Oral Biosciences & Medicine
Oral Biosci Med 1 (2004), No. 2     7. July 2004

Oral Biosci Med 2/2004, S. 93-108

REVIEW ARTICLE

Oral Microflora in Patients with Salivary Gland Hypofunction

Esther Hofer a, b / Siri Beier Jensen a / Anne Marie Lynge Pedersen a / Allan Bardow a / Birgitte Nauntofte a

Abstract

Summary:
Saliva plays a significant role in the maintenance of oral hard and soft tissue integrity as well as for the oral microflora by providing mechanical cleansing, buffering effect and antimicrobial actions. Saliva not only enhances the clearance of micro-organisms and dietary carbohydrates from the oral cavity, but also regulates the composition and growth conditions of the oral microflora. It is well documented that the susceptibility to dental caries and oral mucosal infections is increased in patients suffering from low saliva flow rates. Nonetheless, only a limited number of studies have dealt with the impact of salivary gland hypofunction on the composition of oral microflora. Most of these studies have not included additional variables regarding environmental and behavioural factors that may contribute to changes in the oral microflora such as dental and general health status and sugar intake. This review has its main focus on the oral microflora in patients suffering from salivary gland hypofunction, be it temporary or permanent, due to different aetiologies like Sjgrens syndrome, radiation therapy of tumours in the head and neck region, cancer chemotherapy and intake of other medications. It also outlines the methods used for assessment of oral micro-organisms, and the numerous underlying factors affecting the interpretation of salivary and oral microbial findings.

Conclusions:
Despite the different causes of salivary gland hypofunction, these patient groups show some similarities with regard to their oral microbial composition and increased counts of oral pathogens associated with caries activity (mutans streptococci and lactobacilli) and mucosal infections (in particular, Candida albicans).

Key words:
Sjgrens syndrome, cancer therapy, medication, Candida, lactobacilli, mutans streptococci


INTRODUCTION

In healthy individuals, the saliva fluid and its solutes constantly covers the oral hard and soft tissues. Moreover, micro-organisms as well as dietary sugars are removed from the oral cavity by a cleansing process referred to as oral clearance (Dawes, 1983; Lagerlf and Oliveby, 1994; Lenander-Lumikari and Loimaranta, 2000), which is dependent on the whole saliva flow rates and the swallowing frequency by the individual. The oral microbial composition and growth conditions are also influenced by numerous salivary antimicrobial factors that are part of the oral defence mechanisms (for review, see Lenander-Lumikari and Loimaranta, 2000).

The saliva composition is dependent on the flow rate, the type of gland from which the saliva is secreted, and the nature and duration of the stimuli applied to activate the secretion reflexes (for review, see Pedersen et al, 2002a). The composition of salivary antimicrobial proteins may therefore vary from one oral site to another in an individual. Subsequently, oral sites can harbour specific microfloras depending on the sites morphology and the specific saliva composition (Rudney, 2000). Other local factors such as oral hygiene, dental caries, periodontitis, dental restorations and life-style factors can also affect the oral microflora (for review, see Almsthl, 2001a). This furthermore accounts for a number of systemic factors like diseases and their medications.

The significant role of saliva in the maintenance of a natural balance between oral host tissues and the oral microflora becomes evident when the saliva flow is reduced. In general, about 25% of the adult population is assumed to suffer from oral dryness (Sreebny and Valdini, 1988; see Table 1 for definitions). The most common causes of salivary gland hypofunction include intake of certain medications and systemic diseases. However, regardless of the aetiology of salivary gland hypofunction, changes in the oral ecology occur already at unstimulated whole saliva flow rates below 0.20 ml/min. At such flow rates, the oral microbial profile includes increased candidal scores (Navazesh et al, 1995) and increased numbers of lactobacilli (Bardow et al, 2001) leading to an increased risk of candidiasis and a high caries activity.

Although several clinical studies indicate that salivary gland hypofunction of various aetiologies leads to a seriously compromised oral health, only a few studies have addressed the impact on the oral microflora (for review, see Almsthl, 2001a). Most of these studies, however, suffer from lack of information concerning the dental and general health status and nutritional behaviour like sugar intake, and often it is not stated whether use of the term xerostomia covers the patients feeling of dry mouth, or if it is based on the objective measurement of reduced salivary flow rate. Oral microbiological findings and their interpretation are dependent on the cultivation techniques and sampling methods applied. The growth of oral microbial cultures under in vitro conditions (growth on a plain agar surface with controlled nutritional and environmental factors such as constant temperature and oxygen/carbon dioxide tension), however, does not resemble those found under in vivo conditions.

Furthermore, the use of different sampling methods makes comparisons of microbiological findings between studies very complicated (Soto-Rojas et al, 1998; Almsthl, 2001a). Even oral biofilm models have their limitations when extrapolating findings to the in vivo conditions of the oral cavity. Thus, in the oral cavity the micro-organisms are exposed to continuously varying nutritional and environmental conditions including saliva quantity and quality as well as dynamic changes in gas tension and pH (Schonfeld, 1992).

Although a limited number of studies have dealt with the impact of salivary gland hypofunction on the composition of oral microflora, this review attempts to present the current status of the field. The review focuses on data obtained from patients suffering from chronically or temporary impaired saliva secretion due to Sjgrens syndrome, cancer therapy (radiation therapy or chemotherapy) and intake of certain medications. These patient groups are selected because they are characterised by having an increased risk of developing oral diseases like dental caries and oral candidiasis. The methods used for assessment of oral micro-organisms, and the numerous underlying factors and effect modifiers affecting the interpretation of salivary and oral microbial findings in these patient groups, are outlined.

Table 1 Definitions of xerostomia and hyposalivation as well as ‘cut-off’ values of normal unstimulated and stimulated whole saliva flow rates and hyposalivation (Sreebny et al, 1991), Xerostomia: the subjective feeling of oral dryness.

Hyposalivation: decreased whole saliva flow rates measured by sialometry.

Whole saliva flow rates (ml/min)

Normal

Hyposalivation

Unstimulated whole saliva

0.3-0.5

≤0.1

Stimulated whole saliva

1.0-2.0

≤0.5*

* In the diagnosis of Sjögren's syndrome the value is ≤0.7 ml/min (Workshop on diagnostic criteria for Sjögren's syndrome, 1989).


SALIVA AND ORAL MICROFLORA IN SJGRENS SYNDROME

Sjgrens syndrome (SS) is a common chronic inflammatory systemic autoimmune disease of unknown aetiology, which predominantly affects women. It is characterised by impaired function of the exocrine glands, especially the salivary and lacrimal glands, which presumably is caused by lymphocyte-mediated destruction of the glandular tissue (for review, see Pedersen and Nauntofte, 2001). SS is classified into two forms: primary SS (pSS) is the simultaneous presence of keratoconjunctivitis sicca and hyposalivation in patients not fulfilling internationally accepted criteria for another chronic inflammatory connective tissue disease; secondary SS (sSS) defines the disease entity in the presence of another chronic inflammatory connective tissue disease such as rheumatoid arthritis (Manthorpe et al, 1986). The syndrome may develop into a disabling disease that impairs the patients general well-being and health-related quality of life (Pedersen et al, 1999a; Strmbeck et al, 2000).

Not only the quantity, but also the quality of saliva is affected in SS (Thorn et al, 1989; Kalk et al, 2001). The salivary gland hypofunction results in reduced buffering capacity, saliva pH and reduced oral clearance (Pedersen et al, 2004). These salivary changes, in combination with an inadequate oral hygiene (Najera et al, 1997) and an increased intake of fermentable carbohydrates (Cermak et al, 2003), may favour an aciduric and acidophilic oral microflora, which may promote development of oral diseases commonly seen in SS, i.e. dental caries and oral candidiasis (Sota-Rojas et al, 1998; Pedersen et al, 1999b, 2004). However, only few studies, of which all are cross-sectional, have investigated alteration of the oral microflora in patients with SS in relation to the development of oral diseases in the hard and soft tissues. Furthermore, most of the studies have compared the oral microflora between SS patients and healthy controls, whereas only a few studies have related microbial findings of SS to patients with hyposalivation of other aetiologies (Kindelan et al, 1998; Almsthl et al, 2001b).

Candidiasis-related Yeasts in the Saliva and on the Oral Mucosa

Recurrent oral candidiasis is prevalent among patients with SS and the most common clinical presentation of Candida albicans (C. albicans) isation is erythematous candidiasis and angular cheilitis (MacFarlane and Mason, 1974; Tapper-Jones et al, 1980; Hernandez and Daniels, 1989; Lundstrm and Lindstrm, 1995; Soto-Rojas et al, 1998; Pedersen et al, 1999b). Further, papillary tongue atrophy, dorsal tongue fissuring and erythema of the oral mucosa including a burning sensation may be signs of fungal infection (Pedersen and Nauntofte, 2001).

