The salivary proteome in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients: a labelled and label-free proteomics approach.

BACKGROUND: Oral mucositis is a frequently seen complication in the first weeks after hematopoietic stem cell transplantation recipients which can severely affects patients quality of life. In this study, a labelled and label-free proteomics approach were used to identify differences between the salivary proteomes of autologous hematopoietic stem cell transplantation (ASCT) recipients developing ulcerative oral mucositis (ULC-OM; WHO score ≥ 2) or not (NON-OM). METHODS: In the TMT-labelled analysis we pooled saliva samples from 5 ULC-OM patients at each of 5 timepoints: baseline, 1, 2, 3 weeks and 3 months after ASCT and compared these with pooled samples from 5 NON-OM patients. For the label-free analysis we analyzed saliva samples from 9 ULC-OM and 10 NON-OM patients at 6 different timepoints (including 12 months after ASCT) with Data-Independent Acquisition (DIA). As spectral library, all samples were grouped (ULC-OM vs NON-OM) and analyzed with Data Dependent Analysis (DDA). PCA plots and a volcano plot were generated in RStudio and differently regulated proteins were analyzed using GO analysis with g:Profiler. RESULTS: A different clustering of ULC-OM pools was found at baseline, weeks 2 and 3 after ASCT with TMT-labelled analysis. Using label-free analysis, week 1-3 samples clustered distinctly from the other timepoints. Unique and up-regulated proteins in the NON-OM group (DDA analysis) were involved in immune system-related processes, while those proteins in the ULC-OM group were intracellular proteins indicating cell lysis. CONCLUSIONS: The salivary proteome in ASCT recipients has a tissue protective or tissue-damage signature, that corresponded with the absence or presence of ulcerative oral mucositis, respectively. TRIAL REGISTRATION: The study is registered in the national trial register (NTR5760; automatically added to the International Clinical Trial Registry Platform).

Significant salivary changes in relation to oral mucositis following autologous hematopoietic stem cell transplantation.

The aim of this multicentre, longitudinal study was to determine salivary changes in relation to oral mucositis (OM) in multiple myeloma patients following high-dose melphalan and autologous hematopoietic stem cell transplantation (ASCT). Unstimulated and stimulated whole-mouth saliva samples (UWS and SWS) were collected before ASCT, 1×/wk during the hospitalisation phase, and 3 and 12 months post-ASCT. During the hospitalisation period OM was scored 3×/wk (WHO system). Flow rate, pH, total protein concentration (Nanodrop), albumin, lactoferrin, neutrophil defensin-1 (HNP1), total IgA and S100A8/A9 (ELISA) were determined. Mixed models were used to evaluate differences between ulcerative (u)OM (≥2 WHO, n = 20) and non-uOM (n = 31) groups. Until 18 days after ASCT, flow rate, pH, total IgA and HNP1 levels decreased in UWS and/or SWS, while log lactoferrin levels were significantly increased (UWS: p = 0.016 95% CI [0.36, 3.58], SWS: p < 0.001 95% CI [1.14, 3.29]). Twelve months post-ASCT, salivary protein levels were similar to baseline except for log total IgA, which was higher (UWS: p < 0.001 95% CI [0.49, 1.29], SWS: p < 0.001 95% CI [0.72, 1.45]). No differences between uOM and non-uOM groups were observed. Changes in salivary proteins indicated an inflammatory reaction in salivary glands coinciding with mucosal and systemic reactions in response to high-dose melphalan.

Theoretical and hands-on guidance from dental hygienists promotes good oral health in elderly people living in nursing homes, a pilot study.

