Neurophysiology and genetics of burning mouth syndrome.

BACKGROUND AND AIMS: Neuropathic mechanisms are involved in burning mouth syndrome (BMS), and variation of the dopamine D2 receptor (DRD2) gene contributes to experimental pain perception. We investigated whether neurophysiologic findings differ in BMS patients compared to healthy controls, and whether 957C>T polymorphism of the DRD2 gene influences thermal sensitivity or pain experience in BMS. METHODS: Forty-five BMS patients (43 women), mean age 62.5 years, and 32 healthy controls (30 women), mean age 64.8 years, participated. Patients estimated pain intensity, interference, suffering and sleep with Numeric Rating Scale. Blink reflex tests of the supraorbital (SON), mental (MN) and lingual (LN) nerves, and thermal quantitative sensory testing were done. The results were analysed with ANOVA. DRD2 gene 957C>T polymorphism was determined in 31 patients, and its effects on neurophysiologic and clinical variables were analysed. RESULTS: Cool (p = 0.0090) and warm detection thresholds (p = 0.0229) of the tongue were higher in BMS patients than controls. The stimulation threshold for SON BR was higher in patients than in controls (p = 0.0056). The latencies of R2 component were longer in BMS patients than in controls (p = 0.0005) at the SON distribution. Habituation of SON BR did not differ between the groups. The heat pain thresholds were highest (p = 0.0312) in homozygous patients with 957TT, who also reported most interference (p = 0.0352) and greatest suffering (p = 0.0341). Genotype 957CC associated with sleep disturbances (p = 0.0254). CONCLUSIONS: Burning mouth syndrome patients showed thermal hypoesthesia within LN distribution compatible with small fibre neuropathy. The DRD2 957C>T genotype influences perception and experience of BMS pain. SIGNIFICANCE: The results confirm earlier findings of neuropathic pain in BMS. The DRD2 957 C>T genotype influences perception and experience of clinical pain in BMS.

The analgesic effect of therapeutic rTMS is not mediated or predicted by comorbid psychiatric or sleep disorders.

BACKGROUND: Mechanisms underlying alleviation of neuropathic pain by repetitive transcranial magnetic stimulation (rTMS) of primary motor cortex (M1) and right secondary somatosensory cortex (S2) are only partly known. Patients with chronic neuropathic pain often have comorbidities like depression and sleep problems. Through functional connectivity, rTMS of M1 and S2 may activate dorsolateral prefrontal cortex, the target for treating depression with rTMS. Thus, the analgesic effect of rTMS could be mediated indirectly via improvement of psychiatric comorbidities or sleep. We examined whether rTMS has an independent analgesic effect or whether its clinical benefits depend on effects on mood or sleep. We also evaluated if comorbid psychiatric or sleep disorders predict the treatment outcome. METHODS: Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized controlled crossover rTMS study. Patients' psychiatric history was evaluated by a specialist in psychiatry. Intensity and interference of pain, mood, and the quality of sleep and life were evaluated at baseline and after 2 active (primary somatosensory cortex [S1]/M1 and S2) and placebo rTMS treatments. A logistic regression analysis was done to investigate predictors of treatment outcome. RESULTS: The analgesic effect of the right S2 stimulation was not associated with improvement of psychiatric conditions or sleep, whereas S1/M1 stimulation improved sleep without significant analgesic effect (P = 0.013-0.046 in sleep scores). Psychiatric and sleep disorders were more common in patients than in the general population (P = 0.000-0.001 in sleep scores), but these comorbidities did not predict the rTMS treatment outcome. CONCLUSION: We conclude that rTMS to the right S2 does not exert its beneficial analgesic effects in chronic neuropathic orofacial pain via indirect improvement of comorbid psychiatric or sleep disorders.

Right secondary somatosensory cortex-a promising novel target for the treatment of drug-resistant neuropathic orofacial pain with repetitive transcranial magnetic stimulation.