Only a few studies have examined the frequency and number of C. albicans in saliva of SS patients (Abraham et al, 1998; Kindelan et al, 1998; Soto-Rojas et al, 1998; Almsthl et al, 1999a). C. albicans is the most frequently isolated (6672%) species in saliva of patients with SS. It may occur as the only Candida species or mixed with other Candida species such as C. tropicalis, C. pseudotropicalis, C. parasilosis, C. kefyr and C. glabrata (Soto-Rojas et al, 1998; Kindelan et al, 1998). The prevalence of Candida as well as the numbers of y-forming units per ml (CFU/ml) not only varies between studies, but also between the pSS and sSS patients (Table 2). The diversity of results may reflect differences in the patient groups regarding dental status, oral hygiene habits, concomitant diseases, medication and/or immunological status. On the other hand, the severity of salivary gland hypofunction does not appear to differ between the two disease entities (Dawson et al, 2001). Generally, the results of saliva cultures and oral rinses correspond well to the clinical signs and symptoms of oral candidiasis (Abraham et al, 1998; Kindelan et al, 1998; Soto-Rojas et al, 1998). Although patients with sSS appear to have a higher prevalence of clinical oral candidiasis as well as isation of Candida than patients with pSS (Soto-Rojas et al, 1998), Kindelan et al (1998) found no significant differences in the incidence of Candida carriage and the total CFU/ml between pSS, sSS and xerostomic controls. On the other hand, Almsthl et al (2001b) showed that patients with pSS had significantly higher levels of C. albicans in rinsing samples than subjects with hyposalivation of unknown cause. There appears to be a trend toward an inverse correlation between stimulated parotid flow rate and Candida count in oral rinses among patients with SS (Abraham et al, 1998). Additionally, it has been shown that SS patients with immeasurable unstimulated whole saliva flow rates have the highest levels of C. albicans in oral rinses (Almsthl et al, 1999a). Overall, results of the studies performed on Candida in saliva indicate that both pSS and sSS patients have a higher frequency of Candida present in saliva cultures and higher numbers of CFU/ml obtained from oral rinses than the healthy controls (Abraham et al, 1998; Soto-Rojas et al, 1998; Almsthl et al, 1999a).

The microbial sampling demonstrating the presence of Candida species on the oral mucosa have usually been conducted by smears or culture swabs taken from the dorsum of the tongue, the buccal or palatal mucosa, the right tonsillar area, and/or from the fitting surface of the denture (MacFarlane and Mason, 1974; Tapper-Jones et al, 1980; MacFarlane, 1984; Rhodus et al, 1997; Soto-Rojas et al, 1998; Almsthl et al, 2001c; Pedersen et al, 2002b). Results revealed a significantly higher mucosal isation of C. albicans in both pSS and sSS patients as compared to healthy controls (Tapper-Jones et al, 1980; MacFarlane, 1984; Rhodus et al, 1997; Soto-Rojas et al, 1998) and in pSS as compared to patients with oral lichen planus (Pedersen et al, 2002b). Furthermore, patients with sSS harboured higher numbers of C. albicans than the patients with pSS, which was attributed to the presence of an additional inflammatory disease in sSS (Rhodus et al, 1997). Results also suggest an approximate inverse relationship between the presence and the density of C. albicans and salivary flow rates (Tapper-Jones et al, 1980; Hernandez and Daniels, 1989; Rhodus et al, 1997). Clinical atrophic changes on the dorsum of the tongue have been observed in 9 out of 10 SS patients of whom 90% had immeasurable stimulated parotid secretion (MacFarlane, 1984). In addition, Hernandez and Daniels (1989) found that SS patients with clinical chronic atrophic candidiasis were older, had oral symptoms for a longer period, more extensively inflamed labial salivary gland tissue and lower stimulated parotid flow rates than the SS patients without clinical atrophic candidiasis. In contradiction to oral rinses, not all mucosal cultures correspond to the clinical signs and symptoms. Thus, MacFarlane (1984) found that 73% of the patients with pSS had clinical signs of oral candidiasis, although cultures obtained from the dorsum of the tongue were only positive in 52% of the cases. This discrepancy between clinical signs and results of Candida cultures may reflect difficulties in obtaining representative material from a dry mucosa (Lundstrm and Lindstrm, 1995; Soto-Rojas et al, 1998). It also emphasizes the importance of using a standardised method regarding sampling site and sampling area. On the other hand, subjects infected with Candida species do not necessarily exhibit oral lesions. This could be due to an asymptomatic carrier status or early candidiasis without clinically apparent lesions or a less virulent strain of Candida. Regarding site specificity, it is noteworthy that C. albicans were found twice as frequently in the supragingival plaque than on the tongue in the pSS patients, but could not be detected in the gingival crevicular region using the paper point technique (Almsthl et al, 2001c). Finally, saliva culture has been suggested as the most proper method for identification of Candida in SS patients corresponding better to clinical oral candidiasis than tongue smear and tongue smear culture (Sota-Rojas et al, 1998).

Table 2 Frequency (%) of Candida species determined semi-quantitatively, and the numbers of colony-forming units per ml (CFU/ml) in patients with primary Sjögren's syndrome (pSS) compared to patients with secondary Sjögren's syndrome (sSS)

Microbiological tests

pSS

sSS

References

Tongue smear

33%

76%

Sota-Rojas et al (1998)

Tongue swab culture

52%

76%

Sota-Rojas et al (1998)

Saliva culture/oral rinsing technique

76%, 81%, 65%

79%, 67%, 60%

Sota-Rojas et al (1998), Kindelan et al (1998), Almståhl et al (1999a)

Numbers of CFU/ml, Tongue/palate swab culture, Saliva culture, Oral rinse, Oral rinse

3.1×106 (mean), 419/µl (mean), 2100 (median), 380 (median)

1.2×105, 739/µl, 1710, 500

Rhodus et al (1997), Sota-Rojas et al (1998), Kindelan et al (1998)*, Almståhl et al (1999a)**

* The study included denture-wearers (44% pSS/25% sSS).

** The study only included dentate subjects. Two studies state flow rates of the two groups: in Rhodus et al (1997) and Almståhl et al (1999a) pSS patients had lower unstimulated whole saliva flow rates and lower stimulated whole saliva flow rates as compared to patients with sSS.


Caries-related Micro-organisms

Only few studies have examined bacteria cultures from saliva of patients with SS (Lundstrm and Lindstrm, 1995; Kolavic et al, 1997; Almsthl et al, 2001c). Kolavic et al (1997) found higher counts of Streptococcus mutans (S. mutans) and lactobacilli (by means of Dentocult SM strip and LB assay) in caries-in- active SS patients, having stimulated parotid flow rates 0.25 ml/min, than in healthy controls with significantly higher parotid flow rates. Almsthl et al (1999a) showed that the pSS patients harboured higher numbers of both S. mutans and Lactobacillus species, whereas the sSS patients only harboured higher numbers of Lactobacillus species as compared to the healthy controls. Despite good oral hygiene, the pSS group had the highest proportions of subjects harbouring the highest levels of S. mutans compared to other patients with hyposalivation due to radiotherapy in the head and neck region and patients on neuroleptic treatment (Almsthl et al, 1999a). The counts and numbers of S. mutans and lactobacilli have been found positively correlated (Kolavic et al, 1997) as well as inversely correlated to stimulated whole saliva flow rates (Lundstrm and Lindstrm, 1995). The low salivary flow rates, low pH, reduced buffering capacity, impaired salivary antibacterial activity, high number of retention sites as well as high caries activity have been suggested as contributing factors to the high number of S. mutans and Lactobacillus species found in pSS patients (Almsthl et al, 1999a). In this context, the activity of salivary amylase, which also has antibacterial properties (Scannapieco, 1994), has been found inversely correlated to the number of lactobacilli, whereas the salivary concentration of MUC5B (high molecular weight mucin, MG1) did not correlate to any of the numbers of micro-organisms studied (Almsthl et al, 2001b). Surprisingly, the concentration of the salivary antibacterial component lactoferrin was positively correlated to the number of Lactobacillus species as well as C. albicans (Almsthl et al, 2001b). However, with decreasing flow rates, the output of salivary antibacterial components decreases and the concentration increases. This means that the overall available amount of salivary antibacterial components in the oral cavity is in fact diminished.

Conclusions

Both pSS and sSS patients harbour an oral microflora which is associated with caries activity and fungal infections. Furthermore, recent studies indicate site specificity regarding oral micro-organisms in SS. These findings may have an impact on the planning of preventive dental care strategies. In SS, changes in the oral microflora are related to permanently reduced salivary flow rates, low saliva pH, decreased clearance of micro-organisms in the oral cavity and reduced oral sugar clearance, which lead to an increase in acidophilic micro-organisms such as S. mutans, lactobacilli and C. albicans. Furthermore, the autoimmune disease itself resulting in an altered immune response may in addition to intake of immune-modulating medications and intake of a more cariogenic diet affect the oral microflora. Some studies have revealed slight differences in certain oral micro-organisms between the pSS and sSS groups that may be attributed to diversity in salivary changes. Despite good oral hygiene, the majority of pSS patients harbour significant high levels of S. mutans compared to patients with hyposalivation of other aetiologies.

SALIVA AND ORAL MICROFLORA IN PATIENTS RECEIVING CHEMOTHERAPY

During chemotherapy, cancer patients have a significantly increased risk of oral infections due to the direct effects of the cytotoxic drugs on oral epithelial barrier function and the indirect effects of the systemic immunosuppression. In some patients such opportunistic infections may even have a fatal outcome. Most studies on changes in the oral microflora caused by chemotherapy have been conducted during and shortly after initiation of the treatment. Only few studies deal with the long-term effects of chemotherapy on salivary flow rates and composition and the impact of these changes on the oral microflora. It is therefore still an open question if chemotherapy results in temporary or permanent salivary gland hypofunction.

Chemotherapeutics target cells characterised by a high mitotic turnover, like cancer cells, but effects on more slowly dividing cells like in healthy tissues also occur. Studies have shown that saliva flow rates decrease during chemotherapy, although there is some controversy whether it is caused by the chemotherapy per se or by other factors, e.g. concomitant intake of anticholinergic antiemetic drugs (Main et al, 1984; Harrison et al, 1998; Wahlin, 1991). Nevertheless, specific and non-specific salivary antimicrobial components are influenced by chemotherapy. Accordingly, the concentration of salivary immunoglobulin secretory-IgA (s-IgA) has been found to decrease both during and following chemotherapy (Main et al, 1984; Laine et al, 1992; Meurman et al, 1997a; Harrison et al, 1998) and the concentration of lysozyme to decrease after chemotherapy (Meurman et al, 1997a). The salivary peroxidase system in stimulated whole saliva is impaired during chemotherapy due to a lower concentration of thiocyanate and its oxidised form hypothiocyanate with antibacterial properties (Mansson-Rahemtulla et al, 1992). It has also been reported that unstimulated whole saliva pH and stimulated whole saliva buffer capacity decrease during chemotherapy (Schum et al, 1979; Pajari et al, 1989). Thus, salivary gland hypofunction and reduced output of antibacterial factors may impair the oral defence against micro-organisms and thereby disturb the balance of the patients normal oral microflora.

