory tests. RESULTS: Thirty-nine (57%) of the oligodontia patients had disturbances in either hair, nails and/or sweat production in addition to teeth and were classified as the ED group. The remaining 29 oligodontia patients had no obvious signs of EDs (non-ED group). The prevalences of dry skin, asthma and eczema were higher, and whole salivary secretory rates lower, in the ED group as compared to the control group. Intermediate values were observed in the non-ED group. Incisors, canines and molars were more frequently missing in the ED group than in the non-ED group, whereas no differences were observed in the frequency of missing premolars. Negative correlations between the number of missing teeth and unstimulated and chewing stimulated whole salivary secretory rates were found.

Basal cell carcinoma of the buccal mucosa.

True basal cell carcinoma (BCC) involving the oral mucous membranes is extraordinarily rare. Most of those described as occurring in the oral cavity usually involve the gingiva and are not true BCCs but peripheral ameloblastomas. A true BCC, which arose on the buccal mucosa of a 69-year old man, is reported. It presented as a 1.3 cm ulcerated plaque without gingival connection. Histologically, the lesion exhibited classic features of BCC with palisading and retraction spaces, and focally communicated with the overlying squamous epithelium. Although it is possible that this lesion also arose from a heterotopic odontogenic rest, the anatomical location, focal squamous (metatypical) features, and positive staining for Ber-EP4 support an origin from the basal cell layer of stratified squamous mucosa.

Primary Sjögren's syndrome: salivary gland function and clinical oral findings.

OBJECTIVE: To evaluate salivary gland function, saliva composition and oral findings in patients with primary Sjögren's syndrome (pSS) subdivided into patients with and without focus score > or = 1 (FS) and/or antibodies to SSA/SSB (AB) as well as in healthy controls. SUBJECTS AND METHODS: Unstimulated (UWS) and chewing stimulated (SWS) whole saliva, and stimulated parotid saliva (SPS) were collected in 16 patients fulfilling the European classification criteria for pSS subdivided into those with FS and/or AB (n = 8) and those without FS and AB (n = 8), and in age-matched (n = 14) and young healthy controls (n = 13). UWS and SWS were analysed for Na+ and K+. SPS was analysed for Na+, K+, statherin, and proline-rich proteins (PRPs). Sicca symptoms, DMFT/DMFS, plaque (PI) and gingival (GI) scores, periodontal pocket depth (PPD), and mucosal status were recorded. RESULTS: The young healthy controls had lower UWS as compared to the aged controls (P = 0.03). However, the aged controls had higher DMFT/DMFS (P < 0.001) and PI, GI and PPD (P < 0.01). Patients with FS and/or AB generally had lower saliva secretory rates than patients without FS and/or AB (P = 0.01 for UWS and SPS) and age-matched healthy controls (P = 0.001). There was no significant difference in the content of Na+ and K+, statherin and PRPs between groups. Patients with FS and/or AB had the highest frequency of oral mucosal changes and higher DMFT/DMFS than patients without FS and/or AB and healthy controls (P < 0.01). However, PI, GI, and PPD did not differ significantly. CONCLUSION: Patients with FS and/or AB had lower salivary secretory rates, higher DMFT/DMFS, and more oral mucosal changes than patients without FS and/or AB. Additionally, data suggest that salivary gland function in healthy individuals do not decrease with age.

Oral and ocular sicca symptoms and findings are prevalent in systemic lupus erythematosus.

The aims of this study were 1) to examine the frequency of oral and ocular sicca symptoms in patients with systemic lupus erythematosus (SLE); 2) to compare saliva and tear volume, salivary proteins, and features of the oral microflora and mucosa to a matched healthy control group; and 3) to relate the findings to disease parameters. Median disease duration was 5.5 (0.5-28) years, disease activity 5 (2-20), damage score 1 (0-7), and Schirmer I test 7.5 (0-30 mm). Seventeen and twelve patients complained of oral and ocular dryness, respectively. Unstimulated whole saliva and proline-rich proteins in submandibular saliva were significantly reduced in SLE. Oral microbial counts were generally higher in the patients than controls, and the number of oral mucosal changes was increased. The results show that sicca symptoms, although frequent, were not correlated to secretory rates of saliva or tears, but to oral microbial counts. There was no obvious correlation to patient's age, disease activity or duration.

Outpatient 5-fluorouracil, folinic acid and cisplatin in patients with advanced esophageal carcinoma.

