Chronic fatigue study shows syndrome's complexity.

Psychiatrist and journalist win prize for defending science

We examined plasma LDL particle size in 55 patients (35 males, 20 females) with NIDDM (diet alone) or IGT (WHO), and investigated the relationship between LDL particle size and plasma lipids, obesity, and peripheral insulin sensitivity. 55 healthy adults of similar sex, age, and body mass index (BMI) were used as a control group. Peak LDL particle size was measured by nondenaturing 2% to 16% polyacrylamide gradient gel electrophoresis and oil red O staining. In this study any LDL particle size less than 25.7nm was defined as “small LDL”, and anything over 25.7nm was defined as “normal LDL”. The mean peak LDL particle sizes of the patients and controls were 25.81±0.79 and 26.66±0.75nm, respectively. The frequency of small LDL in the patients was significantly higher than that in the control group (43.6% vs. 5.5%). In the patients, there was no difference in the blood pressure in the small LDL group and the normal LDL group. The total cholesterol, triglyceride, and apo B levels in both male and female patients were significantly higher in the small LDL group than in the normal LDL group. By contrast, the HDL-C level in male patients was significantly lower in the small LDL group. The BMI and the ratio of waist-to-hip circumference in both male and female patients tended to be higher in the small LDL groups than those in the normal LDL groups (female: 27.1±4.2vs. 22.4±5.4, 1.004±0.041vs. 0.911±0.066; male: 26.1±2.5vs. 23.7±3.6, 0.956±0.036vs. 0.931±0.043). Moreover the ratio of intra-abdominal visceral fat to subcutaneous fat, which was measured using an abdominal CT scan, was higher in the small LDL group of male patients (0.549±0.135vs. 0.382±0.069). The fasting IRI levels of both male and female patients were significantly higher in the small LDL groups than those in the normal LDL groups (female: 19.38±16.80vs. 9.17±4.84μU/ml; male: 12.45±7.67vs. 7.14±3.22μU/ml). A euglycemic insulin clamp study showed that the glucose disposable rate in the small LDL group was significantly lower than that in the healthy control group (female: 2.34±0.04vs. 7.90±1.57mg/min/kg; male: 3.61±1.79vs. 7.11±1.38mg/min/kg). These results suggest that glucose intolerance in the small LDL group is closely related to hypertriglyceridemia, low HDL-C, visceral obesity and peripheral insulin resistance.

Patients who undergo orbital exenteration often experience social problems because of their facial disfigurement. The authors studied the interaction of cancer patients who had undergone orbital exenteration with family members and friends (primary groups) and with acquaintances and strangers (secondary groups) in small and large groups. In-depth telephone interviews were conducted with 12 patients treated at a cancer center (7 men and 5 women aged 51-81 years) and 12 family members (8 spouses and 4 children or siblings). Three patients had adenoid cystic carcinoma of lacrimal gland, 3 had squamous cell carcinoma of conjunctiva/eyelid, and 1 each had conjunctival melanoma, eyelid sebaceous gland carcinoma, transitional cell carcinoma of lacrimal sac, adenocarcinoma of orbit, neuroendocrine carcinoma of orbit, and basal cell carcinoma of eyelid. Time from orbital exenteration to interview ranged from 8 months to 36 years (median, 44 months). Two patient groups were identified according to comfort in interactions with acquaintances and strangers. Always comfortable patients were always at ease. Occasionally comfortable patients were at ease in large groups in situations of "benign neglect" and in small groups when they received "sympathy"; were uncomfortable in large and small groups when episodes of "intrusion" occurred; and had mixed responses to benign neglect in small groups and sympathy in large groups. Both patient groups felt comfortable with family members and friends. Patients who will undergo orbital exenteration should be warned about possible difficulties with social interactions. Healthcare personnel should be trained to help patients and family members prepare for such difficulties.