Candidiasis-related Yeasts During Chemotherapy

The oral yeast counts and especially the prevalence of Candida species may increase significantly from a prevalence of about 50% in the normal population to 7580% in cancer patients during combination chemotherapy (Main et al, 1984; Samaranayake et al, 1984; Wahlin and Holm, 1988; Sixou et al, 1996; Meurman et al, 1997b; Sonis, 1997). This could partly be explained by a simultaneous decrease in unstimulated and stimulated whole saliva flow rates and a reduced output of salivary antimicrobial factors (Main et al, 1984; Wahlin, 1991; Umazume et al, 1995; Epstein et al, 2002) (Table 3). Other studies have not revealed any changes in the composition of the oral microflora (Bergmann, 1991; OSullivan et al, 1993), but an initial doubling of the concentration of micro-organisms concomitant with a transient decrease of stimulated whole saliva flow during chemotherapy (Bergmann, 1991). C. albicans is the predominant yeast in the oral flora during chemotherapy and accounts for up to 88% of the salivary yeasts (Samaranayake et al, 1984). Clinical candidiasis and angular cheilitis have been found to correlate to higher oral yeast counts and low salivary flow rates (Wahlin and Holm, 1988; Wahlin, 1991). Yeasts have also been detected in both dental plaque and the crevicular fluid of chronic leukaemia patients, but not in the acute leukaemia patients (Pompei et al, 1993). A clinical study found that 68.9% of all oral infections during chemotherapy were caused by yeasts such as C. albicans, Histoplasma capsulatum and Cryptococcus neoformans (Dreizen et al, 1983).

Table 3 Effect of cancer chemotherapy (CT) and CT induced decrease of saliva flow rates on the number of candidiasis-related yeasts and caries-related bacteria (mutans streptococci (MS) and lactobacilli (LB)) during and after CT

During CT

After CT

Authors

Yeast

Caries-related bacteria

Saliva flow rates

Yeast

Caries-related bacteria

Saliva flow rates

Meurman et al (1997)

MS↓, LB↑

SWS→

MS+LB↓

SWS→

Bergmann (1991)

*↑

SWS↓

Wahlin (1991)

SWS↓ initially

Main et al (1984)

*↑

SWS↓

SWS: Stimulated whole saliva, ↑:High; →: Unchanged; ↓: Low, *: Candida species


Candidiasis-related Yeasts After Chemotherapy

A follow-up study found that salivary yeast counts remained high in spite of normal saliva flow rates 5 years after chemotherapy for lymphoma (Meurman et al, 1997b) (Table 3). The salivary concentrations of the immunoglobulins s-IgA, IgG, IgM and lysozyme in stimulated whole saliva were concomitantly found to be significantly decreased as compared to baseline values (Meurman et al, 1997a). These findings suggest that the disease itself or the chemotherapy may affect the body defences against Candida in the long term. Furthermore, a significantly decreased amylase concentration and an increased albumin concentration were found in stimulated whole saliva 5 years after chemotherapy (Meurman et al, 1997a), which indicate long-lasting impaired salivary gland function. Amylase is synthesised in the serous acini of the salivary glands and the concentration is positively correlated to saliva flow rates (Froehlich et al, 1987). A lower stimulated whole saliva concentration of amylase suggests acinar degeneration, and increased albumin concentration in whole saliva indicates leakage of plasma components into the oral cavity, as saliva normally contains low concentrations of this protein. In whole saliva the leakage can result from a direct damage of the salivary gland tissue or from the breakdown of other oral epithelial barrier functions, e.g. inflamed periodontal pockets (Cimasoni, 1974).

Caries-related Salivary Micro-organisms During Chemotherapy

Studies have shown that the salivary concentration of caries-related micro-organisms may decrease during chemotherapy in spite of any salivary gland hypofunction. To interpret the results, it is necessary to take into consideration that in most studies the patients are concomitantly treated by antibiotics, antifungal drugs and chlorhexidine mouth rinses, and that the prevalence of open caries lesions also influence the oral presence of e.g. S. mutans and lactobacilli. Salivary counts of S. mutans are found to decrease during chemotherapy (OSullivan et al, 1993; Meurman et al, 1997b) (Table 3), which could be attributed to the cytotoxic effect of the chemotherapeutic drugs. Accordingly, S. mutans has been found to be sensitive to daunorubicin, a frequently prescribed cytotoxic antibiotic in chemotherapeutic protocols (OSullivan et al, 1993). Along this line, a study showed that salivary S. mutans counts decreased, whereas lactobacilli counts increased during chemotherapy (Meurman et al, 1997b). Accordingly, examinations of the oral microflora during chemotherapy in leukaemia and lymphoma patients revealed no change in the total number of salivary micro-organisms and lactobacilli (Wahlin and Holm, 1988). A study of the supra- and subgingival dental plaque in adult acute leukaemia patients during chemotherapy found that the percentage of total viable counts of S. mutans in supragingival dental plaque increased and the percentage in subgingival dental plaque decreased (Reynolds et al, 1989). In contradiction, other investigators found the percentage of viridans streptococci (S. mutans not specified) to be lower in the supragingival dental plaque of children with acute leukaemia during chemotherapy as compared to a healthy control group (Sixou et al, 1998). As chemotherapy is a time-limited treatment and caries is a process that progresses relatively slowly, it may be debatable whether it is possible to assess an increased progression rate of caries during chemotherapy.

Caries-related Salivary Micro-organisms After Chemotherapy

Only few studies have examined the oral microflora after chemotherapy and its relation to salivary gland function. One study found that 5 years after chemotherapy, salivary counts of S. mutans and lactobacilli were on same low levels as baseline values before chemotherapy (Meurman et al, 1997b) (Table 3). Another study found no significant correlation between salivary immunoglobulin levels in stimulated whole saliva and S. mutans or Lactobacillus counts in long-term (6 months to 10 years) event-free paediatric patients treated for childhood malignancies by chemotherapy (Dens et al, 1995). The salivary immunoglobulin level was within normal limits, but there was a negative correlation between saliva s-IgA concentration and caries prevalence (DMFT/dmft), although only significant in some age groups. The study is cross-sectional and comparison of intra- and interindividual changes in the immunoglobulin level and caries prevalence before, during, and after the chemotherapy is therefore not possible. In bone marrow transplanted patients, a significant decrease in stimulated whole saliva flow, lower buffer capacity and a change in the oral microflora towards higher salivary counts of S. mutans and Lactobacillus has been observed during and after the transplantation and chemotherapy (Dens et al, 1996; Dahllof et al, 1997). However, stimulated saliva flow rates reached normal values 1 year after the bone marrow transplantation/chemotherapy and no significant differences in caries prevalence were found between the bone marrow transplanted children receiving chemotherapy and healthy children 4 years after the treatment, but all participants also underwent preventive dental care (Dahllof et al, 1997).

Conclusions

Most studies have demonstrated that salivary flow rates and the output of salivary antimicrobial components decrease during chemotherapy. Also a shift in the oral microflora from a predominance of gram-positive micro-organisms to gram-negative pathogens and yeasts has been observed during chemotherapy. However, other studies demonstrated no changes in the composition of the oral microflora. In this context it is important to bear in mind that changes in the oral microflora are not only attributable to the chemotherapy itself, but also to other factors such as concomitant medication, local and systemic antimicrobial treatment, underlying cancer disease and duration of hospitalisation. During chemotherapy, cancer patients have an increased risk of oral infections and especially fungal infections, whereas it is unclear whether the risk of caries is increased. Only few studies have dealt with the long-term effects of chemotherapy on salivary gland function and composition, and thereby the impact on the oral microflora. At present results are contradictory, and further studies are necessary to elucidate whether cancer patients who have completed chemotherapy have an increased risk of oral infection and dental caries in the long term.

SALIVA AND ORAL MICROFLORA IN PATIENTS RECEIVING RADIATION THERAPY

Radiation therapy (RT) of tumours in the head and neck region often includes the major and minor salivary glands in the radiation field depending on the anatomical location and the extension of the tumour. RT can cause severe salivary gland hypofunction (for review, see Jensen et al, 2003). The severity depends on the volume of salivary gland tissue included in the radiation field and on the total radiation dose (Mossman, 1983). RT targets cells with a rapid mitotic turnover like tumour cells and damages the DNA thereby leading to cell death. Acinar salivary gland cells are radiosensitive in spite of their slow mitotic turnover (Berthrong, 1986) and the serous cells appear to be more sensitive to radiation than the mucous ones (Kashima et al, 1965). Radiation damage to the salivary glands may be seen as early as 1 week after initiation of RT (Dreizen et al, 1977) and results in both acute and long-term effects characterised by reduced saliva flow rates, high saliva viscosity and changes of saliva composition. During RT, saliva flow rates decrease and may even reach immeasurable levels (Mira et al, 1981). With decreasing flow rates the salivary pH drops and the buffer capacity decreases both during and after RT (Valdez et al, 1993). RT also affects the salivary antimicrobial components. The salivary concentrations of IgA and IgG, lactoferrin, lysozyme and peroxidase have been shown to increase during RT due to acute tissue destruction. But after RT the concentrations of these salivary components decrease due to reduced functioning of the glands (Brown et al, 1976; Makkonen et al, 1986). In the long term, recovery of salivary gland function is dependent on the total radiation dose that the tissue has received. Thus, saliva flow rates may remain severely decreased (Liu et al, 1990) and the compositional changes may persist in response to the decrease in saliva flow rates. The standard therapeutic radiation dose for head and neck carcinoma amounts to a total dose of 6070 Gy (1 Gy=1 J kg1) (Vissink, 2003). A mean parotid gland dose of 26 Gy has been suggested as a threshold level for preservation of parotid gland function (Eisbruch, 2003). A compensatory increase in saliva flow from salivary glands not included in the radiation field may be seen (Eisbruch et al, 2001). Irradiation-induced salivary gland hypofunction is associated with a shift of the normal oral microflora increasing the risk for this patient group to develop rampant dental caries and oral infections like candidiasis (Guggenheimer, 2003). Both cross-sectional and longitudinal studies have been conducted on changes in the oral microflora and salivary gland function during and after RT. Regarding evaluation of the salivary gland function many studies characterize the study groups as having radiation-induced hyposalivation or xerostomia and do not specify the saliva flow rates or saliva composition.