In a multicenter phase II study, 30 patients with unresectable, locally advanced or metastatic squamous cell or adenocarcinoma of the esophagus were treated with folinic acid 200 mg/m2/d, 5-FU 300 mg/m2/d, and cisplatin 20 mg/m2/d intravenously for 5 days every 4 weeks. Two of 13 patients with squamous cell carcinoma (SCC) had a complete response (CR), but one died of pneumonia after 9 months while still in CR, and the other still in CR after more than 5 years. Six other patients (3 SCC, 2 of 16 with adenocarcinoma, 1 mixed histology) had a partial response with a median duration of 9 months (range 5 to 57 + months) for an overall response rate of 27%. A further 6 patients (20%) had stable disease. Grade 4 neutropenia occurred in 6 patients (20%), with 5 requiring antibiotics for associated fever. Other grade 4 toxicities were nausea and vomiting (1), anemia (1), and thrombocytopenia (1); there were three early deaths (emphysema, cardiac arrest, pulmonary embolism). This combination appears to be an active, convenient regimen for advanced esophageal cancer, resulting in prolonged remission and survival in some patients.

Salivary secretions: narcolepsy and central nervous system stimulants.

In an ongoing attempt to develop a model to study the influence of various diseases and drugs on saliva, we studied persons with narcolepsy treated with central nervous system stimulants. The aim was to study the secretion of salivary proteins in narcolepsy in the presence and absence of central nervous system stimulants. For this purpose, two proteins synthesized in acinar cells, acidic proline-rich proteins (PRPs) and statherin, were selected. Persons with narcolepsy treated with central nervous system stimulants only were included, n = 12, ages 14 to 68, seven females. Citric-acid-stimulated parotid and submandibular/sublingual saliva samples were collected from these persons during medication, after a drug-free period of one week, at least two weeks after the drug had been re-introduced, and from a matched healthy control group. PRP and statherin concentrations were determined by means of reversed-phase and anion exchange chromatography, respectively. Both concentration and output of statherins and PRPs were increased in persons with narcolepsy receiving central nervous system stimulants compared with healthy control individuals. When the drug was withdrawn, salivary flow rates were not influenced. In contrast, withdrawal of the drug led to a significantly decreased secretion of PRPs and statherin. The reduced protein secretion may reflect decreased adrenergic activation in narcolepsy, to be reversed by treatment with central nervous system stimulants. It can be concluded that measurements of both salivary fluid and salivary proteins may be necessary for an overall evaluation of the effects of a given drug or disease on salivary secretion.

Salivary gland involvement in hypohidrotic ectodermal dysplasia.

Ectodermal dysplasias (EDs) are a group of developmental disorders (more than 100) mainly affecting ectodermal tissues and organs. The X-linked hypohidrotic ED (HED) is the most common form of EDs, involving defects in teeth, sweat glands, and hair. In a few reports, HED has been associated with reduced salivary function. In the present case report, a dramatically reduced salivary fluid and acidic proline rich protein production was identified in a 38-year-old man with HED. Computed tomography was performed, revealing that one submandibular gland and both parotid glands were hypoplastic, whereas the right submandibular gland seemed to be absent. These findings are in line with a general developmental disturbance also involving the salivary glands. As salivary tests are inexpensive and easy to perform, it is suggested to routinely evaluate salivary secretion in persons with HED, to prevent a possible negative impact on oral health.

Clinical implications of the dry mouth. Oral mucosal diseases.

Salivary hypofunction caused by salivary gland disease, medication, or radiation may predispose for secondary oral mucosal diseases. In these patients the protective coating of saliva is reduced or absent, leaving the oral mucosa more vulnerable. Candidiasis, burning mouth syndrome, and white lesions of the oral mucosa are increased in frequency. The aim of management is to prevent oral pathological changes. The management procedure may include proper oral hygiene, saliva-stimulating agents, or saliva substitutes, depending on the severity of the salivary dysfunction. Treatment includes antifungal therapy if candidiasis is diagnosed. In severely distressed patients, local or systemic corticosteroids may be indicated. Precautions, like refraining from smoking and avoiding toothpastes containing sodium lauryl sulfate, should also be taken. In the future, agents combining antibacterial and antiinflammatory actions, like triclosan, may show promising effects in patients with oral mucosal diseases secondary to salivary hypofunction.

Salivary acidic proline-rich proteins in rheumatoid arthritis.

