Factors influencing the clinical outcome of preimplantation genetic testing for polycystic kidney disease.

STUDY QUESTION: What are the factors influencing the success rate for couples undergoing preimplantation genetic testing (PGT) for polycystic kidney disease (PKD)? SUMMARY ANSWER: In our study cohort, the live birth delivery rate is significantly associated with female age while the male infertility accompanying autosomal dominant PKD (ADPKD) does not substantially affect the clinical outcome. WHAT IS KNOWN ALREADY: While women with ADPKD have no specific fertility problems, male ADPKD patients may present with reproductive system abnormalities and infertility. STUDY DESIGN, SIZE, DURATION: This retrospective cohort study involves 91 PGT cycles for PKD for 43 couples (33 couples for PKD1, 2 couples for PKD2 and 8 couples for autosomal recessive PKD (ARPKD)) from January 2005 until December 2016 with follow-up of transfers until end of 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Sixteen single-cell clinical tests for PKD based on multiplex PCR of short tandem repeat markers, with or without a specific mutation were developed and applied for diagnosis of 584 Day 3 cleavage stage embryos. In 18 couples, the male partner was affected with ADPKD (=Group A) and 12 of them had a documented infertility status. Group A underwent 52 cycles to oocyte retrieval. For 18 other couples, the female partner was affected with ADPKD (=Group B) and four male partners from this group had a documented history of infertility. This group underwent 31 cycles to OR. MAIN RESULTS AND THE ROLE OF CHANCE: Genetic analysis resulted in 545 embryos (93.3%) with a diagnosis, of which 215 (36.8%) were genetically transferable. Transfer of 74 embryos in 53 fresh cycles and of 34 cryopreserved embryos in 33 frozen-warmed embryo transfer cycles resulted in a live birth delivery rate of 38.4% per transfer with 31 singleton live births, two twin live births and one ongoing pregnancy. The observed cumulative delivery rate was 57.8% per couple after five treatment cycles. Thirty cryopreserved embryos still remain available for transfer. The clinical pregnancy rate per transfer (fresh + frozen; 45.9% in group A versus 60.0% in group B, P < 0.05) and the live birth delivery rate per transfer (fresh + frozen; 27.0% in group A versus 42.9% in group B, P < 0.05) was significantly lower for couples with the male partner affected with ADPKD compared with couples with the female partner affected with ADPKD. However, a multivariate logistic regression analysis showed that only female age was associated with live birth delivery rate (odds ratio = 0.87; 95% CI: 0.77-0.99; P = 0.032). LIMITATIONS, REASONS FOR CAUTION: This study is based on retrospective data from a single centre with Day 3 one-cell and two-cell biopsy. Further analysis of a larger cohort of PKD patients undergoing PGT is required to determine the impact of male infertility associated with ADPKD on the cumulative results. WIDER IMPLICATIONS OF THE FINDINGS: Knowledge about factors affecting the clinical outcome after PGT can be a valuable tool for physicians to counsel PKD patients about their reproductive options. Males affected with ADPKD who suffer from infertility should be advised to seek treatment in time to improve their chances of conceiving a child. STUDY FUNDING/COMPETING INTEREST(S): No funding was obtained. There are no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.

A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome.