Candidiasis-related Yeasts

The number of yeasts increases in the oral cavity of cancer patients with hyposalivation due to RT (Table 4). The increase in the oral yeast ization is observed during RT and the ization level remains elevated after RT (Llory et al, 1972; Brown et al, 1975; Silverman et al, 1984; Kuten et al, 1986; Ramirez-Amador et al, 1997; Epstein et al, 1998; Leung et al, 2000). Both number of yeast species and ization rise to higher levels during and after RT. C. albicans, which is the predominant yeast species associated with clinical oral candidiasis in RT patients (Redding et al, 1999), and C. tropicalis are the dominant yeasts isolated from the oral cavity in RT (Llory et al, 1972; Martin et al, 1981; Paula et al, 1990). It has been shown that the increase in C. albicans in oral rinses is positively related to the radiation dose and the volume of parotid gland tissue included in the radiation field (Rossie et al, 1987). Epstein et al (1998) found a direct correlation between the increase in C. albicans in saliva and reduced saliva flow rates during RT. The increased ization of oral yeasts in RT patients reflect the importance of good oral hygiene in RT patients due to the risk of developing clinical candidiasis (Rossie et al, 1987; Redding et al, 1999).

Table 4 Effect of radiotherapy (RT) of the head and neck region, and RT-induced decrease of saliva flow rates on the number of candidiasis-related yeasts and caries-related bacteria (mutans streptococci (MS) and lactobacilli (LB)) during and after RT

During RT

After RT

Authors

Yeast

Caries-related bacteria

Saliva flow rates

Yeast

Caries-related bacteria

Saliva flow rates

Vuotila et al (2002)

**→

LB↑, MS→

SWS↓

**→

LB↑, MS→

SWS↓

Leung et al (2000)+(2001)

*↑

SWS↓

Schwarz et al (1999)

MS+LB↑

SWS↓

Epstein et al (1998)

**↑

#MS→, LB↑ initially

UWS+SWS↓

**↑

MS+LB→

UWS+SWS↓

Ramirez-Amador et al (1997)

*↑

↓?

*↑

↓?

Keene and Fleming (1987)

MS↓, LB↑, no fluoride MS↑

↓?

Kuten et al (1986)

*↑

UWS↓

Silverman et al (1984)

*↑

↓?

*↑

↓?

Brown et al (1975)

*↑

MS+LB↑

SWS↓

*↑

MS+LB↑

SWS↓

Llory et al (1972)

MS↑

↓?

UWS: Unstimulated whole saliva; SWS: Stimulated whole saliva, ↑: High; →: Unchanged; ↓: Low, ↓?: Xerostomia or hyposalivation due to RT are stated in the article, but no measurements are reported.

*: Candida species, **: Candida albicans, #: Daily use of fluoride gel


Caries-related Salivary Micro-organisms

Higher levels of S. mutans and Lactobacillus species are often observed in the oral cavity (oral rinses, mucosal swabs, saliva samples, gingival sulcus fluid and dental plaque samples) during and after RT as compared to preradiation levels (Llory et al, 1972; Brown et al, 1975; Brown et al, 1978; Keene and Fleming, 1987; Schwarz et al, 1999; Vuotila et al, 2002) (Table 4). Oral ization with S. mutans is lower and stimulated saliva flow rates are higher at the end of treatment in patients receiving unilateral RT as compared to bilaterally irradiated patients (Beer et al, 2002). In oral rinses, it has been demonstrated that the predominant acid-producing species of the oral microflora may change from Streptococcus sanguis (S. sanguis), S. mitis and S. salivarius before RT to S. mitis, S. salivarius and lactobacilli with a concomitant decrease in saliva flow rates after RT (Tong et al, 2003). The acid-sensitive S. sanguis appears to be inhibited by the more acidic oral environment after RT (Tong et al, 2003). The decrease in the presence of S. sanguis after RT has been shown in other studies (Brown et al, 1975; Brown et al, 1978). Vuotila et al (2002) found unchanged levels of S. mutans after RT as compared to pre-radiation levels. The RT patients suffering from impaired saliva secretion are to be considered a high-risk group regarding dental caries as the oral environment favours acid-producing and acidophilic species of the oral microflora.

Conclusions

RT in the head and neck region can result in a severe and permanent hypofunction of the salivary glands. The severity depends on the volume of salivary gland tissue included in the radiation field and on the total radiation dose. In cancer patients with RT-induced salivary gland hypofunction, the bacterial clearance decreases and the total oral microbial ization rate therefore increases. It is mainly the ization of yeasts that increases, but also acidogenic micro-organisms such as Lactobacillus species, S. mutans and other potentially pathogenic micro-organisms increase dramatically in this patient group. Inconsistency in the reported changes of the oral microflora in relation to salivary gland hypofunction following RT may be due to a wide variation in the underlying cancer diagnosis, concomitant medication, total radiation doses, radiation technique and the irradiated volume of salivary gland tissue in the examined study groups, which renders comparison between studies difficult. The altered oral microflora and chronically impaired salivary gland function following RT imply a marked increased risk of oral infection and dental caries in post-irradiated pa- tients.

SALIVA AND ORAL MICROFLORA IN RELATION TO MEDICATION INTAKE

The most common cause of salivary gland hypofunction is the intake of prescribed medications (sterberg et al, 1984; Handelman et al, 1986; Nrhi et al, 1992), which increases with age. More than 75% of adults aged 65 and older take at least one prescription medication (Chrischilles et al, 1992) and the prevalence of xerostomia in this population is about 30% (Ship, 2002). Xerostomia has been associated with 80% of the most commonly prescribed medications (Smith and Burtner, 1994), and many of these have adverse effects directly on the mechanisms responsible for saliva secretion (Sreebny and Schwartz, 1997). Regardless of the type of medication, saliva flow rates have been shown to decrease as the number of medications (polypharmacy) increases (Thorselius et al, 1988; Nrhi et al, 1992). Also the duration of medication intake might affect saliva flow rates. Navazesh et al (1996) found that unstimulated and stimulated whole saliva flow rates were significantly lower in adults who had been taking medication for more than two years as compared to those who had been taking medication for less than two years. Furthermore, the patient compliance in following instructions to take prescribed medication is reflected in salivary gland function.

Medications interacting with the central nervous system (CNS) such as sedatives, anxiolytics (Loesche et al, 1995a), and morphine-based analgesics (Zacny et al, 1994) negatively affect saliva flow rates. There are, however, different types of medication-induced effects leading to salivary gland hypofunction. Some medications affecting the CNS also exert effects on the peripheral nervous system and interact with the target organ receptor complexes. Examples are: tricyclic antidepressants (Clemmesen, 1988; Hunter and Wilson, 1995); the serotonin reuptake inhibitors (Loesche et al, 1995a); some neuroleptics (Hyttel et al, 1985); antihistamines (Monroe et al, 1992): and medications for Parkinsons disease (Suchowersky, 2002) all of which inhibit the muscarinergic receptors on the salivary glands leading to impaired saliva flow. The salivary gland 1-adrenergic receptors are inhibited by: 1-receptor blocking antihypertensives (Croog et al, 1994; Gregoire and Sheps, 1995); some neuroleptics (Mueck-Weymann et al, 2002); and some antidepressants (Dissing et al, 1990), which also induce a decrease in saliva flow rates. -blockers inhibit the -adrenergic receptor systems on the salivary glands decreasing the protein secretion into the saliva, while the saliva flow rates remain relatively unaffected (Nederfors et al, 1994). Some medications such as antihypertensives and diuretics may affect the electrolyte transport mechanisms in the salivary glands directly giving rise to changes in saliva composition (Nederfors et al, 1989).

Medication-induced Effects on the Oral Microflora

Several medications have the potential to cause salivary gland hypofunction leading to decreased saliva pH and antimicrobial clearance, which affect the number and composition of oral micro-organisms. Medications used locally may also affect the oral microflora directly. Examples are sugar-containing cough syrups and antimycotics that may increase the growth of oral micro-organisms. Beigthon et al (1991) showed that the salivary level of mutans streptococci, lactobacilli and yeasts in elderly patients treated with sucrose-containing medication was significantly higher than in patients taking non-sucrose-containing medication. The oral microflora can also be directly affected by systemic medications such as antibiotics (Stark et al, 1996) that are released into saliva. Anticonvulsant agents (Yamada et al, 2001), immunosuppressives (Das et al, 2001), and some cardiovascular medications such as calcium channel blockers (Nery et al, 1995) may lead to gingival hyperplasia, thereby affecting the composition of the microflora. In addition, the intake of hormonal contraceptives may be associated with gingival inflammation (Kalkwarf, 1978; Pankhurst et al, 1981). It has been suggested that hormonal contraceptives influence the microbiological parameters in the gingival sulcus leading to an increased risk for periodontal disease (Klinger et al, 1998).