In an ongoing attempt to investigate qualitative salivary parameters in diseases affecting salivary glands, patients with rheumatoid arthritis (RA) were examined. Patients were selected from the Oslo RA register for the present study if they fulfilled the following criteria: age 52-74 years, disease duration 10-20 years, and disability score as assessed by the Modified Health Assessment Questionnaire < or = 2.5. From these 105 patients, two subgroups of patients were selected, one group with pronounced sicca symptoms from eyes and mouth, and one group without such symptoms. Sicca symptoms were assessed using a postal questionnaire with the questions on dry mouth and dry eyes of the European classification criteria for Sjögren's syndrome. Patients were excluded from further examinations if they used medication that could cause dryness in eyes or mouth. Thus, nine patients remained in the sicca group (having four or more sicca symptoms), and ten matched RA patients were selected for the nonsicca group. A healthy sex- and age-matched control group (n = 10) was also examined. In a preliminary report we have shown that differences in flow rates between sicca and nonsicca RA patients were limited to lower values of unstimulated whole saliva. To further evaluate salivary changes in RA, a disease frequently associated with secondary Sjögren's syndrome, we have studied qualitative salivary parameters in these patients,' including secretory rates of proline-rich proteins (PRPs), statherins, and histatins. In the present report, phenotypes of PRPs, the ratio of PRPs derived from the two loci (PRH1 and PRH2), and PRP concentration and output in parotid and submandibular saliva derived from the two loci are presented. Parotid (PS) and submandibular saliva (SS) were collected from all individuals using 2% citric acid as a saliva stimulus. PRPs in PS and SS were identified using a SMART microchromatographic system with a Mono Q column and a Tris-HCl/NaCl gradient (method adapted from ref. 5). For PRPs, the primary polypeptide products are coded for on two loci (PRH1 and PRH2), which have three and two commonly occurring gene variants, respectively. On PRH1, the proteins PIF-s, Db-s, and Pa are coded for, whereas PRP-1 and PRP-2 are coded for on the PRH2 locus. As each protein variant has a postranscriptional cleavage product, individuals will exhibit four, six, or eight PRPs in their saliva, depending on whether they are homozygous at both, one, or neither of the two loci. Accordingly, 18 possible phenotypes may exist, but as few as three phenotypes were found in 79% of the 127 healthy individuals examined by Hay et al. The SMART system allows the determination of the different acidic PRPs present in saliva. Concentrations of the various phenotypes were calculated by peak integration versus pure PRP standards. Total PRP concentration derived from each locus was calculated as the sum of the concentrations of PRP variants from that locus.

Millimeter wave-induced vibrational modes in DNA as a possible alternative to animal tests to probe for carcinogenic mutations.

Developing methods for alternative testing is increasingly important due to dwindling funding resources and increasing costs associated with animal testing and legislation. We propose to test the feasibility of a new and novel method for detecting DNA mutagenesis using millimeter wave spectroscopy. Although millimeter wave spectroscopy has been known since the 1950s, the cost was prohibitive and studies did not extend to large biological proteins such as DNA. Recent advances have made this technology feasible for developing laboratory and field equipment. We present preliminary findings for lesion-induced vibrational modes in DNA observed from 80 to 1000 gigahertz (GHz). These findings suggest that there are vibrational modes that can be used as identification resonances. These modes are associated with localized defects of the DNA polymers. They are unique for each defect/lesion, and should be easy to detect. We described a field-detecting detector based on the local modes.

Doppler evaluation of left and right ventricular diastolic function: a technical guide for obtaining optimal flow velocity recordings.

Doppler mitral flow velocities and related variables are used to assess left (LV) and right ventricular filling and, indirectly, ventricular diastolic function. Three abnormal ventricular filling patterns (impaired relaxation and pseudonormal and restrictive physiology) are recognized in patients with various heart diseases and have been related to alterations in LV diastolic properties and filling pressures. More recently, these variables have been used to assess the hemodynamic effects of drug therapy or heart surgery and prognosis in patients with restrictive and dilated cardiomyopathies. Despite these encouraging results, widespread clinical use of these Doppler techniques has been hampered by difficulties in obtaining accurate and reproducible measurements from Doppler flow velocity recordings. This is due, in part, to an underappreciation of factors such as cardiac filling mechanics, Doppler examination principles, and ultrasound machine settings, which can markedly affect the quality of the flow velocity recordings. The purpose of this article is to provide the technical information for performing a systematic and comprehensive Doppler evaluation of LV diastolic function that can be used on a routine basis. This information includes discussing the different flow velocity recordings required for a Doppler assessment of LV diastolic function, their proper recording technique, and the common technical pitfalls.

[Temporary radiation-induced hypo-salivation in a child]. / Forbigående stråleindusert hyposalivasjon hos barnepasient.

This case report deals with the diagnosis and treatment of hyposalivation after radical radiation therapy and cytotoxic treatment of a metastasising nasopharyngeal carcinoma in an eight-year old girl. After cancer treatment the patient suffered from xerostomia, and pronounced hyposalivation was demonstrated. Frequent chewing of sugar-free gum and use of lozenges was recommended, and the patient was followed up for one year. During this time, the values for unstimulated whole saliva increased by a factor of five, and stimulated whole saliva values increased as well, but less so. Two years after cancer treatment, the patient no longer suffers from xerostomia.

