Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models

Fragile X syndrome is caused by the absence or reduction of the fragile X mental retardation protein (FMRP) because FMR1 gene expression is reduced. Alleles with repeat sizes of 55–200 are classified as premutations, and it has been demonstrated that FMR1 expression is elevated in the premutation range. However, the majority of the studies reported were performed in males. We studied FMR1 expression in 100 female fragile X family members from the northern region of Spain using quantitative (fluorescence) real-time polymerase chain reaction. Of these 100 women, 19 had normal alleles, 19 were full mutation carriers, and 62 were premutation carriers. After confirming differences between the three groups of females, and increased levels of the FMR1 transcript among premutation carriers, we found that the relationship between mRNA levels and repeat size is nonlinear. These results were obtained using a novel methodology that, based on the size of the CGG repeats, allows us to find out the most probable threshold from which the relationship between CGG repeat number and mRNA levels changes. Using this approach, a significant positive correlation between CGG repeats and total mRNA levels has been found in the premutation range <100 CGG, but this correlation diminishes from 100 onward. However, when correcting by the X inactivation ratio, mRNA levels increase as the number of CGG repeats increases, and this increase is highly significant over 100 CGG. We suggest that due to skewed X inactivation, mRNA levels tend to normalize in females when the number of CGG repeats increases

Multimorbidity patterns of chronic conditions and geriatric syndromes in older patients from the MoPIM multicentre cohort study

To estimate the frequency of chronic conditions and geriatric syndromes in older patients admitted to hospital because of an exacerbation of their chronic conditions, and to identify multimorbidity clusters in these patients. Multicentre, prospective cohort study. Internal medicine or geriatric services of five general teaching hospitals in Spain. 740 patients aged 65 and older, hospitalised because of an exacerbation of their chronic conditions between September 2016 and December 2018. Active chronic conditions and geriatric syndromes (including risk factors) of the patient, a score about clinical management of chronic conditions during admission, and destination at discharge were collected, among other variables. Multimorbidity patterns were identified using fuzzy c-means cluster analysis, taking into account the clinical management score. Prevalence, observed/expected ratio and exclusivity of each chronic condition and geriatric syndrome were calculated for each cluster, and the final solution was approved after clinical revision and discussion among the research team. 740 patients were included (mean age 84.12 years, SD 7.01; 53.24% female). Almost all patients had two or more chronic conditions (98.65%; 95% CI 98.23% to 99.07%), the most frequent were hypertension (81.49%, 95% CI 78.53% to 84.12%) and heart failure (59.86%, 95% CI 56.29% to 63.34%). The most prevalent geriatric syndrome was polypharmacy (79.86%, 95% CI 76.82% to 82.60%). Four statistically and clinically significant multimorbidity clusters were identified: osteoarticular, psychogeriatric, cardiorespiratory and minor chronic disease. Patient-level variables such as sex, Barthel Index, number of chronic conditions or geriatric syndromes, chronic disease exacerbation 3 months prior to admission or destination at discharge differed between clusters. In older patients admitted to hospital because of the exacerbation of chronic health problems, it is possible to define multimorbidity clusters using soft clustering techniques. These clusters are clinically relevant and could be the basis to reorganise healthcare circuits or processes to tackle the increasing number of older, multimorbid patients.

Multimorbidity patterns of chronic conditions and geriatric syndromes in older patients from the MoPIM multicentre cohort study

Objectives: to estimate the frequency of chronic conditions and geriatric syndromes in older patients admitted to hospital because of an exacerbation of their chronic conditions, and to identify multimorbidity clusters in these patients. Design: Multicentre, prospective cohort study. Setting: internal medicine or geriatric services of five general teaching hospitals in Spain. Participants: 740 patients aged 65 and older, hospitalised because of an exacerbation of their chronic conditions between September 2016 and December 2018. Primary and secondary outcome measures: active chronic conditions and geriatric syndromes (including risk factors) of the patient, a score about clinical management of chronic conditions during admission, and destination at discharge were collected, among other variables. Multimorbidity patterns were identified using fuzzy c-means cluster analysis, taking into account the clinical management score. Prevalence, observed/expected ratio and exclusivity of each chronic condition and geriatric syndrome were calculated for each cluster, and the final solution was approved after clinical revision and discussion among the research team. Results: 740 patients were included (mean age 84.12 years, SD 7.01; 53.24% female). Almost all patients had two or more chronic conditions (98.65%; 95% CI 98.23% to 99.07%), the most frequent were hypertension (81.49%, 95% CI 78.53% to 84.12%) and heart failure (59.86%, 95% CI 56.29% to 63.34%). The most prevalent geriatric syndrome was polypharmacy (79.86%, 95% CI 76.82% to 82.60%). Four statistically and clinically significant multimorbidity clusters were identified: osteoarticular, psychogeriatric, cardiorespiratory and minor chronic disease. Patient-level variables such as sex, Barthel Index, number of chronic conditions or geriatric syndromes, chronic disease exacerbation 3 months prior to admission or destination at discharge differed between clusters. Conclusions: in older patients admitted to hospital because of the exacerbation of chronic health problems, it is possible to define multimorbidity clusters using soft clustering techniques. These clusters are clinically relevant and could be the basis to reorganise healthcare circuits or processes to tackle the increasing number of older, multimorbid patients

Complement Activation and Thrombotic Microangiopathies.

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment

Complement Activation and Thrombotic Microangiopathies

BACKGROUND AND OBJECTIVES: Atypical hemolytic uremic syndrome is a form of thrombotic microangiopathy caused by dysregulation of the alternative complement pathway. There is evidence showing complement activation in other thrombotic microangiopathies. The aim of this study was to evaluate complement activation in different thrombotic microangiopathies and to monitor treatment response. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Complement activation was assessed by exposing endothelial cells to sera or activated-patient plasma-citrated plasma mixed with a control sera pool (1:1)-to analyze C5b-9 deposits by immunofluorescence. Patients with atypical hemolytic uremic syndrome (n=34) at different stages of the disease, HELLP syndrome (a pregnancy complication characterized by hemolysis, elevated liver enzymes, and low platelet count) or severe preeclampsia (n=10), and malignant hypertension (n=5) were included. RESULTS: Acute phase atypical hemolytic uremic syndrome-activated plasma induced an increased C5b-9 deposition on endothelial cells. Standard and lower doses of eculizumab inhibited C5b-9 deposition in all patients with atypical hemolytic uremic syndrome, except in two who showed partial remission and clinical relapse. Significant fibrin formation was observed together with C5b-9 deposition. Results obtained using activated-plasma samples were more marked and reproducible than those obtained with sera. C5b-9 deposition was also increased with samples from patients with HELLP (all cases) and preeclampsia (90%) at disease onset. This increase was sustained in those with HELLP after 40 days, and levels normalized in patients with both HELLP and preeclampsia after 6-9 months. Complement activation in those with malignant hypertension was at control levels. CONCLUSIONS: The proposed methodology identifies complement overactivation in patients with atypical hemolytic uremic syndrome at acute phase and in other diseases such as HELLP syndrome and preeclampsia. Moreover, it is sensitive enough to individually assess the efficiency of the C5 inhibition treatment