High-frequency repetitive transcranial magnetic stimulation (rTMS) of the motor cortex has analgesic effect; however, the efficacy of other cortical targets and the mode of action remain unclear. We examined the effects of rTMS in neuropathic orofacial pain, and compared 2 cortical targets against placebo. Furthermore, as dopaminergic mechanisms modulate pain responses, we assessed the influence of the functional DRD2 gene polymorphism (957C>T) and the catechol-O-methyltransferase (COMT) Val158Met polymorphism on the analgesic effect of rTMS. Sixteen patients with chronic drug-resistant neuropathic orofacial pain participated in this randomized, placebo-controlled, crossover study. Navigated high-frequency rTMS was given to the sensorimotor (S1/M1) and the right secondary somatosensory (S2) cortices. All subjects were genotyped for the DRD2 957C>T and COMT Val158Met polymorphisms. Pain, mood, and quality of life were monitored throughout the study. The numerical rating scale pain scores were significantly lower after the S2 stimulation than after the S1/M1 (P = 0.0071) or the sham (P = 0.0187) stimulations. The Brief Pain Inventory scores were also lower 3 to 5 days after the S2 stimulation than those at pretreatment baseline (P = 0.0127 for the intensity of pain and P = 0.0074 for the interference of pain) or after the S1/M1 (P = 0.001 and P = 0.0001) and sham (P = 0.0491 and P = 0.0359) stimulations. No correlations were found between the genetic polymorphisms and the analgesic effect in the present small clinical sample. The right S2 cortex is a promising new target for the treatment of neuropathic orofacial pain with high-frequency rTMS.

Variation in the dopamine D2 receptor gene plays a key role in human pain and its modulation by transcranial magnetic stimulation.

We tested whether variation of the dopamine D2 receptor (DRD2) gene contributes to individual differences in thermal pain sensitivity and analgesic efficacy of repetitive transcranial magnetic stimulation (rTMS) in healthy subjects (n=29) or susceptibility to neuropathic pain in patients with neurophysiologically confirmed diagnosis (n=16). Thermal sensitivity of healthy subjects was assessed before and after navigated rTMS provided to the S1/M1 cortex. All subjects were genotyped for the DRD2 gene 957C>T and catechol-O-methyltransferase (COMT) protein Val158Met polymorphisms. In healthy subjects, 957C>T influenced both innocuous and noxious thermal detection thresholds that were lowest in 957TT homozygotes (P values from .0277 to .0462). rTMS to S1 cortex had analgesic effect only in 957TT homozygote genotype (P=.0086). In patients, prevalence of 957TT homozygote genotype was higher than in a healthy Finnish population (50% vs 27%; P=.0191). Patients with 957TT genotype reported more severe pain than patients with other genotypes (P=.0351). COMT Val158Met polymorphism was not independently associated with the studied variables. Genetic regulation of DRD2 function by 957C>T polymorphism thus seems to influence thermal and pain sensitivity, its modulation by rTMS, and susceptibility to neuropathic pain. This indicates a central role for the dopamine system and DRD2 in pain and analgesia. This may have clinical implications regarding individualized selection of patients for rTMS treatment and assessment of risks for neuropathic pain.

The effects of heat stress on physical functioning in persons with multiple sclerosis.

Heat sensitivity is a well-recognised feature in multiple sclerosis (MS). However, little is known about how heat affects physical performance in persons with MS. The objective of the study was to evaluate the effects of short-term heat stress on physical functioning in persons with MS. Twenty-three heat-sensitive MS subjects and 19 healthy controls participated. Moderate heat exposure took place in a dry Finnish sauna. Measures of upper and lower extremity function, static and dynamic balance, and walking capacity were applied. Core body temperature was measured by a telemetric physiological monitoring system. Assessments were conducted before, immediately, 1 hour, and 1 day after the heat exposure. Subjects with MS showed a significantly (P=0.002) higher core body temperature than the controls following the heat stress. Performances in walking (P<0.001), chair rise (P=0.005) and functional reach (P=0.04) were poorer in MS subjects than in controls immediately after the heat. No prolonged heat effects were observed. An increase in ambient temperature causes a higher core body temperature rise in MS subjects than in healthy controls. This rise in temperature is associated with acute, but not prolonged detrimental effects on physical functioning.

Subjective sensory symptoms associated with axonal and demyelinating nerve injuries after mandibular sagittal split osteotomy.