In order to distinguish between the possible effects of medication intake on the oral microflora, attention was paid to the effects on the number of oral micro-organisms caused by medication intake per se and the effects caused by medication-induced salivary gland hypofunction (Table 5). Due to the lack of data regarding specific medication-induced changes in the saliva composition in relation to changes in the oral microflora, the following mainly focuses on the changes related to saliva flow rates.

Table 5 Effect of medication intake (Medication) and medication-induced decrease of saliva flow rates (Saliva flow rates) on the number of yeasts, mutans streptococci and lactobacilli

5.1: Yeasts

Authors

Medication

Saliva flow rates

NS

S

NS

S

Torres et al (2002)

B

Bergdahl and Bergdahl (2001)

B

Almståhl and Wikström (1999)

A

Närhi et al (1998)

B

Loesche et al (1995b)

C

Navazesh et al (1995)

B

Meurman and Rantonen (1994)

A

A

Beighton et al (1991)

A

Kreher et al (1991)

A

B

Laine et al (1991)

C

Parvinen et al (1984)

A

A

 

5.2: Mutans streptococci

Authors

Medication

Saliva flow rates

NS

S

NS

S

Almståhl and Wikström (1999)

A

Närhi et al (1998)

B

Lundgren et al (1997)

B

Loesche et al (1995b)

C

Närhi et al (1994)

A

A

Beighton et al (1991)

A

Laine et al (1991)

C

Ryberg et al (1991)

A

Fure and Zickert (1990)

B

Arneberg et al (1989)

B

 

5.3: Lactobacilli

Authors

Medication

Saliva flow rates

NS

S

NS

S

Bardow et al (2001)

B

Almståhl and Wikström (1999)

A

Anttila et al (1999)

A

A

Närhi et al (1998)

B

Lundgren et al (1997)

B

Loesche et al (1995b)

C

Närhi et al (1994)

A

A

Beighton et al (1991)

A

Laine et al (1991)

C

Ryberg et al (1991)

A

Fure and Zickert (1990)

B

Arneberg et al (1989)

B

B

Parvinen et al (1984)

A

A

The column Medication states if the authors tested the effect of medication intake on the number of micro-organisms and the column Saliva flow rates states if the authors tested the effect of saliva flow rates on the number of micro-organisms. NS: Non-significant higher number of micro-organisms, S: Significant higher number of micro-organisms. A: bivariate analysis (medicated to non-medicated or hyposalivating to non-hyposalivating), B: correlation analysis (containing the variables: medication intake versus number of micro-organisms and saliva flow rate versus number of micro-organisms), C: multivariate analysis. Level of significance set at p<0.05.


Candidiasis-related Yeasts

Table 5.1 shows the number of studies that have analysed the effect of medication intake on the number of yeasts. Four studies did not find any significant effect on the number of yeasts, but when groups were separated with regard to gender, Parvinen et al (1984) found significantly higher yeast counts in medicated men as compared to non-medicated men. Interestingly, Kreher et al (1991) showed that C. glabrata was the most frequent yeast strain in the oral cavity of medicated patients, when using a test culture that distinguishes C. glabrata from C. albicans. Regarding the effect of saliva flow rates, 4 out of 8 studies found a significant higher number of yeasts when saliva flow rates were low (Table 5.1). In fact, Navazesh et al (1995) showed significant negative correlations between the flow rates of unstimulated whole saliva, chewing-stimulated whole saliva, sour candy-stimulated parotid saliva, and the level of C. albicans. Four studies found a tendency of higher yeast counts. Finally, one study demonstrated a clear negative correlation between unstimulated saliva flow rates and the presence of Candida pseudohyphae (Bergdahl and Bergdahl, 2001).

Caries-related Micro-organismsMutans streptococci

Table 5.2 presents the studies that have analysed the effect of medication intake on the number of mutans streptococci. In all these studies no significant effect on the number of bacteria was found. Nevertheless, some studies reported a tendency for higher counts of mutans streptococci with medication intake. Table 5.2 also shows five studies that tested the effect of saliva flow rates on the mutans streptococci level. Generally, the number of mutans streptococci was significantly higher when saliva flow rates were low. However, one study did not find any significant effect of saliva flow rates on the mutans streptococci counts, but the mutans streptococci level was higher in patients with medication-induced hyposalivation as compared to an age-, gender-, and number of teeth-matched control group with normal saliva flow rates and to a group of healthy young adults. A factor that facilitates the ization of mutans streptococci is the preference of these bacteria for products containing sugar and for an acidic oral environment. The concomitant presence of Streptococcus sobrinus (S. sobrinus) may be an indicator of a change to a more carbohydrate-rich diet, since the ization of S. sobrinus seems to be more dependent on a sucrose-containing diet than that of S. mutans (Huis int Veld et al, 1982). A frequent intake of fermentable carbohydrates leads to a dental plaque with low pH, which favours the growth conditions for aciduric bacteria such as S. mutans (Marsh, 1994). Also poor oral hygiene and dental caries activity favour the selection of this species (Loesche et al, 1984; Schpbach et al, 1996).

Lactobacilli

Table 5.3 shows eight studies that have tested the effect of medication intake on the number of lactobacilli. Five of these studies did not find any significant effect on the number of these bacteria, but when groups were separated with regard to gender, Parvinen et al (1984) showed a significant higher number of lactobacilli in medicated men as compared to non-medicated men. The other studies reported a significantly higher number of lactobacilli with medication intake. Eight studies have tested the effect of saliva flow rates on the number of lactobacilli (Table 5.3). Most of these studies found a significant higher number of lactobacilli when saliva flow rates decreased. Two studies did not find significant higher numbers of bacteria, however, one study (Nrhi et al, 1994) reported high lactobacilli counts in a higher number of subjects with hyposalivation than in subjects with normal saliva flow rates. A decrease in saliva flow rates leads to a reduced cleansing effect, a low pH, an impaired buffer capacity, and thereby to a more aciduric environment that seem to play an important role for the growth conditions of lactobacilli (Arneberg et al, 1989). A high lactobacilli level in the oral cavity may therefore be an indicator of a low saliva pH and decreased saliva flow rates. However, dental caries activity (Bowden et al, 1990; Bardow et al, 2001) and the presence of dental plaque retention sites (Kidd et al, 1995) can also increase the number of lactobacilli.

Conclusions

Medication intake, which may be temporary or permanent, is likely to have an impact on the oral microflora by direct and indirect medication-induced effects on the salivary glands. Several medications have the potential to cause salivary gland hypofunction and changes in saliva composition. However, in contrast to chronic autoimmune diseases like Sjgrens syndrome, RT in the head and neck region and presumably chemotherapy, medication-induced salivary gland changes are reversible. In patients with medication-induced hyposalivation the number of mutans streptococci, lactobacilli and yeasts increases and results indicate an increased risk of dental caries and fungal infections among these patients. A simultaneous treatment with antibacterial agents as well as frequent intake of easily fermentable carbohydrates, hygiene habits, dental status and the underlying systemic disease also influence the level of cariogenic bacteria.

CONCLUDING REMARKS

Studies on patients with salivary gland hypofunction of various aetiologies such as Sjgrens syndrome, cancer chemotherapy, RT to the head and neck region and intake of certain medications show that these patients groups harbour an oral microflora that is associated with common oral diseases like dental caries and oral candidiasis. The decreased clearance of micro-organisms and dietary sugars from the oral cavity, as well as low salivary pH and buffer capacity, simply contributes to an increase in the acidophilic flora comprising S. mutans, lactobacilli and C. albicans. On the other hand, the studies also reveal differences in the oral microflora between the patient groups. For example, despite having a good oral hygiene, pSS patients may harbour higher levels of S. mutans than patients with hyposalivation of other aetiologies such as patients receiving RT and patients receiving certain antidepressants or antipsychotics. Besides the salivary characteristics, the microbial diversity between, and even within patient groups may be attributed to various variables such as the intake of easily fermentable carbohydrates, oral hygiene habits and their dental status. Other variables that come into play when evaluating the impact of salivary gland hypofunction on the oral microflora are the underlying local and systemic diseases as well as their medical treatments (such as irradiation or medication). In contrast to the permanently reduced salivary gland function due to Sjgrens syndrome and RT in the head and neck region, the effect of certain medications on the salivary gland function are reversible, i.e. after cessation of medication the salivary gland function usually recovers.

In conclusion, dental caries and oral candidiasis are both multifactorial diseases occurring as a result of complex interactions between oral micro-organisms and host environment and behaviour. Further improvement of our understanding of the oral microbial ecology in patients suffering from impaired saliva secretion and salivary compositional changes will provide us with new tools and evidence based strategies for prevention, diagnosis and treatment of hyposalivation-related oral diseases.

ACKNOWLEDGEMENT

The authors wish to thank Dr M.M. Koller, Clinic for Special Care Dentistry, University of Zrich, for his support of this review.