OBJECTIVE: The Holmes and Fukuda criteria are widely used criteria all over the world, yet a specific European study regarding chronic fatigue syndrome (CFS) patient symptomatology has not been conducted so far. This study was performed to answer the need to assess the homogeneity of a large CFS population in relationship to the Fukuda or Holmes definitions and to assess the importance of a symptom severity scale. DESIGN: Multivariate analyses were performed to assess the symptom presentation within a fatigued population and the differences between the Fukuda and Holmes definitions compared with an excluded chronic fatigued group in a large cohort of fatigued patients. SETTING: An outpatient tertiary care setting fatigue clinic in Brussels. MAIN OUTCOME MEASURES: Prevalence and severity of symptoms and signs in a CFS population and in a chronic fatigued population. SUBJECTS AND METHODS: A total of 2073 consecutive patients with major complaints of prolonged fatigue participated in this study. Multivariate analyses were performed to assess the symptom presentation and severity and the differences between the Fukuda and Holmes definitions. RESULTS: Of the 2073 patients complaining of chronic fatigue (CF), 1578 CFS patients fulfilled the Fukuda criteria (100% of CFS group) and 951 (60.3% of the CFS group) fulfilled the Holmes criteria. Discriminant function analysis revealed that the Fukuda and Holmes definitions can be differentiated by symptom severity and prevalence. The Holmes definition was more strongly associated than the Fukuda definition with the symptoms that differentiated the CFS patients from the patients that did not comply with the CFS definitions. The inclusion of 10 additional symptoms was found to improve the sensitivity/specificity and accuracy for selection of CFS patients. CONCLUSIONS: The CFS patients fulfilling the Holmes criteria have an increased symptom prevalence and severity of many symptoms. Patients fulfilling the Fukuda criteria were less severely affected patients which leads to an increase in clinical heterogeneity. Addition of certain symptoms and removal of others would strengthen the ability to select CFS patients.

Exercise capacity in chronic fatigue syndrome.

BACKGROUND: Patients with chronic fatigue syndrome (CFS) suffer from various symptoms, including debilitating fatigue, muscle pain, and muscle weakness. Patients with CFS can experience marked functional impairment. In this study, we evaluated the exercise capacity in a large cohort of female patients with CFS. METHODS: Patients with CFS and matched sedentary control subjects performed a maximal test with graded increase on a bicycle ergometer. Gas exchange ratio was continuously measured. In a second stage, we examined only those persons who achieved a maximal effort as defined by 2 end points: a respiratory quotient of at least 1.0 and an age-predicted target heart rate of at least 85%. Data were assessed using univariate and multivariate statistical methods. RESULTS: The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects. The maximal workload and maximal oxygen uptake attained by the patients with CFS were almost half those achieved by the control subjects. Analyzing only those persons who performed a maximal exercise test, similar findings were observed. CONCLUSIONS: When compared with healthy sedentary women, female patients with CFS show a significantly decreased exercise capacity. This could affect their physical abilities to a moderate or severe extent. Reaching the age-predicted target heart rate seemed to be a limiting factor of the patients with CFS in achieving maximal effort, which could be due to autonomic disturbances. Arch Intern Med. 2000;160:3270-3277.

A 37 kDa 2-5A binding protein as a potential biochemical marker for chronic fatigue syndrome.

PURPOSE: Recent studies have revealed abnormalities in the ribonuclease L pathway in peripheral blood mononuclear cells of patients with the chronic fatigue syndrome. We conducted a blinded study to detect possible differences in the distribution of 2-5A binding proteins in the cells of patients with chronic fatigue syndrome and controls. PATIENTS AND METHODS: We studied 57 patients with chronic fatigue syndrome and 53 control subjects (28 healthy subjects and 25 patients with depression or fibromyalgia). A radioactive probe was used to label 2-5A binding proteins in unfractionated peripheral blood mononuclear cell extracts and to compare their distribution in the three groups. RESULTS: A 37 kDa 2-5A binding polypeptide was found in 50 (88%) of the 57 patients with chronic fatigue syndrome compared with 15 (28%) of the 53 controls (P < 0.01). When present, the amount of 37 kDa protein was very low in the control groups. When expressed as the ratio of the 37 kDa protein to the 80 kDa protein, 41 (72%) of the 57 patients with chronic fatigue syndrome had a ratio > 0.05, compared with 3 (11%) of the 28 healthy subjects and none of the patients with fibromyalgia or depression. CONCLUSION: The presence of a 37 kDa 2-5A binding protein in extracts of peripheral blood mononuclear cells may distinguish patients with chronic fatigue syndrome from healthy subjects and those suffering from other diseases.

Dehydroepiandrosterone (DHEA) response to i.v. ACTH in patients with chronic fatigue syndrome.