PURPOSE: The effect of the type of nerve injury on subjective sensory disturbances and recovery has not been addressed in orthognathic surgery. Using neurophysiologic monitoring during 19 bilateral sagittal split osteotomy operations, we were able to classify intraoperative inferior alveolar nerve injuries as either axonal or demyelinating. This study aimed to analyze the quality and extent of the subjective sensations experienced by the patients after these 2 injury types at different time points up to 12 months. MATERIALS AND METHODS: Of the 36 injured nerves, 21 showed signs of demyelinating injury and 15 showed signs of axonal damage. The quality of subjective sensory symptoms was asked about at 2 weeks and 1, 3, 6, and 12 months postoperatively and classified into 4 categories: normal, negative, positive (including pain), and mixed sensations. In addition, the extent of the sensory alteration was determined by measuring the affected skin regions from symptom charts. RESULTS: The quantity, quality, and evolution of experienced subjective sensations differed between the injury types during follow-up: Subjective sensations normalized more rapidly after demyelinating-type injuries than after axonal-type injuries. Persistence of mixed sensation patterns at 3 months and appearance instead of disappearance of positive sensory phenomena after 3 months indicated axonal damage. Painful sensations at 1 month or later after surgery indicated axonal damage and predicted poor recovery and more long-term sequelae. CONCLUSIONS: Postoperative pain at 1 month and type of nerve injury are important prognostic factors for the persistence of subjective symptoms and development of neuropathic pain.

Modulation of facial sensitivity by navigated rTMS in healthy subjects.

Repetitive transcranial magnetic stimulation (rTMS) has had partly incongruous effects on cutaneous sensibility, and there are no systematic studies on the effects of rTMS on facial sensory function. We assessed modulation of thermal sensitivity of facial skin in healthy subjects by navigated rTMS (10 Hz), enabling accurate localization of predefined cortical targets: right primary motor cortex (M1) of facial muscles, primary somatosensory cortex (S1) representing the cheek, dorsolateral prefrontal cortex (DLPFC), and secondary somatosensory cortex (S2); the control site was occipital cortex (OCC). Applying signal detection theory, we investigated whether the rTMS-induced changes in heat-pain threshold (HPT) relate to an alteration in the subject's discriminative capacity (sensory factor) or response criterion (non-sensory factor). HPT increased after stimulation of S2, but also 45 min after stimulation of DLPFC and OCC. S2 stimulation produced the most effective and long-lasting heat hypoalgesia that was associated with a decrease in discriminative capacity and an increase in response criterion. Cold-pain threshold was elevated after S2 stimulation only in men. Stimulation of M1 decreased capacity to discriminate painful heat without influencing HPT; there was large interindividual variation in rTMS effects in the M1/S1 areas. Detection threshold for innocuous warming rose similarly after rTMS of M1, S1, DLPFC, S2 and OCC, whereas sensibility to innocuous cooling transiently improved after rTMS of S1. The results indicate that rTMS applied anatomically accurately to S2 may produce analgesia in the face via multiple mechanisms, partly depending on gender, and involving decreased discriminative capacity and increased response criterion.

NSAID use and the risk of hospitalization for first myocardial infarction in the general population: a nationwide case-control study from Finland.

AIMS: To evaluate the risk of first myocardial infarction (MI) associated with the use of various non-steroidal anti-inflammatory drugs (NSAIDs) in the general population. METHODS AND RESULTS: We conducted a population-based matched case-control study over the years 2000-3 in outpatient residents of Finland. In the nationwide Hospital Discharge Register 33 309 persons with first time MI were identified. A total of 138 949 controls individually matched for age, gender, hospital catchment area, and index day were selected from the Population Register. For combined NSAIDs, the adjusted odds ratio for the risk of first MI with current use was 1.40 (95% CI, 1.33-1.48). The risk was similar for conventional (1.34; 1.26-1.43), semi-selective (etodolac, nabumetone, nimesulide, and meloxicam) (1.50; 1.32-1.71), and cyclo-oxygenase-2 (COX-2) selective NSAIDs (rofecoxib, celecoxib, valdecoxib, and etoricoxib) (1.31; 1.13-1.50). Age of current user did not consistently modify the risk. No NSAID was associated with an MI-protective effect. All durations from 1 to 180 days of conventional NSAIDs and from 31 to 90 days duration of COX-2 selective NSAIDs were associated with an elevated risk of MI. CONCLUSION: Current use of all NSAIDs is associated with a modest risk of first time MI.

Effects of diet and simvastatin on fatty acid composition in hypercholesterolemic men: a randomized controlled trial.

