Use of 2,6-diaminopurine as a potent suppressor of UGA premature stop codons in cystic fibrosis.

Nonsense mutations are responsible for around 10% of cases of genetic diseases, including cystic fibrosis. 2,6-diaminopurine (DAP) has recently been shown to promote efficient readthrough of UGA premature stop codons. In this study, we show that DAP can correct a nonsense mutation in the Cftr gene in vivo in a new CF mouse model, in utero, and through breastfeeding, thanks, notably, to adequate pharmacokinetic properties. DAP turns out to be very stable in plasma and is distributed throughout the body. The ability of DAP to correct various endogenous UGA nonsense mutations in the CFTR gene and to restore its function in mice, in organoids derived from murine or patient cells, and in cells from patients with cystic fibrosis reveals the potential of such readthrough-stimulating molecules in developing a therapeutic approach. The fact that correction by DAP of certain nonsense mutations reaches a clinically relevant level, as judged from previous studies, makes the use of this compound all the more attractive.

Macrophage-Colony-Stimulating Factor Receptor Enhances Prostate Cancer Cell Growth and Aggressiveness In Vitro and In Vivo and Increases Osteopontin Expression.

Prostate cancer is a major public health concern and one of the most prevalent forms of cancer worldwide. The definition of altered signaling pathways implicated in this complex disease is thus essential. In this context, abnormal expression of the receptor of Macrophage Colony-Stimulating Factor-1 (M-CSF or CSF-1) has been described in prostate cancer cells. Yet, outcomes of this expression remain unknown. Using mouse and human prostate cancer cell lines, this study has investigated the functionality of the wild-type CSF-1 receptor in prostate tumor cells and identified molecular mechanisms underlying its ligand-induced activation. Here, we showed that upon CSF-1 binding, the receptor autophosphorylates and activates multiple signaling pathways in prostate tumor cells. Biological experiments demonstrated that the CSF-1R/CSF-1 axis conferred significant advantages in cell growth and cell invasion in vitro. Mouse xenograft experiments showed that CSF-1R expression promoted the aggressiveness of prostate tumor cells. In particular, we demonstrated that the ligand-activated CSF-1R increased the expression of spp1 transcript encoding for osteopontin, a key player in cancer development and metastasis. Therefore, this study highlights that the CSF-1 receptor is fully functional in a prostate cancer cell and may be a potential therapeutic target for the treatment of prostate cancer.

Relationship Between Different Experimental Measures of Distorted Symptom Perception in Functional Syndrome Patients.

OBJECTIVE: Patients with functional somatic syndromes show reduced correspondence between induced physiological changes and self-reported symptoms in a rebreathing paradigm, as well as elevated symptoms unrelated to physiological changes after induction of negative affective states in an affective picture-viewing paradigm. Detailed results of both paradigms separately were published elsewhere. The main goal of the current report is to describe the relationship between the responses to these two paradigms measuring distortions in symptom perception in a well-described sample of patients with fibromyalgia and/or chronic fatigue syndrome. METHODS: Patients (N = 81) with fibromyalgia and/or chronic fatigue syndrome participated in a test session comprising four well-validated paradigms, including the picture-viewing and rebreathing paradigm. Using mixed model analyses, we tested whether the amount of affective modulation of symptom reporting was related to distorted perception of induced dyspnea. In an exploratory way, we assessed the role of several individual difference variables as moderators. RESULTS: There was no relationship between patients' amount of affective modulation of symptom reporting, as assessed with the picture paradigm, and level of distortion in dyspnea perception, as assessed with the rebreathing paradigm (effect of affective modulation in the subjective recovery from induced dyspnea: F1,70 = 0.16, p = .70; time by affective modulation interaction effect: F4,70 = 0.14, p = .97). CONCLUSIONS: Biased symptom reporting in one paradigm is unrelated to biased symptom reporting in the other paradigm, indicating that distortions in symptom perception in patients with functional somatic syndromes are not a trait-like, cross-situationally stable condition, but a versatile dysfunction that is context dependent.