OBJECTIVES: Oral health in nursing homes for elderly is often unsatisfactory, and oral health education to nursing staff has not shown sufficient results why there is need for novel approaches. The aim of the study was to trial a new oral healthcare educational programme and to evaluate the effects on residents' oral health. In addition, attitudes among the nursing staff in the intervention nursing home were explored. METHODS: In a controlled clinical trial, two comparable nursing homes were randomly assigned for intervention or control. Interventions included weekly theoretical and hands-on guidance from dental hygienists on oral hygiene procedures and discussions on oral care routines. The residents' oral health, measured by the Revised Oral Assessment Guide (ROAG), dental plaque and gingival bleeding were evaluated at baseline and after 3 months. Attitudes among the staff to oral health care were measured at the intervention nursing home. RESULTS: Revised Oral Assessment Guide gums and lips scores showed a tendency to decrease in the intervention group, but remained high in the control group. Plaque levels improved significantly after intervention, and a trend towards less gingival bleeding was observed. The intervention nursing staff seemed to be more aware of their own limitations concerning oral health care after intervention and valued more frequent contact with dental services to a greater extent. CONCLUSIONS: The oral healthcare situation for elderly people today is so complex that theoretical education at the group level regarding different aspects of oral health is not sufficient. Individual hands-on guidance by dental hygienists on a regular basis in everyday care may be a new approach.

Oral care perspectives of professionals in nursing homes for the elderly.

OBJECTIVES: Good oral health is an important aspect of quality of life. However, a number of studies have shown that oral care for the dependent elderly is unsatisfactory. The aim was to explore in nursing homes for the elderly what professionals with different responsibilities may consider as being important aspects of well-functioning daily oral care. METHODS: A total of 23 informants from three municipalities in the region of Värmland, Sweden, were interviewed. An interview guide was used, containing some demographic and open-ended questions about individual perceptions of issues according to the study aim. The interviews were tape-recorded and transcribed verbatim. RESULTS: In the manifest and latent analyses, six categories and three themes emerged. The categories were Key Processes, Communication, Priorities, Competence, Good Oral Health and Autonomy. The themes were Organization, Staff Approach and Staff's Views on Residents' Needs. An overall picture emerged that oral care, rather than occupying an integral position, played a peripheral role in nursing care. CONCLUSIONS: To improve oral care, there are opportunities to work with existing structures and clarify responsibilities and key processes. Oral care should be included in nursing work as a more highly prioritized task, and nurses' knowledge needs to be enhanced. A network of activities at all levels is needed to implement oral care in nursing care.

Human papillomaviruses in oral carcinoma and oral potentially malignant disorders: a systematic review.

OBJECTIVES: Human papillomavirus (HPV) in oral carcinoma (OSCC) and potentially malignant disorders (OPMD) is controversial. The primary aim was to calculate pooled risk estimates for the association of HPV with OSCC and OPMD when compared with healthy oral mucosa as controls. We also examined the effects of sampling techniques on HPV detection rates. METHODS: Systematic review was performed using PubMed (January 1966-September 2010) and EMBASE (January 1990-September 2010). Eligible studies included randomized controlled, cohort and cross-sectional studies. Pooled data were analysed by calculating odds ratios, using a random effects model. Risk of bias was based on characteristics of study group, appropriateness of the control group and prospective design. RESULTS: Of the 1121 publications identified, 39 cross-sectional studies met the inclusion criteria. Collectively, 1885 cases and 2248 controls of OSCC and 956 cases and 675 controls of OPMD were available for analysis. Significant association was found between pooled HPV-DNA detection and OSCC (OR = 3.98; 95% CI: 2.62-6.02) and even for HPV16 only (OR = 3.86; 95% CI: 2.16-6.86). HPV was also associated with OPMD (OR = 3.87; 95% CI: 2.87-5.21). In a subgroup analysis of OPMD, HPV was also associated with oral leukoplakia (OR = 4.03; 95% CI: 2.34-6.92), oral lichen planus (OR = 5.12; 95% CI: 2.40-10.93), and epithelial dysplasia (OR = 5.10; 95% CI: 2.03-12.80). CONCLUSIONS: The results suggest a potentially important causal association between HPV and OSCC and OPMD.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact.