Previous studies have demonstrated concentrating neuroendocrinological disturbances in chronic fatigue syndrome (CFS) patients, concentrating in particular on low cortisol levels and a hypothalamic deficiency. In order to investigate the dynamic response of the adrenal glands, we measured dehydroepiandrosterone (DHEA) in serum after adreno-corticotropic hormone (ACTH) stimulation during 60 minutes in 22 CFS-patients and 14 healthy controls. We found normal basal DHEA levels, but a blunted serum DHEA response curve to i.v. ACTH injection. This observation adds to the large amount of evidence of endocrinological abnormalities in CFS. Relative glucocorticoid deficiency might contribute to the overall clinical picture in CFS, and could explain some of the immunological disturbances observed in this syndrome.

Autonomic testing in patients with chronic fatigue syndrome.

The purpose of this study was to determine whether chronic fatigue syndrome (CFS) patients show autonomic dysfunction at the cardiac level and if so, to discover whether these abnormalities explain the fatiguability and/or other symptoms in CFS. The study population consisted of 21 CFS patients (Centers for Disease Control and Prevention [CDC] criteria, 1988) and 13 age- and sex-matched healthy controls. The autonomic testing consisted of: (1) postural challenge: registration of heart rate and blood pressure (BP) and heart rate variability in supine and in upright position (tilted to 70 degrees); (2) Valsalva maneuver; (3) handgrip test; (4) cold pressor test; and (5) heart rate response to deep breathing. Statistical analysis was performed using the Mann Whitney rank sum test; results of the test were considered significant at the 0.05 level. After tilting heart rate was significantly higher in CFS patients compared with healthy controls (mean CFS = 88.9 beats/min vs control = 77.9 beats/min; P <0.01). Low frequency power after tilting was significantly higher in CFS patients compared with controls (mean CFS = 0.603 vs control = 0.428; P = 0.02). There was a trend toward an increased heart rate during the cold pressor test. Other parameters did not differ between the CFS and control populations. The observed changes point toward a sympathetic overactivity in CFS patients when they are exposed to stress. Parasympathetic abnormalities could not be observed. Therefore, our findings provide no real explanation for the fatigue and intolerance to physical exertion in these patients.

Biochemical evidence for a novel low molecular weight 2-5A-dependent RNase L in chronic fatigue syndrome.

Previous studies from this laboratory have demonstrated a statistically significant dysregulation in several key components of the 2',5'-oligoadenylate (2-5A) synthetase/RNase L and PKR antiviral pathways in chronic fatigue syndrome (CFS) (Suhadolnik et al. Clin Infect Dis 18, S96-104, 1994; Suhadolnik et al. In Vivo 8, 599-604, 1994). Two methodologies have been developed to further examine the upregulated RNase L activity in CFS. First, photoaffinity labeling of extracts of peripheral blood mononuclear cells (PBMC) with the azido 2-5A photoaffinity probe, [32P]pApAp(8-azidoA), followed by immunoprecipitation with a polyclonal antibody against recombinant, human 80-kDa RNase L and analysis under denaturing conditions. A subset of individuals with CFS was identified with only one 2-5A binding protein at 37 kDa, whereas in extracts of PBMC from a second subset of CFS PBMC and from healthy controls, photolabeled/immunoreactive 2-5A binding proteins were detected at 80, 42, and 37 kDa. Second, analytic gel permeation HPLC was completed under native conditions. Extracts of healthy control PBMC revealed 2-5A binding and 2-5A-dependent RNase L enzyme activity at 80 and 42 kDa as determined by hydrolysis of poly(U)-3'-[32P]pCp. A subset of CFS PBMC contained 2-5A binding proteins with 2-5A-dependent RNase L enzyme activity at 80, 42, and 30 kDa. However, a second subset of CFS PBMC contained 2-5A binding and 2-5A-dependent RNase L enzyme activity only at 30 kDa. Evidence is provided indicating that the RNase L enzyme dysfunction in CFS is more complex than previously reported.