Chronic fatigue syndrome (CFS) is defined as a medically unexplained fatigue, resulting in impairment of daily activities of at least 50%.1 In the past few years it has been shown that coeliac disease is a common disorder, present in 1 in 200 in the general population,2-4 Serological testing is used to select patients for biopsy of the small intestine, which is required for histological confirmation of the diagnosis of coeliac disease. Assessment of IgA anti-endomysium (EmA) (endomysial antibody) or anti-tissue transglutaminase is considered to be sensitive and specific serological tests for coeliac disease, while IgA antigliadine (AGA-IgA) and IgG antigliadine (AGA-IgG) are less specific.3 Fatigue has been shown to be one of the presenting symptoms of coeliac disease,2 but an association between CFS and coeliac disease has not yet been reported. As an immunological mechanism may underlie both CFS and coeliac disease, a connection between both conditions should not be excluded. The aim of this report was to assess the prevalence of serological antibodies associated with coeliac disease in a population of CFS patients compared with a control group. Because of a study on immunological and clinical correlates of CFS,5 we had available serum of 56 adult patients and 56 age and sex matched controls. Both groups originated from a primary care population. Patients were identified and invited to participate by their general practitioner; healthy controls were recruited from the same environment as the patients. AGA-IgA. AGA-IgG and EmA were assessed in a routine setting using an ELISA for AGA evaluation and monkey oesophagus as substrate for EmA in an indirect immunofluorescence test as described by Lerner et al.6 Mean age of the total group of 112 persons was 37.6 years (range 18–51), of whom 82 (73%) were women. EmA – the primary parameter – was not found in any of the CFS patients or controls. A positive AGA-IgA (>4 AU/ml) was present in one patient (7.3 AU/ml) and one control (4.1 AU/ml). AGA-IgG was positive (>12 AU/ml) in one control (82 AU/ml) but in none of the patients. There was no positive EmA in the patient group. With a sample of 56 persons, the corresponding estimate of population prevalence of zero has a 95% confidence interval of 0–0.054 (Poisson distribution). The prevalence of the serological markers (EmA, AGA-IgA and AGA-IgG) has been reported to be 6.2% in a population-based study.7 McMillan et al8 found a serological prevalence of 1.2% of EmA in a population survey. Hin et al2 have demonstrated a positive EmA test in 30 out of 1000 tested subjects, when they used a case-finding approach in a primary care setting. Coeliac disease was confirmed histologically in all 30 individuals. In our total group of 112, there was no positive test for EmA. AGA-IgA and AGA-IgG, the less specific tests for coeliac disease, were shown to be sporadically positive. The results showed no positive association between CFS and serological markers for coeliac disease. In our study, the patient and control groups were relatively modest in size. The power calculation showed that a prevalence of EmA of less than 5–6% should be expected in a population of CFS patients. Though the prevalence may still be higher than that found in the general population, a strong relationship between CFS and coeliac disease is unlikely to exist.

To study the prevalence of chronic fatigue syndrome (CFS) and association of CFS with other clinical and neuropsychological manifestations of Parkinson's disease (PD) as well as with serum inflammatory markers and genetic polymorphisms. The study included 533 patients with PD. All patients underwent clinical, neurological examination and neuropsychological testing using validated questionnaires: MoCA test, HADS, BDI-II, the Fatigue Severity Scale (FSS). Serum concentrations of inflammatory markers (slCAM-1, sVCAM-1, NCAM, CCL5, PAI-1 and MPO) were assessed in 144 patients using xMAP technology. A case-control study of CCL5 (rs2107538) and PAI-1 (rs2227631) gene polymorphisms was performed in connection with PD development and in groups differing in the presence/absence of CFS in PD. In addition, the relationship of these polymorphisms with variability in the levels of the corresponding proteins in the blood serum of patients was studied. Genotyping of CCL5 (rs2107538) and PAI-1 (rs2227631) polymorphisms was performed using real-time PCR with TaqMan probes. CFS is common in 66.7% of patients in the PD group. In addition, non-motor symptoms (emotional-affective, cognitive, autonomic disorders and pain) were more common in patients with CFS. A strong correlation has been established between the severity of CFS assessed with FSS and serum concentrations of CCL5, sVCAM-1, NCAM and slCAM-1. In newly diagnosed patients with PD who were not taking antiparkinsonian drugs at the time of the study and had CFS, higher correlations were noted between inflammatory markers and the severity of CFS manifestations. When comparing the distribution of genotypes and alleles of CCL5 (rs2107538) and PAI-1 (rs2227631) polymorphisms, some differences were found between the groups of patients with PD and controls (p<0.05). However, these polymorphisms did not affect the variability of serum protein levels CCL5 and PAI-1, respectively, nor did they affect the development of CFS in patients with PD. CFS is common in PD, and patients with PD and CFS are characterized by elevated levels of serum markers CCL5, sVCAM-1, slCAM-1 and NCAM, suggesting the importance of the inflammatory component in the development of neurodegenerative disease. In addition, the clinical course of PD in patients with CFS is aggravated by other non-motor manifestations, including emotional-affective, cognitive, autonomic disorders and pain. These results highlight the potential contribution of an inflammatory component to the development of fatigue associated with PD, starting from the earliest clinical stages of the disease.