PURPOSE: This systematic review aimed to assess the literature for management strategies and economic impact of salivary gland hypofunction and xerostomia induced by cancer therapies and to determine the quality of evidence-based management recommendations. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. For each article, two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions. RESULTS: Seventy-two interventional studies met the inclusion criteria. In addition, 49 intensity-modulated radiation therapy (IMRT) studies were included as a management strategy aiming for less salivary gland damage. Management guideline recommendations were drawn up for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. CONCLUSIONS: There is evidence that salivary gland hypofunction and xerostomia induced by cancer therapies can be prevented or symptoms be minimized to some degree, depending on the type of cancer treatment. Management guideline recommendations are provided for IMRT, amifostine, muscarinic agonist stimulation, oral mucosal lubricants, acupuncture, and submandibular gland transfer. Fields of sparse literature identified included effects of gustatory and masticatory stimulation, specific oral mucosal lubricant formulas, submandibular gland transfer, acupuncture, hyperbaric oxygen treatment, management strategies in pediatric cancer populations, and the economic consequences of salivary gland hypofunction and xerostomia.

A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life.

PURPOSE: This systematic review aimed to assess the literature for prevalence, severity, and impact on quality of life of salivary gland hypofunction and xerostomia induced by cancer therapies. METHODS: The electronic databases of MEDLINE/PubMed and EMBASE were searched for articles published in English since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies until 2008 inclusive. Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results and conclusions for each article. RESULTS: The inclusion criteria were met by 184 articles covering salivary gland hypofunction and xerostomia induced by conventional, 3D conformal radiotherapy or intensity-modulated radiotherapy in head and neck cancer patients, cancer chemotherapy, total body irradiation/hematopoietic stem cell transplantation, radioactive iodine treatment, and immunotherapy. CONCLUSIONS: Salivary gland hypofunction and xerostomia are induced by radiotherapy in the head and neck region depending on the cumulative radiation dose to the gland tissue. Treatment focus should be on optimized/new approaches to further reduce the dose to the parotids, and particularly submandibular and minor salivary glands, as these glands are major contributors to moistening of oral tissues. Other cancer treatments also induce salivary gland hypofunction, although to a lesser severity, and in the case of chemotherapy and immunotherapy, the adverse effect is temporary. Fields of sparse literature included pediatric cancer populations, cancer chemotherapy, radioactive iodine treatment, total body irradiation/hematopoietic stem cell transplantation, and immunotherapy.

Oral and intestinal microflora in 5-fluorouracil treated rats, translocation to cervical and mesenteric lymph nodes and effects of probiotic bacteria.

Serious systemic infections may occur during cancer chemotherapy due to disturbances in the oropharyngeal and gastrointestinal microflora, impaired mucosal barrier functions and immunosuppression. Bacteria may spread from the gastrointestinal tract to the regional lymph nodes. The routes for bacterial spread from the oral cavity are less well known. In the present study we investigated changes in the oral and intestinal microfloras in rats given 50 mg/kg 5-fluorouracil (5-FU) i.v. for 6 days. Bacterial dissemination to the lymph nodes draining the oral cavity and the lymph nodes draining the gastrointestinal tract was examined. Effects of adding the probiotic strain Lactobacillus plantarum 299v in the drinking water to the rats were measured. 5-FU treatment caused an increase in the number of facultative and strictly anaerobic bacteria in biopsies from the oral cavity and an increase in the number of facultative anaerobes in the large intestine. The proportion of facultative gram-negative rods increased in both the oral cavity and intestine. Bacteria translocated to both the cervical and mesenteric lymph nodes in untreated animals and increased in numbers after 5-FU treatment due to an increase in the number of facultative gram-negative rods. Treatment with L. plantarum 299v improved food intake and body weight in 5-FU-treated rats. It also reduced the 5-FU-induced raise in the total numbers of facultative anaerobes in the intestine, but did not reduce translocation and did not prevent diarrhea. This study reinforces the oral cavity, along with the gastrointestinal tract, as a source for bacterial dissemination. The use of probiotic bacteria may reduce some side effects of 5-FU treatment.