OBJECTIVE: To explore the separate and combined effects of simvastatin and a low-saturated diet rich in alpha-linolenic acid on serum fatty acids. METHODS AND RESULTS: 120 hypercholesterolemic men were randomly allocated to a habitual diet or dietary treatment group and to receive, in random order, simvastatin 20 mg/d or placebo, each for 12 weeks, in a double-blind manner. Dietary treatment decreased proportions from total fatty acids of palmitic acid (C16:0) by 3.3% (P<0.05), stearic acid (C18:0) by 3.7% (P<0.05) and increased proportions of oleic acid (C18:1n-9) by 4.2% (P<0.01), and alpha-linolenic acid (C18:3n-3) by 29.8% (P<0.001). Simvastatin decreased proportions from total fatty acids of palmitic acid by 2.0% (P<0.01), linoleic acid (C18:2n-6) by 5.3% (P<0.001), and alpha-linolenic acid by 6.8% (P<0.05), and increased proportions of gamma-linolenic acid (C18:3n-6) by 11.1% (P<0.001), dihomo-gamma-linolenic acid (C20:3n-6) by 4.2% (P<0.01), arachidonic acid (C20:4n-6) by 14.2% (P<0.001), and the sum of long-chain polyunsaturated fatty acids (C20-22) by 9.0% (P<0.001). Simvastatin increased ratios of stearic to palmitic, gamma-linolenic to linoleic, and arachidonic to dihomo-gamma-linolenic acid by 7.6%, 17.0%, and 10.0% (P<0.001 for all), respectively, suggesting increased fatty acid elongase and Delta6- and Delta5-desaturase enzyme activities. CONCLUSIONS: Increased formation of long-chain polyunsaturated fatty acids and their metabolites may contribute a substantial part of the pleiotropic effects of simvastatin.

Frequent prescribing of drugs with potential gastrointestinal toxicity among continuous users of non-steroidal anti-inflammatory drugs.

OBJECTIVE: A number of drugs used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of gastrointestinal (GI) haemorrhage. We studied the prescribing of NSAIDs with corticosteroids, oral anticoagulants or selective serotonin re-uptake inhibitors (SSRIs), as well as the use of gastroprotection among continuous and non-continuous users of NSAIDs in Finland. METHODS: Concurrent use of various drugs was analysed in a nested case-control study in a population-based cohort of NSAID users in 2000 using data in the National Prescription Database. RESULTS: Prescribing of any other drug with the potential to increase the risk of GI bleeding with NSAIDs was five times [5.2; 95% confidence interval (CI) 4.7-5.9] more common among continuous than non-continuous NSAID users, and the odds ratio for oral corticosteroids was 8.0 (95% CI 6.6-9.6). Of patients using continuous NSAIDs with oral corticosteroids, 73.3% had rheumatoid arthritis (RA). After excluding RA patients, the odds ratio remained high (4.5; 95% CI 3.3-6.1) and at the same level as for SSRIs (3.7; 3.1-4.4). Gastroprotective drugs were prescribed for 6.8% of the continuous users of NSAIDs alone, and for 20.4% of patients taking any of the studied drug combinations with NSAIDs. The continuous users of NSAIDs alone had gastroprotection 2.9 (2.5-3.3) times more often than other users of NSAIDs. With drug combinations (NSAID+corticosteroid, NSAID+SSRI, NSAID+anticoagulants), the use of gastroprotection did not differ from patients using lower amounts of NSAIDs. CONCLUSIONS: When prescribing NSAIDs, situations leading to habitual use should be avoided, potential complications due to clustering of risk factors recognised, and gastroprotection prescribed for patients with increased risk of GI haemorrhage.

Long-term exercise improves functional impairment but not quality of life in multiple sclerosis.