Characteristics of rheumatoid arthritis patients with self-reported sicca symptoms: evaluation of medical, salivary and oral parameters.

OBJECTIVES: To examine the prevalence of sicca symptoms in rheumatoid arthritis (RA)-patients, and to evaluate medical, salivary, and oral parameters in matched subgroups of patients with and without sicca symptoms as well as in healthy controls. PATIENTS AND METHODS: The prevalence of self-reported sicca symptoms was examined by a postal questionnaire in a representative cohort of RA-patients (n = 105, aged 52-74 years, disease duration 10-20 years, 77% females, 56% RF-positive). Patient subgroups and controls (9-10 in each group) underwent examinations of disease activity, blood analyses, tests of tear and salivary secretion, and examination of oral mucosa and microflora. Analyses of salivary acidic proline-rich proteins (PRPs), statherin and histatins were performed. RESULTS: One or more sicca symptoms were reported by 65% of RA-patients. Sicca patients (having > or = 4 sicca symptoms) had a more active and severe disease with higher scores for disability, fatigue and tender joints than patients without such symptoms. Other significant findings in the sicca group were lower values of unstimulated whole saliva, output of PRPs, statherin and histatins in submandibular saliva, and higher counts of oral Candida species. CONCLUSIONS: Sicca symptoms were prevalent in RA. Qualitative and quantitative salivary tests distinguished between sicca and non-sicca RA-patients, though overlap was considerable for some parameters.

Meningioma-like tumor of the skin. An ultrastructural and immunohistochemical study.

Three unusual cutaneous tumors are described along with ultrastructural and immunohistochemical studies. All lesions were asymptomatic red-brown papulonodules. Light microscopic examination revealed a whorled configuration of spindle-shaped cells, some concentrically arranged around blood vessels. Immunohistochemical panels exhibited positive staining only with antibody to vimentin and negative staining with antibodies against S-100 protein, muscle markers, cytokeratin, epithelial membrane antigen, Leu 7, type IV collagen, and factor XIIIa, ruling out obvious nevomelanocytic, nerve sheath, meningothelial, smooth muscle, and perithelial differentiation. Electron microscopic examination demonstrated cells producing poorly formed collagen fibrils, sparse collagen fibers, and possessing occasional ill-defined intercellular junctions between their elongated cell processes. This rare tumor is considered to be either an immature fibrohistiocytic or possibly a nerve sheath neoplasm with striking similarities to so-called canine hemangiopericytoma. Because the prominent whorled pattern was reminiscent of meningioma, the lesion was referred to as meningioma-like tumor of the skin.

Verruciform xanthoma of the ear with coexisting epidermal dysplasia.

We report a case of verruciform xanthoma of the ear in a 79-year-old man. The case is unique in that it contained an area of solar keratosis. In situ hybridization using biotin-labeled probe cocktails for human papillomavirus types 6/11, 16/18, and 31/33/35 yielded negative results.

Adsorption of human salivary proteins to hydroxyapatite: a comparison between whole saliva and glandular salivary secretions.

The protein compositions of in vitro pellicles formed from whole saliva and parotid and submandibular secretions were determined by use of synthetic hydroxyapatite as a model for dental enamel. The adsorbed and unadsorbed protein fractions were analyzed by amino acid analysis and both anionic and cationic discontinuous polyacrylamide gel electrophoresis. For further characterization of the in vitro pellicle, the adsorbed fractions were subjected to gel filtration on Sephadex G-100 and reversed-phase chromatography on C18 columns. Amylase, acidic and glycosylated proline-rich proteins, statherins, and histatins were identified in the parotid-derived pellicle. Detailed analysis of the statherin-containing fractions resulted in the observation of several statherin-like proteins. The use of cationic gel electrophoresis allowed for the identification of histatin 3 and histatin 5, which have not been previously detected in pellicle formed in vitro. The protein composition of submandibular-derived pellicle was similar to that of parotid-derived pellicle except for the presence of cystatins and the absence of glycosylated proline-rich proteins. In contrast, in vitro pellicle derived from whole saliva exhibited a vastly different composition, consisting primarily of amylase, acidic proline-rich proteins, cystatins, and proteolytically-derived peptides. The results indicate that acidic phosphoproteins as well as neutral and basic histatins from pure secretions selectively adsorb to hydroxyapatite, whereas in whole saliva some of these proteins are proteolytically degraded, dramatically changing its adsorption pattern.