Inducing Somatic Symptoms in Functional Syndrome Patients: Effects of Manipulating State Negative Affect.

OBJECTIVE: Induction of negative affective states can enhance bodily symptoms in high habitual symptom reporters among healthy persons and in patients with irritable bowel syndrome. The aims of this study were to replicate this effect in patients with fibromyalgia and chronic fatigue syndrome and to investigate the role of moderators, focusing on alexithymia, negative affectivity, and absorption. METHODS: Patients with fibromyalgia and/or chronic fatigue syndrome (n = 81) and HCs (n = 41) viewed series of neutral, positive, and negative affective pictures. After every picture series, participants filled out a somatic symptom checklist and rated emotions experienced during the picture series on valence, arousal, and perceived control. RESULTS: Patients reported more somatic symptoms after viewing negative pictures (least square mean [LSM] = 19.40, standard error (SE) = 0.50) compared with neutral (LSM = 17.59, SE = 0.42, p < .001) or positive (LSM = 17.04, SE = 0.41, p < .001) pictures, whereas somatic symptom ratings of HCs after viewing negative picture series (LSM = 12.07, SE = 0.71) did not differ from ratings after viewing neutral (LSM = 11.07, SE = 0.59, p = .065) or positive (LSM = 11.10, SE = 0.58, p = .93) pictures. Negative affectivity did not moderate the symptom-enhancing effect of negative affective pictures, whereas the alexithymia factor "difficulty identifying feelings" and absorption did (p = .016 and p = .006, respectively). CONCLUSION: Negative affective states elicit elevated somatic symptom reports in patients experiencing fibromyalgia and/or chronic fatigue syndrome. This symptom-enhancing effect is greater in patients having higher difficulty to identify feelings and higher absorption scores. The results are discussed in a predictive coding framework of symptom perception.

Negative Affectivity, Depression, and Resting Heart Rate Variability (HRV) as Possible Moderators of Endogenous Pain Modulation in Functional Somatic Syndromes.

Background: Several studies have shown that patients with functional somatic syndromes (FSS) have, on average, deficient endogenous pain modulation (EPM), as well as elevated levels of negative affectivity (NA) and high comorbidity with depression and reduced resting heart rate variability (HRV) compared to healthy controls (HC). The goals of this study were (1) to replicate these findings and (2) to investigate the moderating role of NA, depression, and resting HRV in EPM efficiency within a patient group with fibromyalgia and/or chronic fatigue syndrome (CFS). Resting HRV was quantified as the root mean square of successive differences between inter-beat intervals (RMSSD) in rest, a vagally mediated time domain measure of HRV. Methods: Seventy-eight patients with fibromyalgia and/or CFS and 33 HC completed a counter-irritation paradigm as a measure of EPM efficiency. Participants rated the painfulness of electrocutaneous stimuli (of individually calibrated intensity) on the ankle before (baseline phase), during (counter-irritation phase) and after (recovery phase) the application of a cold pain stimulus on the forearm. A larger reduction in pain in the counter-irritation phase compared to the baseline phase reflects a more efficient EPM. Results: In contrast to our expectations, there was no difference between pain ratings in the baseline compared to counter-irritation phase for both patients and HC. Therefore, reliable conclusions on the moderating effect of NA, depression, and RMSSD could not be made. Surprisingly, patients reported more pain in the recovery compared to the counter-irritation and baseline phase, while HC did not. This latter effect was more pronounced in patients with comorbid depression, patients who rated the painfulness of the counter-irritation stimulus as high and patients who rated the painfulness of the electrocutaneous stimuli as low. We did not manage to successfully replicate the counter-irritation effect in HC or FSS patients. Therefore, no valid conclusions on the association between RMSSD, depression, NA and EPM efficiency can be drawn from this study. Possible reasons for the lack of the counter-irritation effect are discussed.