5-Fluorouracil induces autophagic degeneration in rat oral keratinocytes.

In this study, we investigated the effect of 5-fluorouracil (5-FU) on the keratinocytes of oral epithelium. Female Lewis rats were given 5-FU i.v. and were killed 12, 24 or 36 h after injection. The buccal mucosa was dissected. The number of nuclei with DNA strand breaks and the total number of nuclei per volume of the epithelial basal cell layer was estimated using terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling. Epithelial cells were analysed by flow cytometry, transmission electron microscopy and a dye exclusion test. The number of cells with DNA strand breaks increased in 5-FU treated rats. Flow cytometry showed a decrease in cell size and an increase in granularity with increasing doses of 5-FU. Dye exclusion gave no indication of degenerate cell membranes. By transmission electron microscopy, the cells showed evidence of degeneration, shrinkage and loss of cell-to-cell contact. Vacuolation was extensive and, in contrast to apoptotic cells, nuclear chromatin condensation seemed to occur centrally in the nuclei. The results show that 5-FU treatment in vivo induces alterations in rat oral keratinocytes that are consistent with autophagic degeneration.

Effects of 5-fluorouracil on mitogen-induced costimulatory capacity of accessory cells from rat oral mucosa and dental pulp.

The present study was designed to investigate the effect of the antimetabolite 5-fluorouracil (5-FU) on the capacity of the oral epithelium and the dental pulp to induce a mitogen-driven T-cell proliferation. Inbred Lewis rats were given 6 i.v. injections of 5-FU (30 mg/kg or 50 mg/kg) over a period of 8 days. Suspensions of oral epithelial and dental pulpal cells were prepared. The costimulatory capacity of the accessory cells from treated animals was monitored by their ability to induce a mitogen (ConA)-mediated proliferation of T cells isolated from regional lymph nodes of untreated animals. Accessory epithelial cells from rats treated with the high dose of 5-FU, but not the low dose, induced a decreased T-cell proliferation compared to controls. Accessory pulpal cells from rats, treated with 30 mg/kg or 50 mg/kg of 5-FU, induced a lower T-cell proliferation. When MHC class II molecule depleted T-cell suspensions from lymph nodes of 5-FU-injected animals were incubated with ConA, a significant proliferative response was observed. This finding correlated with an increase of MHC class II molecule expressing cells detected after incubation, although no such cells were observed immediately following the initial purification step of T cells. This finding demonstrates that the accessory cells could partly restore their expression of MHC class II molecules during incubation. The results of the study suggest that the function of immunocompetent cells of the oral mucosa and dental pulp is influenced by treatment with 5-FU and that the function of accessory cells of the pulp is affected more than the function of accessory cells derived from the oral mucosa.

Disappearance of noradrenaline from different parts of the rabbit external ear following superior cervical ganglionectomy.

Following superior cervical ganglionectomy the noradrenaline tissue levels in the base of the rabbit external ear started to decrease after about 12 hours. About 4 hours later noradrenaline started to decrease about simultaneously in the middle piece and the tip. Within 24 hours after ganglionectomy the noradrenaline decreased rapidly in all three pieces. Thereafter the noradrenaline of the base piece was levelling off at about 15% of the normal whereas the noradrenaline in the two other pieces remained at about 40% of the normal. The results indicate that the adrenergic innervation of the ear is complex, but that the base piece is supplied with adrenergic axons that are shorter than those of the middle and tip pieces. Based on 1: the delay of 4 hours observed in the pattern of the noradrenaline disappearance between the base and the two other pieces, and II: the difference in distance between the three pieces of the ear and the superior cervical ganglion, a transport rate of a "protecting factor" could be discussed to be about 1-2 cm/h. The rate of axonal transport of dopamine-beta-hydroxylase in the rabbit sciatic nerve, was found to be within the same range, being about 2 cm/h.