REFERENCES

  1. Abraham CM, al-Hashimi I, Haghighat N. Evaluation of the levels of oral Candida in patients with Sjgrens syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:65-68.
  2. Almsthl A, Kronfeld U, Tarkowski A, Wikstrm M. Oral microbial flora in Sjgrens syndrome. J Rheumatol 1999a;26:110-114.
  3. Almsthl A, Wikstrm M. Oral microflora in subjects with reduced salivary secretion. J Dent Res 1999b;78:1410-1416.
  4. Almsthl A. Oral microflora at hyposalivation. Thesis. Gteborg University, Sweden. 2001a:1-79.
  5. Almsthl A, Wikstrm M, Groenink J. Lactoferrin, amylase and mucin MUC5B and their relation to the oral microflora at hyposalivation of different origins. Oral Microbiol Immunol 2001b;16:345-352.
  6. Almsthl A, Wikstrm M, Kronfeld U. Microflora in Oral Ecosystems in Primary Sjgrens Syndrome. J Rheumatol 2001c; 28:1007-1013.
  7. Anttila SS, Knuuttila ML, Sakki TK. Depressive symptoms favour abundant growth of salivary lactobacilli. Psychosom Med 1999;61:508-512.
  8. Arneberg P, Storhaug K, Sandvik L. Effect of a slow release transcutaneous scopolamine application on salivary flow, pH, buffering action, and salivary levels of Streptococcus mutans and lactobacilli. Scand J Dent Res 1989;97:408-414.
  9. Bardow A, Nyvad B, Nauntofte B. Relationships between medication intake, complaints of dry mouth, salivary flow rate and composition, and the rate of tooth demineralization in situ. Arch Oral Biol 2001;46:413-423.
  10. Beer KT, Zehnder D, Lussi A, Greiner RH. Sparing of contralateral major salivary glands has a significant effect on oral health in patients treated with radiotherapy of head and neck tumours. Strahlenther Onkol 2002;178:722-726.
  11. Beighton D, Hellyer PH, Lynch EJ, Heath MR. Salivary levels of mutans streptococci, lactobacilli, yeasts, and root caries prevalence in non-institutionalized elderly dental patients. Community Dent Oral Epidemiol 1999;19:302-307.
  12. Bergdahl J, Bergdahl M. Environmental illness: evaluation of salivary flow, symptoms, diseases, medications, and psychological factors. Acta Odontol Scand 2001;59:104-110.
  13. Bergmann OJ. Alterations in oral microflora and pathogenesis of acute oral infections during remission-induction therapy in patients with acute myeloid leukaemia. Scand J Infect Dis 1991; 23:355-366.
  14. Berthrong M. Pathologic changes secondary to radiation. World J Surg 1986;10:155-170.
  15. Bowden GH, Ekstrand J, McNaughton B, Challacombe SJ. Association of selected bacteria with the lesion of root surface caries. Oral Microbiol Immunol 1990;5:346-351.
  16. Brown LR, Dreizen S, Handler S, Johnston DA. Effect of radiation-induced xerostomia on human oral microflora. J Dent Res 1975;54:740-750.
  17. Brown LR, Dreizen S, Rider LJ, Johnston DA. The effect of radiation-induced xerostomia on saliva and serum lysozyme and immunoglobulin levels. Oral Surg Oral Med Oral Pathol 1976; 41:83-92.
  18. Brown LR, Dreizen S, Daly TE, Drane JB, Handler S, Riggan LJ et al. Interrelations of oral micro-organisms, immunoglobulins, and dental caries following radiotherapy. J Dent Res 1978;57:882-893.
  19. Cermak JM, Papas AS, Sullivan RM, Dana MR, Sullivan DA. Nutrient intake in women with primary and secondary Sjgrens syndrome. Eur J Clin Nutr 2003;57:328-334.
  20. Chrischilles EA, Foley DJ, Wallace RB, Lemke JH, Semla TP, Hanlon JT, et al. Use of medications by persons 65 and over: data from the established populations for epidemiologic studies of the elderly. J Gerontol 1992;47:M137-144.
  21. Cimasoni G. Crevicular fluid updated. Monogr Oral Sci 1983;12; 1-152.
  22. Clemmesen L. Anticholinergic side-effects of antidepressants: studies of the inhibition of salivation. Acta Psychiatr Scand Suppl 1988;345:90-93.
  23. Croog SH, Elias MF, Colton T, Baume RM, Leiblum SR, Jenkins CD, et al. Effects of antihypertensive medications on quality of life in elderly hypertensive women. Am J Hypertens 1994;7: 329-339.
  24. Dahllof G, Bagesund M, Ringden O. Impact of conditioning regimens on salivary function, caries-associated micro-organisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study. Bone Marrow Transplant 1997;20:479-483.
  25. Das SJ, Parkar MH, Olsen I. Upregulation of keratinocyte growth factor in cyclosporin A-induced gingival overgrowth. J Periodontol 2001;72:45-752.
  26. Dawes C. A mathematical model of salivary clearance of sugar from the oral cavity. Caries Res 1983;17:321-334.
  27. Dawson LJ, Holt DJ, Higham SM, Longman LP, Field EA. A comparison of salivary gland hypofunction in primary and secondary Sjogrens syndrome. Oral Dis 2001;7:28-30.
  28. Dens F, Boute P, Vinckier F, Declerck D. Quantitative determination of immunologic components of salivary gland secretion in long-term, event-free paediatric oncology patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;79:701-704.
  29. Dens F, Boogaerts M, Boute P, Declerck D, Demuynck H, Vinckier F, et al. Caries-related salivary micro-organisms and salivary flow rate in bone marrow recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:38-43.
  30. Dissing S, Hansen HJ, Unden M, Nauntofte B. Inhibitory effects of amitriptyline on the stimulation-induced Ca2+ increase in parotid acini. Eur J Pharmacol 1990;177:43-54.
  31. Dreizen S, Daly TE, Drane JB, Brown LR. Oral complications of cancer radiotherapy. Postgrad Med 1977;61:85-92.
  32. Dreizen S, Bodey GP, Valdivieso M. Chemotherapy-associated oral infections in adults with solid tumours. Oral Surg Oral Med Oral Pathol 1983;55:113-120.
  33. Eisbruch A, Kim HM, Terrell JE, Marsh LH, Dawson LA, Ship JA. Xerostomia and its predictors following parotid-sparing irradiation of head-and-neck cancer. Int J radiat Oncol Biol Phys 2001;50:95-704.
  34. Eisbruch A, Ship JA, Dawson LA, Kim HM, Bradford CR, Terrell JE et al. Salivary gland sparing and improved target irradiation by conformal and intensity modulated irradiation of head and neck cancer. World J Surg 2003;27:832-837.
  35. Epstein JB, Chin EA, Jacobson JJ, Rishiraj B, Le N. The relationships among fluoride, cariogenic oral flora, and salivary flow rate during radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;86:286-292.
  36. Epstein JB, Tsang AH, Warkentin D, Ship JA. The role of salivary function in modulating chemotherapy-induced oropharyngeal mucositis: a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;94:39-44.
  37. Froehlich DA, Pangborn RM, Whitaker JR. The effect of oral stimulation on human parotid salivary flow rate and alpha-amylase secretion. Physiol Behav 1987;41:209-217.
  38. Fure S, Zickert I. Salivary conditions and cariogenic micro-organisms in 55-, 65-, and 75-year-old Swedish individuals. Scand J Dent Res 1990;98:197-210.
  39. Gregoire JR, Sheps SG. Newer antihypertensive drugs. Curr Opin Cardiol 1995;10:445-449.
  40. Guggenheimer J, Moore PA. Xerostomia: etiology, recognition and treatment. J Am Dent Assoc 2003;134:61-69.
  41. Handelman SL, Baric JM, Espeland MA, Berglund KL. Prevalence of drugs causing hyposalivation in an institutionalized geriatric population. Oral Surg Oral Med Oral Pathol 1986; 62:26-31.
  42. Harrison T, Bigler L, Tucci M, Pratt L, Malamud F, Thigpen JT, et al. Salivary sIgA concentrations and stimulated whole saliva flow rates among women undergoing chemotherapy for breast cancer: an exploratory study. Spec Care Dentist 1998;18:109-112.
  43. Hernandez YL, Daniels TE. Oral candidiasis in Sjgrens syndrome: prevalence, clinical correlations, and treatment. Oral Surg Oral Med Oral Pathol 1989;68:324-329.
  44. Huis in t Veld JH, Drost JS, Havenaar R. Establishment and localization of mixtures of Streptococcus mutans serotypes in the oral cavity of the rat. J Dent Res 1982;61:1199-1205.
  45. Hunter HD, Wilson WS. The effects of antidepressant drugs on salivary flow and content of sodium and potassium ions in human parotid saliva. Arch Oral Biol 1995;40:983-989.
  46. Hyttel J, Larsen JJ, Christensen AV, Arnt J. Receptor-binding profiles of neuroleptics. Psychopharmacology Suppl 1985;2:9-18.
  47. Jensen SB, Pedersen AM, Reibel J, Nauntofte B. Xerostomia and hypofunction of the salivary glands in cancer therapy. Support Care Cancer 2003;11:207-225.
  48. Kalk WWI, Vissink A, Spijkervet FKL, Bootsma H, Kallenberg, Nieuw Amerongen AV. Sialometry and sialochemistry: diagnostic tools for Sjgrens syndrome. Ann Rheum Dis 2001;60: 1110-1116.
  49. Kalkwarf KL. Effects of oral contraceptive therapy on gingival inflammation in humans. J Periodontol 1978;49:560-563.
  50. Kashima HK, Kirkham WR, Andrews JR. Postradiation sialoadenitis. A study of the clinical features, histopathological changes and serum enzyme variations following irradiation of human salivary glands. AJR Am J Roentgenol (Radiother Ther Nucl Med) 1965;94:271-291.