Perception of induced dyspnea in fibromyalgia and chronic fatigue syndrome.

OBJECTIVE: Dyspnea perception is distorted in patients with medically unexplained dyspnea. The goals of this study were 1) to replicate these results in patients with fibromyalgia and/or chronic fatigue syndrome (CFS), and 2) to investigate predictors of distorted symptom perception within the patient group, with a focus on negative affectivity (NA), psychiatric comorbidity and somatic symptom severity. METHODS: Seventy-three patients diagnosed with fibromyalgia and/or CFS and 38 healthy controls (HC) completed a rebreathing paradigm, consisting of a baseline (60s of room air), a rebreathing phase (150s, gradually increasing ventilation, partial pressure of CO2 in the blood, and self-reported dyspnea), and a recovery phase (150s of room air). Dyspnea, respiratory flow and FetCO2 levels were measured continuously. RESULTS: Patients reported more dyspnea than HC in the recovery phase (p=0.039), but no differences between patients and HC were found in the baseline (p=0.07) or rebreathing phase (p=0.17). No significant differences between patients and HC were found in physiological reactivity. Within the patient group, the effect in the recovery phase was predicted by somatic symptom severity (p=0.046), but not by negative affectivity or by the number of psychiatric comorbidities. CONCLUSION: This study extended earlier findings in patients with medically unexplained dyspnea to patients with fibromyalgia and CFS. This suggests that altered symptom perception is a non-symptom-specific mechanism underlying functional somatic syndromes in general, particularly in patients with high levels of somatic symptom severity. The results are discussed in a predictive coding framework of symptom perception.

Glucocorticoid receptor DNA methylation and childhood trauma in chronic fatigue syndrome patients.

OBJECTIVE: Although the precise mechanisms are not yet understood, previous studies have suggested that chronic fatigue syndrome (CFS) is associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation and trauma in early childhood. Consistent with findings suggesting that early life stress-induced DNA methylation changes may underlie dysregulation of the HPA axis, we previously found evidence for the involvement of glucocorticoid receptor (GR) gene (NR3C1) methylation in whole blood of CFS patients. METHODS: In the current study, we assessed NR3C1-1F region DNA methylation status in peripheral blood from a new and independent sample of 80 female CFS patients and 91 female controls. In CFS patients, history of childhood trauma subtypes was evaluated using the Childhood Trauma Questionnaire short form (CTQ-SF). RESULTS: Although absolute methylation differences were small, the present study confirms our previous findings of NR3C1-1F DNA hypomethylation at several CpG sites in CFS patients as compared to controls. Following multiple testing correction, only CpG_8 remained significant (DNA methylation difference: 1.3% versus 1.5%, p<0.001). In addition, we found associations between DNA methylation and severity of fatigue as well as with childhood emotional abuse in CFS patients, although these findings were not significant after correction for multiple testing. CONCLUSIONS: In conclusion, we replicated findings of NR3C1-1F DNA hypomethylation in CFS patients versus controls. Our results support the hypothesis of HPA axis dysregulation and enhanced GR sensitivity in CFS.

Relationship between anxiety and gastric sensorimotor function in functional dyspepsia.