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are medically unexplained conditions that often have overlapping symptoms, including sleep-related complaints. However, differences between the 2 conditions have been reported, and we hypothesized that dynamic aspects of sleep would be different in the 2 groups of patients. Subjects were 26 healthy control subjects, 14 patients with CFS but without FM (CFS alone), and 12 patients with CFS and FM (CFS+FM)-all women. We studied transition probabilities and rates between sleep stages (waking, rapid eye movement [REM] sleep, stage 1 [S1], stage 2 [S2], and slow-wave sleep [SWS]) and duration distributions of each sleep stage. We found that the probability of transition from REM sleep to waking was significantly greater in subjects with CFS alone than in control subjects, which may be the specific sleep problem for people with CFS alone. Probabilities of (a) transitions from waking, REM sleep, and S1 to S2 and (b) those from SWS to waking and S1 were significantly greater in subjects with CFS+FM than in control subjects; in addition, rates of these transitions were also significantly increased in subjects with CFS+FM. Result (a) might indicate increased sleep pressure in subjects with CFS+FM whereas result (b) may be the specific sleep problem of subjects with CFS+FM. We also found that shorter durations of S2 sleep are specific to patients with CFS+FM, not to CFS alone. These results suggest that CFS and FM may be different illnesses associated with different problems of sleep regulation.

L’expérience de la fatigue chronique de patients atteints de SFC/EM, d’une MICI et de sujets tout-venant : étude quantitative et qualitative du discours préalable à la création d’une échelle d’évaluation de l’asthénie chronique

Fatigue in Cirrhosis: Is Transplant the Answer?

Ideal versus reality: physicians perspectives on patients with chronic fatigue syndrome (CFS) and fibromyalgia

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by unexplained fatigue not improved by rest. An area of investigation is the likely connection of CFS with defective mitochondrial function. In a previous work, we investigated the proteomic salivary profile in a couple of monozygotic twins discordant for CFS. Following this work, we analyzed mitochondrial proteins in the same couple of twins. Nano-liquid chromatography electrospray ionization mass spectrometry (nano-LC-MS) was used to study the mitochondria extracted from platelets of the twins. Subsequently, we selected three proteins that were validated using western blot analysis in a big cohort of subjects (n=45 CFS; n=45 healthy), using whole saliva (WS). The selected proteins were as follows: aconitate hydratase (ACON), ATP synthase subunit beta (ATPB) and malate dehydrogenase (MDHM). Results for ATPB and ACON confirmed their upregulation in CFS. However, the MDHM alteration was not confirmed. Thereafter, seeing the great variability of clinical features of CFS patients, we decided to analyze the expression of our proteins after splitting patients according to clinical parameters. For each marker, the values were actually higher in the group of patients who had clinical features similar to the ill twin. In conclusion, these results suggest that our potential markers could be one of the criteria to be taken into account for helping in diagnosis. Furthermore, the identification of biomarkers present in particular subgroups of CFS patients may help in shedding light upon the complex entity of CFS. Moreover, it could help in developing tailored treatments.