  51. Keene HJ, Fleming TJ. Prevalence of caries-associated microflora after radiotherapy in patients with cancer of the head and neck. Oral Surg Oral Med Oral Pathol 1987;64:421-426.
  52. Kidd EA, Joyston-Bechal S, Beighton D. Marginal ditching and staining as a predictor of secondary caries around amalgam restorations: a clinical and microbiological study. J Dent Res 1995;74:1206-1211.
  53. Kindelan SA, Yeoman CM, Douglas CW, Franklin C. A comparison of intraoral Candida carriage in Sjgrens syndrome patients with healthy xerostomic controls. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1998;85:162-167.
  54. Klinger G, Eick S, Klinger G, Pfister W, Graser T, Moore C, et al. Influence of hormonal contraceptives on microbial flora of gingival sulcus. Contraception 1998;57:381-384.
  55. Kolavic SA, Gibson G, al-Hashimi I, Guo IY. The level of cariogenic micro-organisms in patients with Sjgrens syndrome. Spec Care Dentist 1997;17:65-69.
  56. Kreher JM, Graser GN, Handelman SL, Eisenberg AD. Oral yeasts, mucosal health, and drug use in an elderly denture-wearing population. Spec Care Dentist 1991;11:222-226.
  57. Kuten A, Ben Aryeh H, Berdicevsky I, Ore L, Szargel R, Gutman D et al. Oral side effects of head and neck irradiation: correlation between clinical manifestations and laboratory data. Int J Radiat Oncol Biol Phys 1986;12:401-405.
  58. Lagerlf F, Oliveby A J. Caries-protective factors in saliva. Adv Dent Res 1994;8:229-238.
  59. Laine M, Pienihakkinen K, Ojanotko-Harri A, Tenovuo J. Effects of low-dose oral contraceptives on female whole saliva. Arch Oral Biol 1991;36:549-552.
  60. Laine P, Meurman JH, Tenovuo J, Murtomaa H, Lindqvist C, Pyrhonen S, Teerenhovi L. Salivary flow and composition in lymphoma patients before, during and after treatment with cytostatic drugs. Eur J Cancer B Oral Oncol 1992;28B:125-128.
  61. Lenander-Lumikari M, Loimaranta V. Saliva and dental caries. Adv Dent Res 2000;14:40-47.
  62. Leung WK, Dassanayake RS, Yau JY, Jin LJ, Yam WC, Samaranayake LP. Oral ization, phenotypic, and genotypic profiles of Candida species in irradiated, dentate, xerostomic nasopharyngeal carcinoma survivors. J Clin Microbiol 2000;38: 2219-2226.
  63. Liu RP, Fleming TJ, Toth BB, Keene HJ. Salivary flow rates in patients with head and neck cancer 0.5 to 25 years after radiotherapy. Oral Surg Oral Med Oral Pathol 1990;70:724-729.
  64. Llory H, Dammron A, Gioanni M, Frank RM. Some population changes in oral anaerobic micro-organisms, Streptococcus mutans and yeasts following irradiation of the salivary glands. Caries Res 1972;6:298-311.
  65. Loesche WJ, Eklund S, Earnest R, Burt B. Longitudinal investigation of bacteriology of human fissure decay: epidemiological studies in molars shortly after eruption. Infect Immun 1984;46:465-772.
  66. Loesche WJ, Bromberg J, Terpenning MS, Bretz WA, Dominguez BL, Grossman NS, et al. Xerostomia, xerogenic medications and food avoidances in selected geriatric groups. J Am Geriatr Soc 1995a;43:401-407.
  67. Loesche WJ, Schork A, Terpenning MS, Chen YM, Stoll J. Factors which influence levels of selected organisms in saliva of older individuals. J Clin Microbiol 1995b;33:2550-2557.
  68. Lundgren M, Emilson CG, Osterberg T, Steen G, Birkhed D, Steen B. Dental caries and related factors in 88- and 92-year-olds. Cross-sectional and longitudinal comparisons. Acta Odontol Scand 1997;55:282-291.
  69. Lundstrm IMC, Lindstrm FD. Subjective and clinical oral symptoms in patients with primary Sjgrens syndrome. Clin Exp Rheumatol 1995;13:725-731.
  70. MacFarlane TW, Mason DK. Changes in the oral flora in Sjgrens syndrome. J Clin Pathol 1974;27:416-419.
  71. MacFarlane TW. The oral ecology of patients with severe Sjgrens syndrome. Microbios 1984;41:99-106.
  72. Main BE, Calman KC, Ferguson MM, Kaye SB, MacFarlane TW, Mairs RJ, et al. The effect of cytotoxic therapy on saliva and oral flora. Oral Surg Oral Med Oral Pathol 1984;58:545-548.
  73. Makkonen TA, Tenovuo J, Vilja P, Heimdahl A. Changes in the protein composition of whole saliva during radiotherapy in patients with oral or pharyngeal cancer. Oral Surg Oral Med Oral Pathol 1986;62:270-275.
  74. Mansson-Rahemtulla B, Techanitiswad T, Rahemtulla F, McMillan TO, Bradley EL, Wahlin YB. Analyses of salivary components in leukemia patients receiving chemotherapy. Oral Surg Oral Med Oral Pathol 1992;73:35-46.
  75. Manthorpe R, Oxholm P, Prause JU, Schidt M. The Copenhagen criteria for Sjgrens syndrome. Scand J Rheumatol Suppl 1986;61:19-21.
  76. Marsh PD. Microbial ecology of dental plaque and its significance in health and disease. Adv Dent Res 1994;8:263-271.
  77. Martin MV, Al Tikriti U, Bramley PA. Yeast flora of the mouth and skin during and after irradiation for oral and laryngeal cancer. J Med Microbiol 1981;14:457-467.
  78. Meurman JH, Laine P, Keinanen S, Pyrhonen S, Teerenhovi L, Lindqvist C. Five-year follow-up of saliva in patients treated for lymphomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997a;83:447-452.
  79. Meurman JH, Laine P, Lindqvist C, Teerenhovi L, Pyrhonen S. Five-year follow-up study of saliva, mutans streptococci, lactobacilli and yeast counts in lymphoma patients. Oral Oncol 1997b;33: 439-443.
  80. Meurman JH, Rantonen P. Salivary flow rate, buffering capacity, and yeast counts in 187 consecutive adult patients from Kuopio, Finland. Scand J Dent Res 1994;102:229-34.
  81. Mira JG, Wescott WB, Starcke EN, Shannon IL. Some factors influencing salivary function when treating with radiotherapy. Int J Radiat Oncol Biol Phys 1981;7:535-541.
  82. Monroe EW, Bernstein DI, Fox RW, Grabiec SV, Honsinger RW, Kalivas JT, et al. Relative efficacy and safety of loratadine, hydroxyzine, and placebo in chronic idiopathic urticaria. Arzneimittelforschung 1992;42:1119-1121.
  83. Mossman KL. Quantitative radiation dose-response relationships for normal tissues in man. II. Response of the salivary glands during radiotherapy. Radiat Res 1983;95:392-398.
  84. Mueck-Weymann M, Rechlin T, Ehrengut F, Rauh R, Acker J, Dittmann RW, et al. Effects of olanzapine and clozapine upon pulse rate variability. Depress Anxiety 2002;16:93-99.
  85. Najera MP, al-Hashimi I, Plemons JM, Rivera-Hidalgo F, Rees TD, Haghighat N, et al. Prevalence of periodontal disease in patients with Sjogrens syndrome. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;83:453-457.
  86. Nrhi TO, Meurman JH, Ainamo A, Nevalainen JM, Schmidt-Kaunisaho KG, Siukosaari P, et al. Association between salivary flow rate and the use of systemic medication among 76-, 81-, and 86-year-old inhabitants in Helsinki, Finland. J Dent Res 1992;71:1875-1880.
  87. Nrhi TO, Ainamo A, Meurman JH. Mutans streptococci and lactobacilli in the elderly. Scand J Dent Res 1994;102:97-102.
  88. Nrhi TO, Vehkalahti MM, Siukosaari P, Ainamo A. Salivary findings, daily medication and root caries in the old elderly. Caries Res 1998;32:5-9.
  89. Navazesh M, Wood GJ, Brightman VJ. Relationship between salivary flow rates and Candida albicans counts. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1995;80:284-288.
  90. Navazesh M, Brightman VJ, Pogoda JM. Relationship of medical status, medications, and salivary flow rates in adults of different ages. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1996;81:172-176.
  91. Nederfors T, Twetman S, Dahlof C. Effects of the thiazide diuretic bendroflumethiazide on salivary flow rate and composition. Scand J Dent Res 1989;97:520-527.
  92. Nederfors T, Ericsson T, Twetman S, Dahlof C. Effects of the beta-adrenoceptor antagonists atenolol and propranolol on human parotid and submandibular-sublingual salivary secretion. J Dent Res 1994;73:5-10.
  93. Nery EB, Edson RG, Lee KK, Pruthi VK, Watson J. Prevalence of nifedipine-induced gingival hyperplasia. J Periodontol 1995;66: 572-578.
  94. sterberg T, Landahl S, Hedegard B. Salivary flow, saliva, pH and buffering capacity in 70-year-old men and women. Correlation to dental health, dryness in the mouth, disease and drug treatment. J Oral Rehabil 1984;11:157-170.
  95. OSullivan EA, Duggal MS, Bailey CC, Curzon ME, Hart P. Changes in the oral microflora during cytotoxic chemotherapy in children being treated for acute leukemia. Oral Surg Oral Med Oral Pathol 1993;76:161-168.
  96. Pajari U, Poikonen K, Larmas M, Lanning M. Salivary immunoglobulins, lysozyme, pH, and microbial counts in children receiving anti-neoplastic therapy. Scand J Dent Res 1989;97:171-177.
  97. Pankhurst CL, Waite IM, Hicks KA, Allen Y, Harkness RD. The influence of oral contraceptive therapy on the periodontium - duration of drug therapy. J Periodontol 1981;52:617-20.
  98. Parvinen T, Parvinen I, Larmas M. Stimulated salivary flow rate, pH and lactobacillus and yeast concentrations in medicated persons. Scand J Dent Res 1984;92:524-532.
  99. Paula CR, Sampaio MC, Birman EG, Siqueira AM. Oral yeasts in patients with cancer of the mouth, before and during radiotherapy. Mycopathologia 1990;112:119-124.