OBJECTIVE: To investigate the relationship between anxiety and gastric sensorimotor function in patients with (hypersensitive) functional dyspepsia (FD). Comorbidity between FD and anxiety disorders is high. In FD, epigastric pain is associated with gastric hypersensitivity and neuroticism, a personality trait related to anxiety. Experimentally induced anxiety in healthy volunteers is associated with changes in sensorimotor function of the proximal stomach. METHODS: A total of 139 patients with FD (n = 102 women) underwent a barostat investigation to determine gastric compliance, meal accommodation, and thresholds for discomfort and pain. Anxiety was measured by the State-Trait Anxiety Inventory (STAI) scale (anxiety as a stable personality trait) and the STAI-State scale (momentary anxiety). The anxiety subscale of the Hospital Anxiety and Depression Scale (HADS-A) was filled out to detect comorbid anxiety disorders. RESULTS: Hyper- and normosensitive patients had similar anxiety scores, but gastric compliance was significantly lower in hypersensitive patients (11.4 versus 32.8 ml/mm Hg; p < .001). In the whole patient group, no significant correlations between STAI scores and gastric sensorimotor function were found. In hypersensitive patients (n = 53, 43 women), state anxiety was negatively correlated with discomfort threshold (rho = -.49; p = .001), pain threshold (rho = -.48; p = .02), and gastric compliance (rho = -.46; p = .002). These results were confirmed by multiple linear and logistic regression analyses. CONCLUSION: In hypersensitive patients with FD, state anxiety is significantly and negatively correlated with discomfort threshold, pain threshold, and compliance. These results strengthen the hypothesis that anxiety is important in FD, especially in hypersensitive patients.

Evaluation of short-term responsiveness and cutoff values of inflammatory bowel disease questionnaire in Crohn's disease.

BACKGROUND: The inflammatory bowel disease questionnaire (IBDQ) is a frequently used outcome parameter in clinical trials. Whereas the validity and reproducibility of the IBDQ have been extensively studied, there are limited data on its short-term responsiveness and cutoff values for remission and partial clinical response. METHODS: The IBDQ score and its bowel (BD), systemic (SysD), emotional (ED), and social (SocD) dimensions were tested for responsiveness in a cohort of 224 patients with Crohn's disease (CD) treated with infliximab for refractory luminal disease. Changes in the IBDQ score and its dimensions 4 weeks after therapy were analyzed and correlated with changes in the Crohn's Disease Activity Index (CDAI). The responsiveness ratios of the IBDQ and its dimensions were analyzed. Using regression line with DeltaCDAI, the cutoff values for the IBDQ remission and response were calculated. RESULTS: Overall, there was a good correlation between the CDAI and IBDQ at week 0 (correlation coefficient, 0.69; P < .001) and week 4 (-0.76; P < .001) and change after 4 weeks (0.74; P < .001). The correlation coefficients for DeltaCDAI and changes in BD, SysD, ED, and SocD were 0.753, 0.552, 0.620, and 0.631, respectively; all P < 0.001. The responsiveness ratios for DeltaIBDQ, BD, SysD, ED, and SocD were 2.6, 2.1, 1.9, 1.7, and 1.9, respectively. Regression line for the IBDQ (r = -0.76, P < .001) resulted in a cutoff value for remission of 168 points and for DeltaIBDQ resulted in a cutoff value of 22 and 27 points for clinical improvement based on DeltaCDAI > or = -70 and > or = -100 points. CONCLUSIONS: The IBDQ is a responsive instrument for reflecting quick change in the quality of life of patients with CD. Cutoff values for the IBDQ remission and partial response were 168 and > or = 27 points.

Long-term methylphenidate intake in chronic fatigue syndrome.

OBJECTIVE: Concentration disturbances are frequent in chronic fatigue syndrome (CFS). In a placebo-controlled double-blind crossover study, methylphenidate over 4 weeks was superior to placebo in the relief of fatigue and concentration disturbance. This observational study describes the effect of long-term methylphenidate intake on fatigue, concentration, and daily life activities, as reported by the patients themselves. METHODS: A questionnaire was sent to all CFS patients who were prescribed methylphenidate at the general internal medicine department of a university hospital between August 2004 and February 2007, for possible improvement of concentration difficulties and fatigue. RESULTS: Out of 194 consecutive patients, 149 (76.8%) sent the questionnaire back. At the time of the questionnaire, 65.3% had stopped the intake of methylphenidate, 34.7% still took it daily or occasionally. Among the patients who continued methylphenidate, 48% reported an at least 50% improvement of fatigue, and 62% reported an at least 50% improvement of concentration difficulties. This continued intake of methylphenidate resulted in more working hours in these patients. Side effects (agitation, palpitations, and dry mouth) were reported significantly more in patients who had stopped methylphenidate than in those who still took it. CONCLUSION: The long-term intake of methylphenidate by CFS patients with concentration difficulties has a positive effect in about one out of three patients.