Our study [1] had two main purposes: first, to examine the occurrence of sleep-disordered breathing (SDB) in patients with chronic fatigue syndrome (CFS), and then to exclude patients with this confound in order to evaluate the structure of sleep in a group of patients with pure CFS to look for relations with the symptoms of fatigue and sleepiness. In order to do this, we had to define an upper limit for the occurrence of respiratory events that might explain the daytime symptoms. Martinez and Cassol are correct that the currently accepted cutpoint for abnormality proposed by the American Academy of Sleep Medicine (AASM) and Centers for Medicare & Medicaid Services (CMS) in the US is an apnea-hypopnea index (AHI) ≥ 5 per hour but less than 15 per hour – but only if symptoms such as EDS are present. However, the AHI is an insensitive measure of the severity of mild respiratory events (such as respiratory event-related arousals (RERAs)) as it requires either a 3 or 4% desaturation for the definition of hypopnea and this is frequently not present in respiratory events that cause arousal and may contribute to sleep disruption (RERA). For this reason, our cutpoint for SDB is based on a respiratory disturbance index (RDI) of 18 events per hour and not the AHI. The RDI includes RERAs along with the AHI, although we used a slightly different definition of hypopneas beginning with any event showing flow limitation rather than the current amplitude based entry criterion. The rationale for this is from an earlier paper by our group [2] that shows that the sensitivity and specificity for explaining EDS in a group composed of symptomatic but mild SDB and non-complaining controls were greater using the RDI criterion than the AHI criterion. Since that paper, it has become customary to use a cut-off of 15 events per hour for RDI in many applications. It is important to note that for RDI, using 5 events per hour will include essentially 80% of the normal population. Furthermore, as pointed out in our current paper [1], although we chose 18 events per hour as a cut-off to exclude three subjects (one with CFS and two normal subjects) when defining the final group for our sleep analysis who might have SDB, in fact the highest RDIs we saw in the non-SDB group were 10.4, 10.8, 10.1, and 9.5 events per hour; we feel these numbers are within a range seen in many normal subjects without EDS [2]. Thus, our cut-off of 18 is not effectively different from the more recently accepted number of 15 events per hour. And after excluding those subjects with high RDI values, there was no significant difference in the AHI of patients with only CFS, those with CFS and fibromyalgia and healthy controls (1.7 ± 1.6, 2.8 ± 2.6, and 2.2 ± 1.7, respectively). In fact, the above logic is not fundamentally different from the choice made by Martinez and Cassol in their own work [3-6], where they define SDB as present in fibromyalgia when the AHI <5 and when more than 10 RERAs per hour occurred (5 + 10 events = 15 per hour, similar to our cut-off of 18 per hour).

Using a sensitive enzyme immunoassay, carcinoplacental alkaline phosphatase (CPAP) was determined in sera of 1266 patients with gyneocological cancers. All these patients were referred after initial surgical treatment elsewhere. There were 95 patients with evidence of disease at the time of the study and 1171 without evidence of disease. Of the 95 patients with active disease, 47 were treated for ovarian carcinoma, 36 for carcinoma of the cervix and 12 for endometrial carcinoma. Raised levels of CPAP were seen in 40% of patients with ovarian carcinoma, in 22% with carcinoma of the cervix and in 41% in the small group with endometrial carcinoma. In patients without evidence of disease, raised levels of CPAP were seen in 12% of patients with carcinoma of the cervix, in 6% of endometrial carcinoma and only in 2% of patients with carcinoma of the ovary. Therefore it was considered that in the latter group CPAP studies would prove of some value. In the group of patients with carcinoma of the ovary and evidence of disease, raised levels of CPAP were seen almost exclusively in patients with epithelial tumors. It is considered that CPAP may be of value as a tumor marker in this group of patients. When compared with CEA, CPAP tends to give fewer false positives and correlates better with the presence of disease.

Symptoms of orthostatic intolerance (OI) are common in Chronic Fatigue Syndrome (CFS) and similar disorders. These symptoms may relate to individual differences in intracranial compliance and cerebral blood perfusion. The present study used phase-contrast, quantitative flow magnetic resonance imaging (MRI) to determine intracranial compliance based on arterial inflow, venous outflow and cerebrospinal fluid flow along the spinal canal into and out of the cranial cavity. Flow-sensitive Alternating Inversion Recovery (FAIR) Arterial Spin Labelling was used to measure cerebral blood perfusion at rest. Forty patients with CFS and 10 age and gender matched controls were scanned. Severity of symptoms of OI was determined from self-report using the Autonomic Symptom Profile. CFS patients reported significantly higher levels of OI (p < .001). Within the patient group, higher severity of OI symptoms were associated with lower intracranial compliance (r = -.346, p = .033) and higher resting perfusion (r = .337, p = .038). In both groups intracranial compliance was negatively correlated with cerebral perfusion. There were no significant differences between the groups in intracranial compliance or perfusion. In patients with CFS, low intracranial compliance and high resting cerebral perfusion appear to be associated with an increased severity of symptoms of OI. This may signify alterations in the ability of the cerebral vasculature to cope with changes to systemic blood pressure due to orthostatic stress, but this may not be specific to CFS.