  100. Pedersen AM, Reibel J, Nauntofte B. Primary Sjgrens syndrome: subjective symptoms and salivary findings. J Oral Pathol Med 1999a;28:303-311.
  101. Pedersen AM, Reibel J, Nordgarden H, Bergman HO, Jensen JL, Nauntofte B. Primary Sjgrens syndrome: salivary gland function and clinical oral findings. Oral Dis 1999b;5:128-138.
  102. Pedersen AM, Nauntofte B. Primary Sjgrens syndrome: oral aspects on pathogenesis, diagnostic criteria, clinical features and approaches for therapy. Expert Opin Pharmacother 2001;2: 1415-1436.
  103. Pedersen AM, Bardow A, Jensen SB, Nauntofte B. Saliva and gastrointestinal functions of taste, mastication, swallowing and digestion. Oral Dis. 2002a;8:117-129.
  104. Pedersen AM, Torpet Andersen L, Reibel J, Holmstrup P, Nauntofte B. Oral findings in patients with primary Sjgrens syndrome and oral lichen planus a preliminary study on the effects of bovine colostrum-containing oral hygiene products. Clin Oral Investig 2002b;6:11-20.
  105. Pompei R, Ingianni A, Cagetti MG, Rizzo A, Cotti S. Evaluation of the opportunistic microbial flora and of some antimicrobial factors in the oral cavity of leukaemic patients. Microbios 1993;75:149-157.
  106. Ramirez-Amador V, Silverman S Jr, Mayer P, Tyler M, Quivey J. Candidal ization and oral candidiasis in patients undergoing oral and pharyngeal radiation therapy. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1997;84:149-153.
  107. Redding SW, Zellars RC, Kirkpatrick WR, McAtee RK, Caceres MA, Fothergill AW et al. Epidemiology of oropharyngeal Candida ization and infection in patients receiving radiation for head and neck cancer. J Clin Microbiol 1999;37:3896-3900.
  108. Reynolds MA, Minah GE, Peterson DE, Weikel DS, Williams LT, Overholser CD, et al. Periodontal disease and oral microbial successions during myelosuppressive cancer chemotherapy. J Clin Periodontol 1989;16:185-189.
  109. Rhodus NL, Bloomquist C, Liljemark W, Bereuter J. Prevalence, density, and manifestations of oral Candida albicans in patients with Sjgrens syndrome. J Otolaryngol 1997;26:300-305.
  110. Rossie KM, Taylor J, Beck FM, Hodgson SE, Blozis GG. Influence of radiation therapy on oral Candida albicans ization: a quantitative assessment. Oral Surg Oral Med Oral Pathol 1987; 64:698-701.
  111. Rudney JD. Saliva and dental plaque. Adv Dent Res 2000;14:29-39.
  112. Ryberg M, Moller C, Ericson T. Saliva composition and caries development in asthmatic patients treated with beta 2-adrenoceptor agonists: a 4-year follow-up study. Scand J Dent Res 1991;99:212-218.
  113. Samaranayake LP, Calman KC, Ferguson MM, Kaye SB, MacFarlane TW, Main B, Welsh J, Willox J. The oral carriage of yeasts and coliforms in patients on cytotoxic therapy. J Oral Pathol 1984;13:390-393.
  114. Scannapieco FA. Saliva-bacterium interactions in oral microbial ecology. Crit Rev Oral Biol Med 1994;5:203-248.
  115. Schonfeld SE. Oral microbial ecology. In: Slots J, Taubman MA (eds). Contemporary oral microbiology and immunology. Mosby Year Book Inc. 1992;267-274.
  116. Schum CA, Izutsu KT, Molbo DM, Truelove EL, Gallucci B. Changes in salivary buffer capacity in patients undergoing cancer chemotherapy. J Oral Med 1979;34:76-80.
  117. Schpbach P, Osterwalder V, Guggenheim B. Human Root Caries: Microbiota of a limited number of root caries lesions. Caries Res 1996;30:52-64.
  118. Schwarz E, Chiu GK, Leung WK. Oral health status of southern Chinese following head and neck irradiation therapy for nasopharyngeal carcinoma. J Dent 1999;27:21-28.
  119. Ship JA, Pillemer Sr, Baum BJ. Xerostomia and the geriatric patient. J Am Geriatr Soc 2002;50:535-543.
  120. Silverman S Jr, Luangjarmekorn L, Greenspan D. Occurrence of oral Candida in irradiated head and neck cancer patients. J Oral Med 1984;39:194-196.
  121. Sixou JL, de Medeiros-Batista O, Bonnaure-Mallet M. Modifications of the microflora of the oral cavity arising during immunosuppressive chemotherapy. Eur J Cancer B Oral Oncol 1996;32B:306-310.
  122. Sixou JL, De Medeiros-Batista O, Gandemer V, Bonnaure-Mallet M. The effect of chemotherapy on the supragingival plaque of paediatric cancer patients. Oral Oncol 1998;34:476-483.
  123. Smith RG, Burtner AP. Oral side-effects of the most frequently prescribed drugs. Spec Care Dent 1994;14:96-102.
  124. Sonis ST. Oral Complications. In: Holland JF, Frei E, Bast RC, Kufe DW, Morton DL, Weichselbaum RR (eds). Cancer Medicine. USA: Williams & Wilkins 1997;3255-3264.
  125. Soto-Rojas AE, Villa AR, Sifuentes-Osornio J, Alarcon-Segovia D, Kraus A. Oral candidiasis and Sjgrens syndrome. J Rheumatol 1998; 25:911-915.
  126. Sreebny LM, Valdini A. Xerostomia. Part I: Relationship to other oral symptoms and salivary gland hypofunction. Oral Surg Oral Med Oral Pathol 1988;4:451-458.
  127. Sreebny LM, Banoczy J, Baum BJ, Edgar WM, Epstein JB, Fox PC et al. Saliva. The Working Group of the Commission on Oral Health, Research and Epidemiology (CORE). Fdration Dentaire Internationale. London: FDI World Dental Press 1991.
  128. Sreebny LM, Schwartz SS. A reference guide to drugs and dry mouth 2nd edition. Gerodontology 1997;14:33-47.
  129. Stark CA, Adamsson I, Edlund C, Sjosted S, Seensalu R, Wikstrom B, et al. Effects of omeprazole and amoxycillin on the human oral and gastrointestinal microflora in patients with Helicobacter pylori infection. J Antimicrob Chemother 1996;38:927-939.
  130. Strmbeck B, Ekdahl C, Manthorpe R, Wikstrm I, Jacobsson L. Health-related quality of life in primary Sjgrens syndrome, rheumatoid arthritis and fibromyalgia compared to normal population using SF-36. Scand J Rheumatol 2000;29:20-28.
  131. Suchowersky O. Parkinsons disease: medical treatment of moderate to advanced disease. Curr Neurol Neurosci Rep 2002;2: 310-316.
  132. Tapper-Jones L, Aldred M, Walker DM. Prevalence and intraoral distribution of Candida albicans in Sjgrens syndrome. J Clin Pathol 1980;33:282-287.
  133. Thorn JJ, Prause JU, Oxholm P. Sialochemistry in Sjgrens syndrome: a review. J Oral Pathol Med 1989;18;457-468.
  134. Thorselius I, Emilson CG, Osterberg T. Salivary conditions and drug consumption in older age groups of elderly Swedish individuals. Gerodontics 1988;4:66-70.
  135. Tong HC, Gao XJ, Dong XZ. Non-mutans streptococci in patients receiving radiotherapy in the head and neck area. Caries Res 2003;37:261-266.
  136. Torres SR, Peixoto CB, Caldas DM, Silva EB, Akiti T, Nucci M, de et al. Relationship between salivary flow rates and Candida counts in subjects with xerostomia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2002;93:149-154.
  137. Umazume M, Ueta E, Osaki T. Reduced inhibition of Candida albicans adhesion by saliva from patients receiving oral cancer therapy. J Clin Microbiol 1995;33:432-439.
  138. Valdez IH, Atkinson JC, Ship JA, Fox PC. Major salivary gland function in patients with radiation-induced xerostomia: flow rates and sialochemistry. Int J Radiat Oncol Biol Phys 1993;25:41-47.
  139. Vissink A, Jansma J, Spijkervet FK, Burlage FR, Coppes RP. Oral sequelae of head and neck radiotherapy. Crit Rev Oral Biol Med 2003;14:199-212.
  140. Vuotila T, Ylikontiola L, Sorsa T, Luoto H, Hanemaaijer R, Salo T et al. The relationship between MMPs and pH in whole saliva of radiated head and neck cancer patients. J Oral Pathol Med 2002;31:329-338.
  141. Wahlin YB, Holm AK. Changes in the oral microflora in patients with acute leukemia and related disorders during the period of induction therapy. Oral Surg Oral Med Oral Pathol 1988;65:411-417.
  142. Wahlin YB. Salivary secretion rate, yeast cells, and oral candidiasis in patients with acute leukemia. Oral Surg Oral Med Oral Pathol 1991;71:689-695.
  143. Workshop on diagnostic criteria for Sjgrens syndrome. Clin Exp Rheumatol 1989;7:212-219.
  144. Yamada H, Nishimura F, Furuno K, Naruishi K, Kobayashi Y, Takashiba S, et al. Serum phenytoin concentration and IgG antibody titre to periodontal bacteria in patients with phenytoin-induced gingival overgrowth. J Int Acad Periodontol 2001;3:42-47.
  145. Zacny JP, Lichtor JL, Flemming D, Coalson DW, Thompson WK. A dose-response analysis of the subjective, psychomotor and physiological effects of intravenous morphine in healthy volunteers. J Pharmacol Exp Ther 1994;268:1-9.

Authors:

a Esther Hofer
Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, and Copenhagen Gerodontological Research Center, Faculty of Health Sciences, University of Copenhagen, Denmark.

b Esther Hofer
Clinic for Geriatric and Special Care Dentistry, Center for Dental and Oral Medicine and Cranio-Maxillofacial Surgery, University of Zürich, Switzerland.

Esther Hofer, Department of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, Faculty of Health Sciences, University of Copenhagen, Nrre All 20, DK-2200 Copenhagen N, Denmark