Associative stigma in family members of psychotic patients in Flanders: An exploratory study.

AIM: To assess presence and severity of associative stigma in family members of psychotic patients and factors for higher associative stigma. METHODS: Standardized semi-structured interview of 150 family members of psychotic patients receiving full time treatment. This study on associative stigma in family members of psychotic patients was part of a larger research program on the burden of the family, using "Interview for the Burden of the Family" and the chapters stigma, treatment and attribution from the "Family interview Schedule". The respondents were relatives, one per patient, either partner or parent. The patients had been diagnosed with schizophrenia or schizo-affective disorder. All contacts with patients and relatives were in Dutch. Relatives were deemed suitable to participate in this research if they saw the patient at least once a week. Recruitment took place in a standardized way: after obtaining the patient's consent, the relatives were approached to participate. The results were analyzed using SPSS Version 18.0. RESULTS: The prevalence of associative stigma in this sample is 86%. Feelings of depression in the majority of family members are prominent. Twenty-one point three percent experienced guilt more or less frequent, while shame was less pronounced. Also, 18.6% of all respondents indicated that they tried to hide the illness of their family member for others regularly or more. Three six point seven percent really kept secret about it in certain circumstances and 29.3% made efforts to explain what the situation or psychiatric condition of their family member really is like. Factors with marked significance towards higher associative stigma are a worsened relationship between the patient and the family member, conduct problems to family members, the patients' residence in a residential care setting, and hereditary attributional factors like genetic hereditability and character. The level of associative stigma has significantly been predicted by the burden of aggressive disruptions to family housemates of the psychotic patient. CONCLUSION: Family members of psychotic patients in Flanders experience higher associative stigma compared to previous international research. Disruptive behavior by the patient towards in-housing family members is the most accurate predictor of higher associative stigma.

Combination therapy with hydrocortisone and fludrocortisone does not improve symptoms in chronic fatigue syndrome: a randomized, placebo-controlled, double-blind, crossover study.

PURPOSE: Chronic fatigue syndrome has been associated with decreased function of the hypothalamic-pituitary-adrenal axis. Although neurally mediated hypotension occurs more frequently in patients with chronic fatigue syndrome than in controls, attempts to alleviate symptoms by administration of hydrocortisone or fludrocortisone have not been successful. The purpose of this study was to investigate the effect of combination therapy (5 mg/d of hydrocortisone and 50 microg/d of 9-alfa-fludrocortisone) on fatigue and well-being in chronic fatigue syndrome. METHODS: We performed a 6-month, randomized, placebo-controlled, double-blind, crossover study in 100 patients who fulfilled the 1994 Centers for Disease Control and Prevention criteria for chronic fatigue syndrome. Between-group differences (placebo minus treatment) were calculated on a 10-point visual analog scale. RESULTS: Eighty patients completed the 3 months of placebo and 3 months of active treatment in a double-blind fashion. There were no differences between treatment and placebo in patient-reported fatigue (mean difference, 0.1; 95% confidence interval [CI]: -0.3 to 0.6) or well-being (mean difference, -0.4; 95% CI: -1.0 to 0.1). There were also no between-group differences in fatigue measured with the Abbreviated Fatigue Questionnaire, the Short Form-36 Mental or Physical Factor scores, or in the Hospital Anxiety and Depression Scale. CONCLUSION: Low-dose combination therapy of hydrocortisone and fludrocortisone was not effective in patients with chronic fatigue syndrome.

In vivo type 1 cannabinoid receptor availability in Alzheimer's disease.