Regular exercise is important for patients with multiple sclerosis (MS) to maintain their functional ability and general health. The aim of this study was to determine whether a long-term exercise program has any effect on functional impairment or healthrelated quality of life (HRQOL) in subjects with mild to moderate MS. In a randomised controlled trial, subjects in the intervention group (n = 47) exercised according to a progressive exercise program, mainly consisting of resistance training, for six months. Subjects in the control group (n = 48) received no intervention. The subjects were assessed at baseline and at six months using the Multiple Sclerosis Functional Composite (MSFC), the Expanded Disability Status Scale (EDSS), the Functional Independence Measure (FIM), the MS Quality of Life-54 (MSQOL-54) questionnaire and the Centre for Epidemiologic Studies Depression Scale (CES-D). The drop-out rate was low (4%) with 91 subjects completing the study. At six months, the exercising subjects showed improvement on the MSFC (mean score change 0.114, 95% confidence interval [CI] 0.010 to 0.218), whereas the control subjects showed deterioration (mean score change -0.128, 95 % CI -0.232 to -0.025). The change between groups was statistically significant (interaction, p = 0.001). Consistent with the physical nature of the intervention, the change predominantly occurred in leg function/ambulation. The effect seen in the EDSS, FIM, MSQOL-54 or CES-D was nil. These findings indicate that MSFC is more sensitive than EDSS in the detection of improvement in functional impairment as a result of regular exercise. The unfavourable results from HRQOL do not rule out the possibility that other types of exercise programs may improve it in MS.

Effects of aerobic and strength exercise on motor fatigue in men and women with multiple sclerosis: a randomized controlled trial.

OBJECTIVE: To investigate the effects of aerobic and strength exercise on motor fatigue of knee flexor and extensor muscles in subjects with multiple sclerosis (MS). DESIGN: A randomized controlled trial. SETTING: At Masku Neurological Rehabilitation Centre, Masku, and the Social Insurance Institution, Research Department, Turku, Finland. SUBJECTS: Ninety-five MS patients with mild to moderate disability were randomized into exercise group (n =47) and a control group (n =48). INTERVENTION: Participants in the exercise group attended in a supervised exercise period of three weeks, which was followed by a home exercise programme lasting for 23 weeks. Patients in the control group continued with their normal living. OUTCOME MEASURES: Motor fatigue of knee flexor and extensor muscles was measured during a static 30-s maximal sustained muscle contraction. The decline in force (Nm) during the 30 s was recorded, and a fatigue index (FI) was calculated. Subjective fatigue was measured by using the Fatigue Severity Scale (FSS). The Ambulatory Fatigue Index (AFI) was calculated on the basis of a 500-m walking test. Assessment took place at baseline, at the third week (not for the control group) and at the 26th week. All outcome variables were analysed, men and women together, and some interesting contrasts were analysed by gender. RESULTS: Associations were observed with changes in extension FI and Expanded Disability Status Scale (EDSS) score and mean extension torque (Nm), but not with changes in FI and aerobic or strength exercise activity, mean AFI, mean FSS or in mean knee flexion torque. AFI was decreased in all subject groups (p =0.007). Motor fatigue was reduced in knee flexion (p=0.0014) and extension (ns) among female but not in male exercisers after six months of exercise. The exercise activity of women was 25% higher than that of the men. CONCLUSIONS: Six months of exercise reduced motor fatigue in women, but not in men.

Assessment of muscle strength and motor fatigue with a knee dynamometer in subjects with multiple sclerosis: a new fatigue index.

OBJECTIVE: To measure muscle strength and motor fatigue with a knee dynamometer and to assess the intra-rater reliability of measurements for maximal isometric extensor and flexor torques and the reliability of a new fatigue index (FI) in patients with mild to moderate multiple sclerosis (MS). DESIGN: Repeated assessments with one-week intervals. SETTING: The Masku Neurological Rehabilitation Centre, Masku, and the Social Insurance Institution, Research Department, Turku, Finland. SUBJECTS: Twenty-eight MS patients. OUTCOME MEASURES: Maximal isometric torque during 5 s and fatigue of knee flexors and extensors during isometric contractions of 30 s were assessed. A new FI was established and compared with the two previously used indices (FI1 and FI2). All three indices are based on the calculated area under the force versus time curve (AUFC), with FI1 using the 30-s recording time in its entirety and F2 omitting the initial 5 s in the calculation. In the new fatigue index (FI3), the time point of maximum (TPM) torque achieved by the subject is used as the starting point in the calculation. The patient's subjective fatigue was measured by Fatigue Severity Scale (FSS). RESULTS: The intraclass correlation coefficient (ICC) was 0.97 in maximal isometric torque measurements. FI3 showed good intra-rater reliability (ICC =0.68-0.86). None of the fatigue indices correlated with FSS. CONCLUSIONS: Maximal isometric torque and motor fatigue of knee flexor and extensor muscles can be reliably measured using a knee dynamometer in MS patients. The new FI proved to be a reliable model for MS patients.

Parametric methods for estimating covariate-dependent reference limits.