BackgroundThe aim of this study was to investigate the possibility that a decreased mitochondrial ATP synthesis causes muscular and mental fatigue and plays a role in the pathophysiology of the chronic fatigue syndrome (CFS/ME).MethodsFemale patients (n = 15) and controls (n = 15) performed a cardiopulmonary exercise test (CPET) by cycling at a continuously increased work rate till maximal exertion. The CPET was repeated 24 h later. Before the tests, blood was taken for the isolation of peripheral blood mononuclear cells (PBMC), which were processed in a special way to preserve their oxidative phosphorylation, which was tested later in the presence of ADP and phosphate in permeabilized cells with glutamate, malate and malonate plus or minus the complex I inhibitor rotenone, and succinate with rotenone plus or minus the complex II inhibitor malonate in order to measure the ATP production via Complex I and II, respectively. Plasma CK was determined as a surrogate measure of a decreased oxidative phosphorylation in muscle, since the previous finding that in a group of patients with external ophthalmoplegia the oxygen consumption by isolated muscle mitochondria correlated negatively with plasma creatine kinase, 24 h after exercise.ResultsAt both exercise tests the patients reached the anaerobic threshold and the maximal exercise at a much lower oxygen consumption than the controls and this worsened in the second test. This implies an increase of lactate, the product of anaerobic glycolysis, and a decrease of the mitochondrial ATP production in the patients. In the past this was also found in patients with defects in the mitochondrial oxidative phosphorylation. However the oxidative phosphorylation in PBMC was similar in CFS/ME patients and controls. The plasma creatine kinase levels before and 24 h after exercise were low in patients and controls, suggesting normality of the muscular mitochondrial oxidative phosphorylation.ConclusionThe decrease in mitochondrial ATP synthesis in the CFS/ME patients is not caused by a defect in the enzyme complexes catalyzing oxidative phosphorylation, but in another factor.Trial registrationClinical trials registration number: NL16031.040.07

Breast cancer is a public health problem with increasing incidence, prevalence, and mortality worldwide. Germline variants in the DNA repair genes BRCA1/2 are involved in the pathogenesis of hereditary breast/ovarian cancer. However, for many ethnic groups that are isolated geographically worldwide, founder variants of breast cancer still have not been found. In this study, we provide whole exome sequencing data performed in a group of breast/ovarian cancer patients who belong to the Buryats. Our study included 56 Buryat patients with histologically confirmed primary breast/ovarian cancer who completed an anonymous questionnaire about basic information and nationality. Genomic DNA was isolated from peripheral blood leukocytes. Libraries were prepared using a BGI Optimal DNA Library Prep kit (MGI, China). An Agilent SureSelect Human All Exon V6 kit (Agilent, USA) was used for hybridization. High-throughput sequencing was performed on a DNA nanoball sequencing platform DNBSeq-G400 (MGI, China). Result: In the overall group of patients with signs of hereditary breast/ovarian cancer, likely pathogenic/pathogenic variants were detected in 16% (9/56). We have discovered likely pathogenic/pathogenic variants that can either directly (BRCA2, RAD51D, FANCG) or indirectly (POLR2C, FOXL2, GDF9, CYP21A4) initiate breast/ovarian cancer. For the first time, three rare germinal variants in the BRCA2 gene were detected in a small Buryat ethnic group. Further studies are required to confirm their role in the pathogenesis of breast /ovarian cancer in this ethnic group. We found that the RAD51D gene variant c.757C>T is recurrent and was observed in 4% of Buryat patients with breast/ovarian cancer. For the first time, rare germinal variants in the BRCA2, RAD51D, FANGC, CYP24A1 genes were detected in a small Buryat ethnic group. Our data are consistent with existing data showing that variants in the RAD51D gene may be involved in the pathogenesis of breast/ovarian cancer. We also showed that the Mongolic-speaking Buryat populations exhibited strong genetic resemblance to those of Chinese.