The endocannabinoid system (ECS) is an important modulatory and potentially neuroprotective homeostatic system in the brain. In Alzheimer's disease (AD), the role of type 1 cannabinoid receptor (CB1R) is unclear, with contradictory findings in post-mortem studies showing upregulation, downregulation or unchanged CB1R status. We have investigated CB1R availability in vivo in patients with AD, in relation to amyloid deposition, cognitive functioning and apolipoprotein E (ApoE) genotype. Eleven AD patients and 7 healthy volunteers (HV) underwent combined [¹8F]MK-9470 PET and [¹¹C]PIB PET scans to assess CB1R availability and amyloid deposition, respectively, and T1 volumetric MRI for partial volume correction. We found no difference in CB1R availability between AD and HV, VOI-based fractional uptake values (FUR) were 0.043±0.01 for AD and 0.045±0.01 for controls (p=0.9). CB1R availability did not correlate with neuropsychological test scores and was not modulated by ApoE genotype. As expected, global [¹¹C]PIB SUVR (standardized uptake value ratio) was increased in AD (SUVR 1.9±0.3) compared to HV (1.2±0.1) with p<0.001, but no correlation was found between amyloid ß (Aß) deposition and CB1R availability. In conclusion, we found no in vivo evidence for a difference in CB1R availability in AD compared to age-matched controls. Taken together with recently reported in vivo CB1R changes in Parkinson's and Huntington's disease, these data suggest that the CB1R is differentially involved in neurodegenerative disorders.

Attachment in old age: theoretical assumptions, empirical findings and implications for clinical practice.

Contemporary theoretical models that conceptualize attachment as a biologically-based behavioral system that is activated under threat offer a heuristic theoretical framework to understand processes involved in aging and particularly individual differences in coping with the inevitable losses associated with aging and age-related disease, including dementia. This paper provides a systematic qualitative review of research concerning attachment in old age published between 1983 and June 2012. Four major findings emerged. First, studies suggest age-related changes with regard to the number and type of attachment figures, with older adults, compared to younger adults, having less attachment relations. Moreover, so-called symbolic attachments (e.g., to God or a deceased loved one) become more prominent in old age. Second, the quality of attachment changes with increasing age, with significant decreases in attachment anxiety, but not in attachment avoidance. Third, late-life attachment is in theoretically predicted ways associated with indices of intraindividual and interindividual functioning. Finally, insecure attachment has a negative impact on subjective caregiver burden and behavior of patients with dementia. There is some evidence suggesting that attachment-based interventions show positive effects in treating problem behaviors associated with dementia. However, these conclusions need to be interpreted within the context of important methodological limitations, stressing the need for future research in this domain. Guidelines for future research are outlined.

Does methylphenidate reduce the symptoms of chronic fatigue syndrome?

PURPOSE: Chronic fatigue syndrome is a clinical entity consisting of prolonged and debilitating fatigue in which concentration disturbances are very frequent. Until now, no medical treatment has shown any efficacy. The objectives of this study were to investigate the short-term effects of methylphenidate, an amphetamine derivative, on fatigue, concentration disturbances, and quality of life. SUBJECTS AND METHODS: A double-blind randomized placebo-controlled crossover study was conducted in 60 patients who fulfilled the 1994 Centers for Disease Control criteria for chronic fatigue syndrome and had concentration difficulties. Patients were enrolled between March 2003 and March 2004 at the outpatient department of a university hospital referral center for chronic fatigue syndrome patients. Random assignment to 4 weeks treatment with methylphenidate 2 x 10 mg/day, followed by 4 weeks of placebo treatment, or 4 weeks of placebo treatment, followed by methylphenidate treatment. Fatigue and concentration were measured with a Checklist Individual Strength (CIS) and a Visual Analogue Scale (VAS). RESULTS: Fatigue scores fell significantly during methylphenidate intake in comparison with baseline (mean difference: -0.7, P = .010 for VAS; mean difference: -11.8, P <.0001 for CIS) and in comparison with placebo (mean difference: -1.0, P = .001 for VAS; mean difference: -9.7, P <.0001 for CIS). Concentration disturbances, measured with a VAS improved significantly under methylphenidate treatment compared with baseline (mean difference: -1.3, P <.0001) and compared with placebo (mean difference: -1.1, P <.0001). A clinical significant effect (> or =33% improvement or CIS < or =76) on fatigue was achieved in 17% of patients, who were considered responders; on concentration in 22% of patients. CONCLUSIONS: Methylphenidate at a dose of 2 x 10 mg/day is significantly better than placebo in relieving fatigue and concentration disturbances in a minority of chronic fatigue syndrome patients. Further studies are needed to investigate the long-term effects of this treatment.