Age-specific reference limits are required for many clinical laboratory measurements. Statistical assessment of calculated intervals must be performed to obtain reliable reference limits. When parametric, covariate-dependent limits are derived, normal distribution theory usually is applied due to its mathematical simplicity and relative ease of fitting. However, it is not always possible to transform data and achieve a normal distribution. Therefore, models other than those based on normal distribution theory are needed. Generalized linear model theory offers one such alternative. Regardless of the statistical model used, the assumptions behind the model should always be examined.

Does simvastatin affect mood and steroid hormone levels in hypercholesterolemic men? A randomized double-blind trial.

Epidemiological and clinical studies have suggested that powerful cholesterol lowering may have adverse effects on mood and psychological well-being. Inhibition of cholesterol biosynthesis by simvastatin (a hydroxymethyl glutaryl coenzyme A reductase inhibitor) may also reduce steroid hormone biosynthesis. To explore if mood changes are related with steroid hormone levels, we designed a randomized double-blind placebo-controlled crossover trial. The separate and combined effects of a Mediterranean-type diet intervention and treatment with simvastatin 20 mg/day PO for 12 weeks were studied in 120 hypercholesterolemic but otherwise healthy middle-aged men. Psychological functioning was assessed with questionnaires, and steroid hormone levels in blood were assayed radioimmunologically before and after the treatments. Simvastatin resulted in a statistically significant increase of depression and somatization without changes in the anxiety, hostility or aggression scores. Mood changes seemed to be unrelated with the statistically significant but clinically insignificant decline in serum testosterone levels and unrelated with the increase in serum dehydroepiandrosterone levels.

Effects of diet and simvastatin on serum lipids, insulin, and antioxidants in hypercholesterolemic men: a randomized controlled trial.

CONTEXT: Limited information exists on the interaction between diet and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) and the interaction's effect on serum lipid and lipoprotein levels, insulin sensitivity, and circulating antioxidant vitamin and provitamin levels. OBJECTIVE: To evaluate the separate and combined effects of diet and simvastatin therapy on serum levels of lipids, lipoproteins, antioxidants, and insulin. DESIGN, SETTING, AND PARTICIPANTS: Randomized, controlled crossover trial conducted from August 1997 to June 1998 in 120 previously untreated hypercholesterolemic men aged 35 to 64 years who were recruited from the community in Turku, southwestern Finland. INTERVENTIONS: After a 4- to 6-week placebo run-in period, participants were randomly allocated to a habitual diet (n = 60) or dietary treatment group (n = 60), and each of these groups was further randomized in a double-blind crossover fashion to receive simvastatin (20 mg/d) or placebo, each for 12 weeks (n = 30 in each group). The main goals of the dietary treatment were to reduce energy intake from saturated plus trans-unsaturated fats to no more than 10% by replacing them partly with monounsaturated and polyunsaturated fats rich in omega-3 fatty acids and to increase intake of fruits, vegetables, and dietary fiber. MAIN OUTCOME MEASURES: Changes in levels of total, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol; triglycerides; apolipoprotein B; insulin; glucose; and antioxidants at week 12 of each treatment period, compared among the 4 groups. RESULTS: Dietary treatment decreased levels of total cholesterol by 7.6% (P<.001), LDL cholesterol by 10.8% (P<.001), HDL cholesterol by 4.9% (P =.01), apolipoprotein B by 5.7% (P =.003), serum insulin by 14.0% (P =.02), and alpha-tocopherol by 3.5% (P =.04). Simvastatin decreased levels of total cholesterol by 20.8%, LDL cholesterol by 29.7%, triglycerides by 13.6%, apolipoprotein B by 22.4%, alpha-tocopherol by 16.2%, beta-carotene by 19.5%, and ubiquinol-10 by 22.0% (P<.001 for all) and increased levels of HDL cholesterol by 7.0% (P<.001) and serum insulin by 13.2% (P =.005). Glucose levels remained unchanged in all groups. The effects of dietary treatment and simvastatin were independent and additive. CONCLUSIONS: A modified Mediterranean-type diet rich in omega-3 fatty acids efficiently potentiated the cholesterol-lowering effect of simvastatin, counteracted the fasting insulin-elevating effect of simvastatin, and, unlike simvastatin, did not decrease serum levels of beta-carotene and ubiquinol-10.