Regional brain activation during proximal stomach distention in humans: A positron emission tomography study.

BACKGROUND & AIMS: Hypersensitivity to proximal gastric distention due to abnormal central nervous system processing of visceral stimuli has been suggested as a possible underlying pathophysiologic mechanism in functional dyspepsia. However, the cortical regions activated by distention of the proximal stomach have not been identified. The aim of this study was to investigate regional brain activation during painful and nonpainful proximal gastric distention in humans. METHODS: Positron emission tomography of the brain was performed in 11 healthy volunteers during 4 conditions: (1) no distention and isobaric distention to the individual thresholds for (2) first, (3) marked, and (4) unpleasant sensation. Data were analyzed using statistical parametric mapping. RESULTS: During maximal distention relative to baseline, significant (P corrected <.05) regional brain activation occurred in the left and right gyrus postcentralis (Brodmann area [BA] 43), the left gyrus temporalis superior (BA 38), the right gyrus frontalis inferior (BA 47, orbitofrontal cortex), the right midanterior cingulate gyrus (BA 24), the right anterior insula, and the left cerebellar hemisphere. These areas showed a progressive increase in activation with increasing intensity of the distending stimulus. CONCLUSIONS: We found evidence for a neuronal network processing distention stimuli of the proximal stomach that is overall consistent with the "visceral stimulation network" described in the literature. In addition, we found activation of the orbitofrontal cortex, confirming its role as a convergence zone for processing of food-related stimuli and regulation of hunger, appetite, satiety, and food intake. We found no evidence for a functional neuroanatomic divergence in the processing of noxious and innocuous gastric stimuli.

Heterogeneity of symptom pattern, psychosocial factors, and pathophysiological mechanisms in severe functional dyspepsia.

BACKGROUND & AIMS: Categorization of functional dyspepsia into subgroups is based on expert opinion according to (dominant) symptoms or on underlying pathophysiological mechanisms. We used an evidence-based approach to the determination of subtypes of functional dyspepsia. METHODS: Consecutive functional dyspepsia patients were recruited from a tertiary referral center. The following were performed: (1) exploratory (EFA) and confirmatory factor analysis (CFA) of symptom patterns in a large group of patients with functional dyspepsia; (2) external validation of these factors by the determination of their association pattern with physio- and psychopathological mechanisms, and with health-related quality of life and sickness behavior; and (3) cluster analysis of their distribution in this population. RESULTS: Both EFA and CFA do not support the existence of functional dyspepsia as a homogeneous (unidimensional) condition. A 4-factor model is found to be valid, with differential distribution within the patient population according to cluster analysis. Factor 1 is characterized by nausea, vomiting, early satiety, and weight loss and factor 2 by postprandial fullness and bloating. Both factor 1 and 2 are associated with delayed emptying, but only factor 1 is associated with younger age, female sex, and sickness behavior. Factor 3 is characterized by pain symptoms and associated with gastric hypersensitivity and several psychosocial dimensions including medically unexplained symptoms and health-related quality of life dimensions. Factor 4, characterized by belching, is also associated with hypersensitivity, but is unrelated to psychosocial dimensions. CONCLUSIONS: In a tertiary care population, functional dyspepsia is a heterogeneous condition characterized by 4 major dimensions differentially associated with psychopathological and physiopathological mechanisms.